Letrozole

1 INDICATIONS AND USAGE Letrozole Tablets, USP are 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, USP 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, USP 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 in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole 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, USP are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer.Letrozole Tablets, USP 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 tablets is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the 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 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 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 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 blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3) ] . The recommended dose of letrozole for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole 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) ].

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 a 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 a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) ( P <0.0001) [ see Adverse Reactions (6) ]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a 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 a 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 a 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 3 to 4 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 x upper limit of normal (ULN) in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than =1.5 x 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 [ s ee Adverse R eactions (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, a 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 tablets 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the…

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

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.

8.1 Pregnancy Risk S ummary 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; however, the data are insufficient to inform a 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 a mg/m 2 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. Data Animal Data In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 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 a mg/m 2 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 a mg/m 2 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 a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 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 a mg/m 2 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.

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 TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-877-736-5697 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 to 4 and Grades 3 to 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 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 Tamoxifen Letrozole Tamoxifen Adverse R eaction s N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) Patients with any adverse reaction 2309 (94.3) 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 (14.5) 426 (17.4) - - - - Weight increase* 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6) Nausea* 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4) Bone fractures** 2 249 (10.2) 175 (7.2) - - - - Fatigue (lethargy, malaise, asthenia)* 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3) Myalgia* 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6) Vaginal bleeding* 129 (5.3) 320 (13.1) 1 (< 0.1) 8 (0.3) Edema* 164 (6.7) 160 (6.5) 3 (0.1) 1 (< 0.1) Weight decrease 140 (5.7) 129 (5.3) 8 (0.3) 5 (0.2) Osteoporosis** 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2) Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4) Bone pain 123 (5.0) 109 (4.5) 6 (0.2) 4 (0.2) Depression 119 (4.9) 114 (4.7) 16 (0.7) 14 (0.6) Vaginal irritation* 112 (4.6) 77 (3.1) 2 (< 0.1) 2 (< 0.1) Headache* 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2) Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2) Osteopenia* 87 (3.6) 76 (3.1) 0 - 3 (0.1) Dizziness/light-headedness* 84 (3.4) 80 (3.3) 1 (< 0.1) 6 (0.2) Alopecia 83 (3.4) 84 (3.4) - - - - Vomiting* 80 (3.3) 80 (3.3) 3 (0.1) 5 (0.2) Cataract* 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7) Constipation* 49 (2.0) 71 (2.9) 3 (0.1) 1 (< 0.1) Myocardial infarction 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) 5…