LETROZOLE

Contraindications ( 4 ) 7/2017 Warnings and Precautions, Embryo-Fetal Toxicity ( 5.6 ) 7/2017

1 INDICATIONS AND USAGE Letrozole tablets are an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. ( 1.1 ) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy. ( 1.2 ) First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer. ( 1.3 ) 1.1 Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 1.2 Extended Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival (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) ].

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 tablets is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for letrozole tablets was 60 months. Seventy-one 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 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) ] .

3 DOSAGE FORMS AND STRENGTHS 2.5 mg tablets: Yellow colored, film-coated, round shaped tablets debossed with one side 'N' and other side 'L'. 2.5 mg tablets. ( 3 )

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) ] . 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 )

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 Breckenridge Pharmaceutical, Inc., at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Treatment of Early Breast Cancer In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving letrozole tablets and tamoxifen. Certain adverse reactions were prospectively specified for analysis (see Table 1 ), based on the known pharmacologic properties and side effect profiles of the two drugs. Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). Table 1: Patients With Adverse Reactions (CTC Grades 1-4) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Adverse Reactions Grades 1-4 Grades 3-4 Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) TIA = Transient ischemic attack. Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded. Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia Target events pre-specified for analysis 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2) Hot flashes 819 (33.5) 929 (38.0) - - - - Arthralgia/arthritis 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0) Bone fractures At median follow-up of 96 months (i.e., any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months). 361 (14.7) 280 (11.4) - - - - Night sweats 356 (14.5) 426 (17.4) - - - - Weight increase 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6) Nausea 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4) Bone fractures Events pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months). 249 (10.2) 175 (7.2) - - - - Fatigue (lethargy, malaise, asthenia) 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3) Myalgia 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6) Vaginal bleeding 129 (5.3) 320 (13.1) 1 (<0.1) 8 (0.3) Edema 164 (6.7) 160 (6.5) 3 (0.1) 1 (<0.1) Weight decrease 140 (5.7) 129 (5.3) 8 (0.3) 5 (0.2) Osteoporosis 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2) Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4) Bone pain 123 (5.0) 109 (4.5) 6 (0.2) 4 (0.2) Depression 119 (4.9) 114 (4.7) 16 (0.7) 14 (0.6) Vaginal irritation 112 (4.6) 77 (3.1) 2 (<0.1) 2 (<0.1) Headache 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2) Pain in extremity 103 (4.2 …

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

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed.( 8.2 ) 8.1 Pregnancy Risk Summary Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets 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), Postmarketing Experience (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%-4% and of miscarriage is 15%-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. 8.2 Lactation Risk Summary It 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 3 weeks after the last dose. Data Animal Data In a 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 0 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 a mg/m 2 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 Testing Based on animal studies, letrozole tablets can cause fe …

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.

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

10 OVERDOSAGE Isolated cases of letrozole tablets 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 a mg/m 2 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 a mg/m 2 basis); death was preceded by depressed blood pressure and arrhythmias.

16 HOW SUPPLIED/STORAGE AND HANDLING Packaged in HDPE bottles with a child resistant closure. 2.5 milligram tablets Bottles of 30 tablets...............................................................................NDC 63850-0025-1 Bottles of 1000 tablets ..........................................................................NDC 63850-0025-4 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59 to 86°F) [see USP Controlled Room Temperature].