letrozole 2.5 MG Oral Tablet

Details

Generic Name: LETROZOLE

Brand Name: Letrozole

Substance Name(s):
LETROZOLE

DRUG INTERACTIONS

7 Tamoxifen Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials 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 showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study 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.

OVERDOSAGE

10 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 a mg/m2 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/m2 basis); death was preceded by depressed blood pressure and arrhythmias.

DESCRIPTION

11 Letrozole tablets USP 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 C17H11N5 M.W. 285.31 Letrozole is a white to yellowish crystalline powder, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a melting range of 184° to 185°C. Letrozole tablets USP are available as 2.5 mg tablets for oral administration. Inactive Ingredients: colloidal silicon dioxide, FD&C blue #2 aluminum lake, FD&C yellow #5 aluminum lake, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, starch, talc, and titanium dioxide. Sturctural Formula of Letrozole

CLINICAL STUDIES

14 14.1 Updated Adjuvant Treatment of Early Breast Cancer In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner: Option 1: A. tamoxifen for 5 years B. letrozole for 5 years C. tamoxifen for 2 years followed by letrozole for 3 years D. letrozole for 2 years followed by tamoxifen for 3 years Option 2: A. tamoxifen for 5 years B. letrozole for 5 years The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5. The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a 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 a median treatment duration of 24 months and a 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 2 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 3 to 4. All of these patients were in Option 1. A 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 Monotherapy Arms Analysis (MAA). The PCA allowed the results of letrozole for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (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 6. 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 Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a 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 5: Adjuvant Study – Patient and Disease Characteristics (ITT Population) Characteristic Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA) Letrozole N = 4003 n (%) Tamoxifen N = 4007 n (%) Letrozole N = 2463 n (%) Tamoxifen N = 2459 n (%) Age (median, years) 61 61 61 61 Age range (years) 38 to 89 39 to 90 38 to 88 39 to 90 Hormone receptor status (%) ER+ and/or PgR+ 99.7 99.7 99.7 99.7 Both unknown 0.3 0.3 0.3 0.3 Nodal status (%) Node negative 52 52 50 52 Node positive 41 41 43 41 Nodal status unknown 7 7 7 7 Prior adjuvant chemotherapy (%) 24 24 24 24 Table 6: Updated Adjuvant Study Results – Monotherapy Arms Analysis (Median Follow-up 73 Months) Letrozole N = 2463 Tamoxifen N = 2459 Hazard ratio Events (%) 5 year rate Events (%) 5 year rate (95% CI) P Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event ITT 445 (18.1) 87.4 500 (20.3) 84.7 0.87 (0.76, 0.99) 0.03 Censor 445 87.4 483 84.2 0.84 (0.73, 0.95) 0 positive nodes ITT 165 92.2 189 90.3 0.88 (0.72, 1.09) 1 to 3 positive nodes ITT 151 85.6 163 83.0 0.85 (0.68, 1.06) ≥ 4 positive nodes ITT 123 71.2 142 62.6 0.81 (0.64, 1.03) Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77 (0.60, 0.98) No chemotherapy ITT 326 87.8 350 86.1 0.91 (0.78, 1.06) Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event ITT 401 88.5 446 86.6 0.88 (0.77, 1.01) Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis ITT 257 92.4 298 90.1 0.85 (0.72, 1.00) Adjuvant chemotherapy ITT 84 – 109 – 0.75 (0.56 to 1.00) No chemotherapy ITT 173 – 189 – 0.90 (0.73, 1.11) Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause ITT 385 89.0 432 87.1 0.87 (0.76, 1.00) Contralateral breast cancer ITT 34 99.2 44 98.6 0.76 (0.49, 1.19) Overall survival ITT 303 91.8 343 90.9 0.87 (0.75, 1.02) Censor 303 91.8 338 90.1 0.82 (0.70, 0.96) 0 positive nodes ITT 107 95.2 121 94.8 0.90 (0.69, 1.16) 1 to 3 positive nodes ITT 99 90.8 114 90.6 0.81 (0.62, 1.06) ≥ 4 positive nodes ITT 92 80.2 104 73.6 0.86 (0.65, 1.14) Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79 (0.58, 1.06) No chemotherapy ITT 227 91.9 247 91.8 0.91 (0.76, 1.08) Definition of: 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 2005 Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis Figure 1. Disease-Free Survival (Median follow-up 73 months, ITT Approach) DFS 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 Monotherapy Arms Analysis (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 6 ). 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 2 years followed by] letrozole 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole 2 years followed by] tamoxifen 3 years versus letrozole beyond 2 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. 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months A double-blind, randomized, placebo-controlled trial of letrozole was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen. The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up. Selected baseline characteristics for the study population are shown in Table 7. Table 7: Selected Study Population Demographics (Modified ITT Population) Baseline Status Letrozole N = 2582 Placebo N = 2586 Hormone Receptor Status (%) ER+ and/or PgR+ 98 98 Both Unknown 2 2 Nodal Status (%) Node Negative 50 50 Node Positive 46 46 Nodal Status Unknown 4 4 Chemotherapy 46 46 Table 8 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 8: Extended Adjuvant Study Results Letrozole N = 2582 Placebo N = 2586 Hazard Ratio (95% CI) P-Value Disease Free Survival (DFS)First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified logrank test. 0.00003 Local Breast Recurrence 9 22 Local Chest Wall Recurrence 2 8 Regional Recurrence 7 4 Distant Recurrence 55 92 0.61 (0.44 to 0.84) 0.003 Contralateral Breast Cancer 19 29 Deaths Without Recurrence or Contralateral Breast Cancer 30 38 CI = 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). 14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months Table 9: Update of Extended Adjuvant Study Results Letrozole N = 2582 (%) Placebo N = 2586 (%) Hazard Ratio Adjusted by receptor status, nodal status and prior chemotherapy (95% CI) P-ValueStratified logrank test, stratified by receptor status, nodal status and prior chemotherapy Disease Free Survival (DFS) events 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. 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12 Breast Cancer Recurrence (Protocol definition of DFS eventsProtocol definition does not include deaths from any cause ) 209 286 0.75 (0.63, 0.89) 0.001 Local Breast Recurrence 15 44 Local Chest Wall Recurrence 6 14 Regional Recurrence 10 8 Distant Recurrence 140 167 Distant Recurrence (first or subsequent events) 142 169 0.88 (0.70, 1.10) 0.246 Contralateral Breast Cancer 37 53 Deaths Without Recurrence or Contralateral Breast Cancer 135 116 Updated analyses were conducted at a median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a 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 9, 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 a 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 A randomized, double-blind, multinational trial 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 10. Table 10: Selected Study Population Demographics Baseline Status Letrozole N = 458 Tamoxifen N = 458 Stage of Disease IIIB 6% 7% IV 93% 92% Receptor Status ER and PgR Positive 38% 41% ER or PgR Positive 26% 26% Both Unknown 34% 33% ER- or PgR-/Other Unknown < 1% 0 Previous Antiestrogen Therapy Adjuvant 19% 18% None 81% 82% Dominant Site of Disease Soft Tissue 25% 25% Bone 32% 29% Viscera 43% 46% Letrozole was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11 ). Table 11 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.) Table 11: Results of First-Line Treatment of Advanced Breast Cancer Letrozole 2.5 mg N = 453 Tamoxifen 20 mg N = 454 Hazard or Odds Ratio (95% CI) P-Value (2-Sided) Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)Hazard ratio P < 0.0001 Objective Response Rate (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)Odds ratio P = 0.0002 (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47) P = 0.0004 Duration of Objective Response Median 18 months(N = 145) 16 months(N = 95) Overall Survival 35 months(N = 458) 32 months(N = 458) P = 0.5136Overall logrank test Figure 2 shows the Kaplan-Meier curves for TTP. Figure 2. Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study) Table 12 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 13, results by disease site and Table 14, the results by receptor status. Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy Variable Letrozole 2.5 mg N = 84 Tamoxifen 20 mg N = 83 Median 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 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Table 13: Efficacy by Disease Site Letrozole 2.5 mg Tamoxifen 20 mg Dominant Disease Site Soft Tissue: N = 113 N = 115 Median TTP 12.1 months 6.4 months Objective Response Rate 50% 34% Bone: N = 145 N = 131 Median TTP 9.5 months 6.3 months Objective Response Rate 23% 15% Viscera: N = 195 N = 208 Median TTP 8.3 months 4.6 months Objective Response Rate 28% 17% Table 14: Efficacy by Receptor Status Variable Letrozole 2.5 mg Tamoxifen 20 mg Receptor Positive N = 294 N = 305 Median 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 Unknown N = 159 N = 149 Median 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 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Figure 3 shows the Kaplan-Meier curves for survival. Figure 3. Survival by Randomized Treatment Arm 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 logrank 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 a 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% CI 29 to 43 months) vs 20 months with tamoxifen (n = 229, 95% CI 16 to 26 months). 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 non-comparative Phase I/II trials 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 Phase I/II trials achieved an objective tumor response (complete or partial response). Two large randomized, controlled, multinational (predominantly European) trials 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 a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg b.i.d. with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had 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 15. Table 15: Selected Study Population Demographics Parameter megestrol acetate study aminoglutethimide study No. of Participants 552 557 Receptor Status ER/PR Positive 57% 56% ER/PR Unknown 43% 44% Previous Therapy Adjuvant Only 33% 38% Therapeutic +/- Adj. 66% 62% Sites of Disease Soft Tissue 56% 50% Bone 50% 55% Viscera 40% 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 a second evaluation 4 to 12 weeks after the documentation of the initial response. Table 16 shows the results for the first trial, with a 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 16: Megestrol Acetate Study Results Letrozole 0.5 mg N = 188 Letrozole 2.5 mg N = 174 Megestrol acetate N = 190 Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%) Median Duration of Response 552 days (Not reached) 561 days Median Time to Progression 154 days 170 days 168 days Median Survival 633 days 730 days 659 days Odds Ratio for Response letrozole 2.5: letrozole 0.5 = 2.33 (95% CI: 1.32, 4.17); P = 0.004two-sided P-value letrozole 2.5: megestrol = 1.58 (95% CI: 0.94, 2.66); P = 0.08 Relative Risk of Progression letrozole 2.5: letrozole 0.5 = 0.81 (95% CI: 0.63, 1.03); P = 0.09 letrozole 2.5: megestrol = 0.77 (95% CI: 0.60, 0.98); P = 0.03 The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4. Figure 4. Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) The results for the study comparing letrozole to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.) Table 17: Aminoglutethimide Study Results Letrozole 0.5 mg N = 193 Letrozole 2.5 mg N = 185 Aminoglutethimide N = 179 Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%) Median Duration of Response 619 days 706 days 450 days Median Time to Progression 103 days 123 days 112 days Median Survival 636 days 792 days 592 days Odds Ratio for Response letrozole 2.5: letrozole 0.5 = 1.05 (95% CI: 0.62, 1.79); P = 0.85two-sided P-value letrozole 2.5: aminoglutethimide = 1.61 (95% CI: 0.90, 2.87); P = 0.11 Relative Risk of Progression letrozole 2.5: letrozole 0.5 = 0.86 (95% CI: 0.68, 1.11); P = 0.25 letrozole 2.5: aminoglutethimide = 0.74 (95% CI: 0.57, 0.94); P = 0.02 The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5. Figure 5. Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study) Figure 1. Disease-Free Survival (Median follow-up 73 months, ITT Approach) Figure 2 Kaplan-Meier Esitmates of Time to Progression (Tamoxifen Study) Figure 3 Survival by Randomized Treatment Arm Figure 4. Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

HOW SUPPLIED

16 /STORAGE AND HANDLING Letrozole tablets USP, 2.5 mg are available as follows: 2.5 mg – dark-yellow, standard convex round, film-coated tablets, debossed with “TEVA” on one side and “B1” on the other side of the tablet, in bottles of 30. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

GERIATRIC USE

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 ≥ 70 years old. In the first-line study, patients ≥ 70 years of age experienced longer time to tumor progression and higher response rates than patients < 70. For the extended adjuvant setting, 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, 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.

DOSAGE FORMS AND STRENGTHS

3 2.5 mg tablets – dark-yellow, standard convex round, film-coated tablet, debossed with “TEVA” on one side and “B1” on the other side of the tablet. 2.5 milligram tablets (3)

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

1 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 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)].

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy category X [See Contraindications (4)]. Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well. Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: 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 doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs [see Nonclinical Toxicology (13.2)]. Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from letrozole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. 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) 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 substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (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 (6.1)]. Updated results from the BMD sub-study 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 (6.2)]. In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6.1)]. In the extended adjuvant trial the incidence of bone 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 [see Adverse Reactions (6.3)]. 5.2 Cholesterol Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC 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 ≥ 1.5 X 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., ≤ 1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see Adverse Reactions (6.1)]. 5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. 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 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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Information for Patients Pregnancy: Letrozole is contraindicated in women of premenopausal endocrine status. The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established. Fatigue and Dizziness: Since fatigue and dizziness have been observed with the use of letrozole 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 In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. B 12/2011 Repackaged by: REBEL DISTRIBUTORS CORP. Thousand Oaks, CA 91320

DOSAGE AND ADMINISTRATION

2 Letrozole tablets USP 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 USP 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. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. 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 USP 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 was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed 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 USP 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 tablets USP 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 USP 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 ≥ 10 mL/min [see Clinical Pharmacology (12.3)].