`
`
`
`
`Femara®
`(letrozole tablets)
`
`2.5 mg Tablets
`
`Rx only
`
`Prescribing Information
`DESCRIPTION
`Femara® (letrozole tablets) for oral administration contains 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, empirical formula C17H11N5, and a melting range of
`184°C-185°C.
`Femara® (letrozole tablets) is available as 2.5 mg tablets for oral administration.
`
`Inactive Ingredients.
` Colloidal silicon dioxide, ferric oxide, hydroxypropyl
`methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline
`cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.
`CLINICAL PHARMACOLOGY
`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
`CELGENE 2135
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`Page 2
`
`(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.
`Pharmacokinetics
`Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is
`not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide
`conjugate is excreted renally, representing the major clearance pathway. About 90% of
`radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about
`2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6
`weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the
`concentrations measured after a single dose, indicating a slight non-linearity in the
`pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels
`are maintained over extended periods, however, and continuous accumulation of letrozole
`does not occur. Letrozole is weakly protein bound and has a large volume of distribution
`(approximately 1.9 L/kg).
`Metabolism and Excretion
`(4,4'-methanol-
`carbinol metabolite
`Metabolism
`to
`a pharmacologically-inactive
`bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the
`major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was
`the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and
`6% was unchanged letrozole.
`
`In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized
`letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone
`analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately
`inhibited CYP2C19.
`
`

`

`Page 3
`
`
`Special Populations
`Pediatric, Geriatric and Race
`In the study populations (adults ranging in age from 35 to >80 years), no change in
`pharmacokinetic parameters was observed with increasing age. Differences in letrozole
`pharmacokinetics between adult and pediatric populations have not been studied. Differences
`in letrozole pharmacokinetics due to race have not been studied.
`Renal Insufficiency
`In a study of volunteers with varying renal function (24-hour creatinine clearance:
`9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg
`of Femara® (letrozole tablets) was found. In addition, in a study of 347 patients with advanced
`breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal
`impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma
`letrozole concentration.
`Hepatic Insufficiency
`In a study of subjects with mild to moderate non-metastatic hepatic dysfunction
`(e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers
`with moderate hepatic impairment were 37% higher than in normal subjects, but still within
`the range seen in subjects without impaired function. In a pharmacokinetics study, subjects
`with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which
`included bilirubins about 2-11 times ULN with minimal to severe ascites) had two-fold
`increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients
`with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole
`than patients with normal liver function receiving similar doses of this drug. (See DOSAGE
`AND ADMINISTRATION, Hepatic Impairment.)
`Drug/Drug Interactions
`A pharmacokinetic interaction study with cimetidine showed no clinically significant effect
`on letrozole pharmacokinetics. An interaction study with warfarin showed no clinically
`significant effect of letrozole on warfarin pharmacokinetics. In in-vitro experiments, letrozole
`showed no significant inhibition in the metabolism of diazepam. Similarly, no significant
`inhibition of letrozole metabolism by diazepam was observed.
`
`Coadministration of Femara 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 pivotal trials indicates that the therapeutic effect of Femara therapy is not impaired if
`Femara is administered immediately after tamoxifen.
`
`There is no clinical experience to date on the use of Femara in combination with other
`anticancer agents.
`Pharmacodynamics
`In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg
`Femara suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95%
`
`

`

`Page 4
`
`from baseline with maximal suppression achieved within two-three days. Suppression is dose-
`related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate
`that were below the limit of detection in the assays. Estrogen suppression was maintained
`throughout treatment in all patients treated at 0.5 mg or higher.
`
`Letrozole is highly specific in inhibiting aromatase activity. There is no impairment
`of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma
`concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or
`in plasma renin activity among postmenopausal patients treated with a daily dose of Femara
`0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with
`daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone
`or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not
`necessary.
`
`No changes were noted in plasma concentrations of androgens (androstenedione and
`testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of
`Femara or in plasma concentrations of androstenedione among postmenopausal patients
`treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen
`biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and
`FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH
`levels, T3 uptake, and T4 levels.
`CLINICAL STUDIES
`Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women
`A multicenter, double-blind study randomized over 8,000 postmenopausal women with
`resected, receptor-positive early breast cancer to one of the following arms:
`A. tamoxifen for 5 years
`B. Femara for 5 years
`C. tamoxifen for 2 years followed by Femara for 3 years
`D. Femara for 2 years followed by tamoxifen for 3 years
`
`
`Median treatment duration was 24 months, median follow-up duration was 26 months, 76% of
`the patients have been followed for more than 2 years, and 16% of patients for 5 years or
`longer.
`
`Data in Table 2 reflect results from non-switching arms (arms A and B) together with
`data truncated 30 days after the switch in the two switching arms (arms C and D). The
`analysis of monotherapy vs sequencing of endocrine treatments will be conducted when the
`necessary number of events has been achieved. Selected baseline characteristics for the study
`population are shown in Table 1.
`
`
`Table 1: Selected Study Population Demographics for Adjuvant Study (ITT Population)
`
`

`

`Baseline Status
`
`Age (median, years)
`Age Range (years)
`Hormone Receptor Status (%)
` ER+ and/or PgR+
` Both Unknown
`Nodal Status (%)
` Node Negative
` Node Positive
` Nodal Status Unknown
`Prior Adjuvant Chemotherapy (%)
`
`
`
`
`Disease-Free Survival1
` Node Positive
`
` Node Negative
`
` Prior Adjuvant Chemotherapy
`
` No Chemotherapy
`
`Systemic Disease-Free Survival2
`Time to Distant Metastasis3
` Node Positive
`
` Node Negative
`
` Prior Adjuvant Chemotherapy
`
` No Chemotherapy
`
`
`
`Contralateral Breast Cancer
`
`Overall Survival
` Node Positive
`
` Node Negative
`
` Prior Adjuvant Chemotherapy
`
`Page 5
`
`
`Femara®
`N=4003
`61
`38-89
`
`99.7
`0.3
`
`52
`41
`7
`25
`
`tamoxifen
`N=4007
`61
`39-90
`
`99.7
`0.3
`
`52
`41
`7
`25
`
`Table 2: Adjuvant Study Results
`Femara®
`N=4003
`
`tamoxifen
`N=4007
`
`296
`
`369
`
`268
`184
`
`19
`
`166
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`321
`249
`
`31
`
`192
`
`Hazard Ratio
`(95 % CI)
`0.79 (0.68, 0.92)
`0.71 (0.59, 0.86)
`
`0.92 (0.70, 1.22)
`
`0.70 (0.53, 0.93)
`
`0.83 (0.69, 1.00)
`
`0.83 (0.70, 0.97)
`0.73 (0.60, 0.88)
`0.67 (0.54, 0.84)
`
`0.90 (0.60, 1.34)
`
`0.69 (0.50, 0.95)
`
`0.75; (0.60, 0.95)
`
`
`0.61 (0.35, 1.08)
`
`
`0.86 (0.70, 1.06)
`0.81 (0.63, 1.05)
`
`0.88 (0.59, 1.30)
`
`0.76 (0.51, 1.14)
`
`P-Value
`
`
`0.002
`0.0005
`
`0.572
`
`0.013
`
`0.046
`
`0.022
`0.001
` 0.0005
`
`0.597
`
`0.024
`
`0.018
`
`0.091
`
`0.155
`0.113
`
`0.507
`
`0.185
`
`
`
`
`
`

`

` No Chemotherapy
`
`
`
`
`
`0.90 (0.71, 1.15)
`
`Page 6
`
`
`0.395
`
`*Definition of
`1 Disease-Free Survival: Time from randomization to the earliest occurrence of invasive loco-regional recurrence, distant
`metastases, invasive contralateral breast cancer, or death from any cause.
`2Systemic Disease-Free Survival: Time from randomization to invasive regional recurrence, distant metastases, or death from
`any cause.
`3Time to Distant Metastasis: Time from randomization to distant metastases.
`
`Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival.
`
`Figure 1
` Disease-Free Survival (ITT Population)
`
`
`
`
`
`
`
`Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal
`Women After Completion of 5 Years of Adjuvant Tamoxifen Therapy
`A double-blind, randomized, placebo-controlled trial of Femara® (letrozole tablets) 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.
`Patients had to be within 3 months of completing the 5 years of 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 Femara 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 3.
`
`Page 7
`
`
`
`
`Table 3: Selected Study Population Demographics (Modified ITT Population)
`Femara®
`N=2582
`
`98
`2
`
`50
`46
`4
`46
`
`Baseline Status
`
`Hormone Receptor Status (%)
` ER+ and/or PgR+
` Both Unknown
`Nodal Status (%)
` Node Negative
` Node Positive
` Nodal Status Unknown
`Chemotherapy
`
`Table 4 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. Data were premature for an
`analysis of survival.
`
`Placebo
`N=2586
`
`98
`2
`
`50
`46
`4
`46
`
`
`
`Table 4: Extended Adjuvant Study Results
`Femara®
`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)
`Local Breast Recurrence
`
`Local Chest Wall Recurrence
`
`Regional Recurrence
`
`Distant Recurrence
`Contralateral Breast Cancer
`
`Deaths Without Recurrence or Contralateral
`Breast Cancer
`DFS by Stratification
`
`Receptor Status
`
`-
`
`-
`
`Positive
`
`Unknown
`
`Nodal Status
`
`122 (4.7%)
`
`
`193 (7.5%)
`
`
`0.62 (0.49, 0.78)1
`
`
`0.00003
`
`
`9
`
`2
`
`7
`
`55
`19
`
`30
`
`
`
`117/2527(4.6%)
`
`22
`
`8
`
`4
`
`92
`29
`
`38
`
`
`
`
`190/2530(7.5%)
`
`5/55(9.1%)
`
`
`3/56(5.4%)
`
`
`
`
`
`0.61 (0.44 - 0.84)
`
`
`
`
`
`0.60(0.48,0.76)
`
`1.78(0.43,7.5)
`
`
`
`
`
`
`0.003
`
`
`
`
`
`
`
`
`
`

`

`Page 8
`
`
`77/1184(6.5%)
`
`123/1187(10.4)
`
`0.61(0.46,0.81)
`
`39/1298(3.0%)
`
`63/1301(4.8%)
`
`0.61(0.41,0.91)
`
`6/100(6.0%)
`
`58/1197(4.8%)
`
`7/98(7.1%)
`
`88/1199(7.3%)
`
`0.81(0.27,2.4)
`
`0.64(0.46,0.90)
`
`64/1385(4.6%)
`
`105/1387(7.6%)
`
`0.60(0.44,0.81)
`
`-
`
`-
`
`-
`
`Positive
`
`Negative
`
`Unknown
`
`Adjuvant Chemotherapy
`
`-
`
`-
`
`Yes
`
`No
`
`
`
`
`
`
`
`CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser
` risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with
`Femara).
`1 Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at
`randomization). P-value based on stratified logrank test.
`
`First-Line Breast Cancer
`A randomized, double-blinded, multinational trial compared Femara 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 5.
`
`Table 5: Selected Study Population Demographics
`Femara®
`N=458
`
` 6%
`93%
`
`38%
`26%
`34%
`<1%
`
`19%
`81%
`
`25%
`32%
`43%
`
`Baseline Status
`
`Stage of Disease
`
`IIIB
`
`IV
`Receptor Status
`
`ER and PgR Positive
`
`ER or PgR Positive
`
`Both Unknown
`ER- or PgR- / Other Unknown
`
`Previous Antiestrogen Therapy
`
`Adjuvant
`
`None
`Dominant Site of Disease
`
`Soft Tissue
`
`Bone
`
`Viscera
`
`
`tamoxifen
`N=458
`
` 7%
`92%
`
`41%
`26%
`33%
` 0
`
`18%
`82%
`
`25%
`29%
`46%
`
`

`

`Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 6).
`Table 6 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.)
`
`Page 9
`
`
`
`
`
`Median Time to Progression
`
`Objective Response Rate
`
`(CR + PR)
`
`
`
`Duration of Objective Response
`
`Median
`
`Overall Survival
`
`1 Hazard ratio
`2 Odds ratio
`3 Overall logrank test
`
`(CR)
`
`Table 6: Results
`
`Femara®
`2.5 mg
`N=453
`9.4 months
`
`
`145 (32%)
`
`42 (9%)
`
`
`18 months
`(N=145)
`35 months
`(N=458)
`
`tamoxifen
`20 mg
`N=454
`6.0 months
`
`
`95 (21%)
`
`15 (3%)
`
`
`16 months
`(N=95)
`32 months
`(N=458)
`
`Hazard or Odds
`Ratio (95% CI)
`P-Value (2-Sided)
`0.72 (0.62, 0.83)1
`P<0.0001
`
`1.77 (1.31, 2.39)2
`P=0.0002
`2.99 (1.63, 5.47)2
`P=0.0004
`
`
`
`
`P=0.51363
`
`

`

`
`
`Figure 2 shows the Kaplan-Meier curves for TTP.
`
`Figure 2
`Kaplan-Meier Estimates of Time to Progression
`(Tamoxifen Study)
`
`Page 10
`
`
`
`Table 7 shows results in the subgroup of women who had received prior antiestrogen
`
`adjuvant therapy, Table 8, results by disease site and Table 9, the results by receptor status.
`
`
`Table 7: Efficacy in Patients Who Received Prior
`Antiestrogen Therapy
`Femara ®
`2.5 mg
`N=84
`
`tamoxifen
`20 mg
`N=83
`
`8.9 months (6.2, 12.5)
`
`5.9 months (3.2, 6.2)
`
`Variable
`
`
`Median Time to
` Progression (95% CI)
` Hazard Ratio for
` TTP (95% CI)
`Objective Response Rate
`
`(CR + PR)
`
`Odds Ratio for
` 3.85 (1.50, 9.60)
` Response (95% CI)
`Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less
`than 1 favors tamoxifen.
`
`
`22 (26%)
`
`0.60 (0.43, 0.84)
`
`7 (8%)
`
`

`

`Page 11
`
`
`
`
`Table 8: Efficacy by Disease Site
`
`
`
`Dominant Disease Site
`
`Soft Tissue:
`
`
`Median TTP
`
`
`Objective Response Rate
`Bone:
`
`Median TTP
`
`
`Objective Response Rate
`
`
`Viscera:
`
`
`
`Median TTP
`
`
`Objective Response Rate
`
`
`Femara®
`2.5 mg
`
`N=113
`12.1 months
`50%
`N=145
`9.5 months
`23%
`N=195
`8.3 months
`28%
`
`tamoxifen
`20 mg
`
`N=115
`6.4 months
`34%
`N=131
`6.3 months
`15%
`N=208
`4.6 months
`17%
`
`Table 9: Efficacy by Receptor Status
`Femara®
`2.5 mg
`N=294
`
`tamoxifen
`20 mg
`N=305
`
`Variable
`
`Receptor Positive
` Median Time to
` Progression (95% CI)
` Hazard Ratio for
` TTP (95% CI)
` Objective Response
` Rate (CR+PR)
` Odds Ratio for Response
` 95% CI)
`Receptor Unknown
` Median Time to
` Progression (95% CI)
` Hazard Ratio for
` TTP (95% CI)
` Objective Response
` Rate (CR+PR)
`Odds Ratio for Response
`
` 1.79 (1.10, 3.00)
` (95% CI)
`Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less
`than 1 favors tamoxifen.
`
`9.4 months (8.9, 11.8)
`
`6.0 months (5.1, 8.5)
`
` 0.69 (0.58, 0.83)
`
`
`
`97 (33%)
`
`66 (22%)
`
` 1.78 (1.20, 2.60)
`N=159
`
`
`N=149
`
`9.2 months (6.1, 12.3)
`
`6.0 months (4.1, 6.4)
`
` 0.77 (0.60, 0.99)
`
`
`
`48 (30%)
`
`29 (20%)
`
`

`

`Figure 3 shows the Kaplan-Meier curves for survival.
`
`Figure 3
`Survival by Randomized Treatment Arm
`
`Page 12
`
`
`
`
`Legend: Randomized Femara: 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 Femara 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 cross over was 17
`months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not
`cross over to the opposite treatment arm, median survival was 35 months with Femara
`(n=219, 95% Cl 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% Cl 16 to 26
`months).
`Second-Line Breast Cancer
`Femara 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 Femara 2.5 mg daily in Phase I/II trials achieved an
`objective tumor response (complete or partial response).
`
`

`

`Page 13
`
`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 Femara 0.5 mg daily, Femara 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 10.
`
`Table 10: Selected Study Population Demographics
`
`aminoglutethimide
`megestrol acetate
`Parameter
`
`study
`study
`No. of Participants
`557
`552
`
`
`Receptor Status
`56%
`57%
`
`ER/PR Positive
`44%
`43%
`
`ER/PR Unknown
`
`
`Previous Therapy
`38%
`33%
`
`Adjuvant Only
`62%
`66%
`
`Therapeutic +/- Adj.
`
`
`Sites of Disease
`50%
`56%
`
`Soft Tissue
`55%
`50%
`
`Bone
`44%
`40%
`
`Viscera
`
`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 4-12 weeks after the documentation of
`the initial response.
`
`Table 11 shows the results for the first trial, with a minimum follow-up of 15 months,
`that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily. (All
`analyses are unadjusted.)
`
`
`Table 11: Megestrol Acetate Study Results
`
`
`
`
`Objective Response (CR + PR)
`Median Duration of Response
`Median Time to Progression
`
`Femara®
`0.5 mg
`N=188
`22 (11.7%)
`552 days
`154 days
`
`Femara®
`2.5 mg
`N=174
`41 (23.6%)
`(Not reached)
`170 days
`
`megestrol
`acetate
`N=190
`31 (16.3%)
`561 days
`168 days
`
`

`

`Page 14
`
`
`Median Survival
`Odds Ratio for Response
`
`Relative Risk of Progression
`
`* two-sided P-value
`
`The Kaplan-Meier curves for progression for the megestrol acetate study is shown in
`Figure 4.
`
`730 days
`633 days
`Femara 2.5: Femara 0.5=2.33
`(95% CI: 1.32, 4.17); P=0.004*
`Femara 2.5: Femara 0.5=0.81
`(95% CI: 0.63, 1.03); P=0.09*
`
`659 days
`Femara 2.5: megestrol=1.58
`(95% CI: 0.94, 2.66); P=0.08*
`Femara 2.5: megestrol=0.77
`(95% CI: 0.60, 0.98), P=0.03*
`
`Figure 4 Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)
`
`
`The results for the study comparing Femara to aminoglutethimide, with a minimum
`
`follow-up of 9 months, are shown in Table 12. (Unadjusted analyses are used.)
`
`

`

`
`
`Table 12: Aminoglutethimide Study Results
`
`Page 15
`
`
`Femara®
`0.5 mg
`N=193
`
`Femara®
`2.5 mg
`N=185
`
`
`aminoglutethimide
`N=179
`
`34 (17.6%)
`
`34 (18.4%)
`
`22 (12.3%)
`
`619 days
`
`706 days
`
`450 days
`
`103 days
`636 days
`
`123 days
`792 days
`
`112 days
`592 days
`
`
`
`
`Objective Response
` (CR + PR)
`Median Duration of
` Response
`Median Time To
` Progression
`Median Survival
`Odds Ratio for
` Response
`
`
`Relative Risk of
` Progression
`
`
`*two-sided P-value
`
`The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in
`Figure 5.
`
`Femara 2.5:
`Femara 0.5=1.05
`(95% CI: 0.62, 1.79); P=0.85*
`
`Femara 2.5:
`aminoglutethimide=1.61
`(95% CI: 0.90, 2.87); P=0.11*
`
`Femara 2.5:
`Femara 0.5=0.86
`(95% CI: 0.68, 1.11); P=0.25*
`
`Femara 2.5:
`aminoglutethimide=0.74
`(95% CI: 0.57, 0.94), P=0.02*
`
`Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)
`
`
`
`

`

`Page 16
`
`
`INDICATIONS AND USAGE
`Femara® (letrozole tablets) is indicated for the adjuvant treatment of postmenopausal women
`with hormone receptor positive early breast cancer (see CLINICAL STUDIES).
`
`The effectiveness of Femara in early breast cancer is based on an analysis of disease-
`free survival in patients treated for a median of 24 months and followed for a median of 26
`months (see CLINICAL STUDIES). Follow up analyses will determine long-term outcomes
`for both safety and efficacy.
`
`Femara is indicated for the extended adjuvant treatment of early breast cancer in
`postmenopausal women who have received 5 years of adjuvant tamoxifen therapy (see
`CLINICAL STUDIES). The effectiveness of Femara in extended adjuvant treatment of early
`breast cancer is based on an analysis of disease-free survival in patients treated for a median
`of 24 months (see CLINICAL STUDIES). Further data will be required to determine long-
`term outcome.
`
`Femara is indicated for first-line treatment of postmenopausal women with hormone
`receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.
`Femara is also indicated for the treatment of advanced breast cancer in postmenopausal
`women with disease progression following antiestrogen therapy.
`CONTRAINDICATIONS
`Femara® (letrozole tablets) is contraindicated in patients with known hypersensitivity
`
`to Femara or any of its excipients.
`
`Femara is contraindicated in women of premenopausal endocrine status (See
`WARNINGS, Pregnancy).
`WARNINGS
`Pregnancy
`Femara® (letrozole tablets)may cause fetal harm when administered to pregnant women.
`Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum
`recommended human dose on a mg/m2 basis) administered during the period of
`organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by
`intrauterine mortality, increased resorption, increased 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 in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum
`recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum
`vertebral fusion.
`
`Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic
`when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily
`maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies
`included incomplete ossification of the skull, sternebrae, and fore- and hindlegs.
`
`

`

`Page 17
`
`There are no studies in pregnant women. Femara is indicated for postmenopausal
`
`women. If there is exposure to letrozole during pregnancy, the patient should be apprised of
`the potential hazard to the fetus and potential risk for loss of the pregnancy.
`
`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.
`
`PRECAUTIONS
`Since fatigue and dizziness have been observed with the use of Femara® (letrozole tablets)
`and somnolence was uncommonly reported, caution is advised when driving or using
`machinery.
`Laboratory Tests
`No dose-related effect of Femara on any hematologic or clinical chemistry parameter was
`evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were
`observed in some patients receiving Femara 2.5 mg. This depression was transient in about
`half of those affected. Two patients on Femara developed thrombocytopenia; relationship to
`the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether
`related to study treatment or not, was infrequent.
`
`Increases in SGOT, SGPT, and gamma GT ≥5 times the upper limit of normal (ULN)
`and of bilirubin ≥1.5 times the ULN were most often associated with metastatic disease in the
`liver. About 3% of study participants receiving Femara had abnormalities in liver chemistries
`not associated with documented metastases; these abnormalities may have been related to
`study drug therapy. In the megestrol acetate comparative study about 8% of patients treated
`with megestrol acetate had abnormalities in liver chemistries that were not associated with
`documented liver metastases; in the aminoglutethimide study about 10% of
`aminoglutethimide-treated patients had abnormalities in liver chemistries not associated with
`hepatic metastases.
`
`In the adjuvant setting, an increase in total cholesterol (generally non-fasting) in
`patients who had baseline values of total serum cholesterol within normal range, and then
`subsequently had an increase in total serum choestrol of 1.5 ULN was 173/3203 (5.4%) on
`letrozole vs 40/3224 (1.2%) on tamoxifen. Lipid lowering drugs were used by 18% of patients
`on letrozole and 12% on tamoxifen.
`Bone Effects
`In the extended adjuvant setting, preliminary results (median duration of follow-up was 20
`months) from the bone sub-study (Calcium 500 mg and Vitamin D 400 IU per day mandatory;
`bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to
`baseline in hip BMD in Femara patients was 3% vs 0.4% for placebo (P=0.048). The mean
`decrease from baseline BMD results for the lumbar spine at 2 years was Femara 4.6%
`decrease and placebo 2.2% (P=0.069). Consideration should be given to monitoring BMD.
`
`

`

`Page 18
`
`
`Drug Interactions
`Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of
`Femara with these drugs does not result in clinically-significant drug interactions. (See
`CLINICAL PHARMACOLOGY.)
`
`Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of
`letrozole plasma levels by 38% on average. There is no clinical experience to date on the use
`of Femara in combination with other anticancer agents.
`Hepatic Insufficiency
`Subjects with cirrhosis and severe hepatic dysfunction (see CLINICAL PHARMACOLOGY,
`Special Populations) who were dosed with 2.5 mg of Femara experienced approximately
`twice the exposure to Femara as healthy volunteers with normal liver function. Therefore, a
`dose reduction is recommended for this patient population. The effect of hepatic impairment
`on Femara exposure in cancer patients with elevated bilirubin levels has not been determined.
`(See DOSAGE AND ADMINISTRATION.)
`Drug/Laboratory Test-Interactions
`None observed.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100
`times the daily maximum recommended human dose on a mg/m2 basis) administered by oral
`gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian
`stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a
`significant trend in females when the high dose group was excluded due to low survival. In a
`separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the
`AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study
`in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum
`recommended human dose on a mg/m2 basis) for up to 2 years also produc