HIGHLIGHTS OF PRESCRIBING INFORMATION -----------------------WARNINGS AND PRECAUTIONS-----------------------

These highlights do not include all the information needed to use • Decreases in bone mineral density may occur. Consider bone mineral
FEMARA safely and effectively. See full prescribing information for density monitoring. (5.1)
FEMARA. • Increases in total cholesterol may occur. Consider cholesterol monitoring.
FEMARA (letrozole) tablets, for oral use (5.2)
Initial U.S. Approval: 1997 • Fatigue, dizziness, and somnolence may occur. Exercise caution when
operating machinery. (5.4)
----------------------------INDICATIONS AND USAGE--------------------------- • Embryo-Fetal Toxicity: Can cause fetal harm when administered to
Femara is an aromatase inhibitor indicated for: pregnant women. Obtain a pregnancy test in females of reproductive
• Adjuvant treatment of postmenopausal women with hormone receptor potential. Advise females of reproductive potential to use effective
positive early breast cancer. (1.1) contraception. (5.6, 8.1, 8.3)
• Extended adjuvant treatment of postmenopausal women with early breast
cancer who have received prior standard adjuvant tamoxifen therapy. (1.2) ------------------------------ADVERSE REACTIONS-------------------------------
• First and second-line treatment of postmenopausal women with hormone The most common adverse reactions (greater than 20%) were hot flashes,
receptor positive or unknown advanced breast cancer. (1.3) arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness,
hypercholesterolemia, sweating increased, bone pain; and musculoskeletal. (6)
-------------------------DOSAGE AND ADMINISTRATION---------------------
Femara tablets are taken orally without regard to meals (2): To report SUSPECTED ADVERSE REACTIONS, contact Novartis
• Recommended dose: 2.5 mg once daily. (2.1) Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
• Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other 1088 or www.fda.gov/medwatch.
day. (2.5, 5.3)
------------------------------USE IN SPECIFIC POPULATIONS-----------------
-----------------------DOSAGE FORMS AND STRENGTHS-------------------- • Lactation: Advise not to breastfeed. (8.2)
2.5 mg tablets. (3)
See 17 for PATIENT COUNSELING INFORMATION.
--------------------------------CONTRAINDICATIONS-----------------------------
• Pregnancy. (4) Revised: 12/2024
• Known hypersensitivity to the active substance, or to any of the excipients.
(4)

FULL PRESCRIBING INFORMATION: CONTENTS* 8.1 Pregnancy

1 INDICATIONS AND USAGE 8.2 Lactation
1.1 Adjuvant Treatment of Early Breast Cancer 8.3 Females and Males of Reproductive Potential
1.2 Extended Adjuvant Treatment of Early Breast Cancer 8.4 Pediatric Use
1.3 First and Second-Line Treatment of Advanced Breast Cancer 8.5 Geriatric Use
2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE
2.1 Recommended Dose 11 DESCRIPTION
2.2 Use in Adjuvant Treatment of Early Breast Cancer 12 CLINICAL PHARMACOLOGY
2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer 12.1 Mechanism of Action
2.4 Use in First and Second-Line Treatment of Advanced Breast 12.2 Pharmacodynamics
Cancer 12.3 Pharmacokinetics
2.5 Use in Hepatic Impairment 13 NONCLINICAL TOXICOLOGY
2.6 Use in Renal Impairment 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL STUDIES
4 CONTRAINDICATIONS 14.1 Updated Adjuvant Treatment of Early Breast Cancer
5 WARNINGS AND PRECAUTIONS 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median
5.1 Bone Effects Treatment Duration of 24 Months
5.2 Cholesterol 14.3 Updated Analyses of Extended Adjuvant Treatment of Early
5.3 Hepatic Impairment Breast Cancer, Median Treatment Duration of 60 Months
5.4 Fatigue and Dizziness 14.4 First-Line Treatment of Advanced Breast Cancer
5.5 Laboratory Test Abnormalities 14.5 Second-Line Treatment of Advanced Breast Cancer
5.6 Embryo-Fetal Toxicity 16 HOW SUPPLIED/STORAGE AND HANDLING
6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION
6.1 Clinical Trials Experience
6.2 Postmarketing Experience *Sections or subsections omitted from the full prescribing information are not
7 DRUG INTERACTIONS listed
8 USE IN SPECIFIC POPULATIONS

Reference ID: 5496852

 FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Early Breast Cancer
Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early
breast cancer.
1.2 Extended Adjuvant Treatment of Early Breast Cancer
Femara is 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 Femara in extended adjuvant treatment of early
breast cancer is based on an analysis of disease-free survival (DFS) in patients treated with Femara for a median of 60
months [see Clinical Studies (14.2, 14.3)].
1.3 First and Second-Line Treatment of Advanced Breast Cancer
Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or 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 [see Clinical Studies (14.4, 14.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose
The recommended dose of Femara 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 Femara 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 Femara 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 Femara 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 Femara blood
concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of
Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and
Precautions (5.3)]. The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect
of hepatic impairment on Femara 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: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on
one side and CG on the other side).

Reference ID: 5496852

 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)].

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects
Use of Femara 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-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 3-4 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 nonfasting) 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 [see Adverse Reactions (6)].
5.3 Hepatic Impairment
Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately
twice the exposure to Femara 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 Femara
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 Femara, caution is advised when driving or
using machinery until it is known how the patient reacts to Femara use.
5.5 Laboratory Test Abnormalities
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.
5.6 Embryo-Fetal Toxicity
Based on post-marketing reports, findings from animal studies and the mechanism of action, Femara 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. Letrozole caused embryo-fetal toxicities in rats and rabbits at
maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m2 basis. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception
during therapy with Femara and for at least 3 weeks after the last dose [see Adverse Reactions (6.2), Use in Specific
Populations (8.1, 8.3), and Clinical Pharmacology (12.1)].

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 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)]
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 Femara 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)
Grades 1-4 Grades 3-4
Femara Tamoxifen Femara Tamoxifen
Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447
n (%) n (%) n (%) n (%)
Patients with any adverse 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8)
reaction
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)
1
Bone fractures 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)
2
Bone fractures** 249 (10.2) 175 (7.2) - - - -
Fatigue (lethargy, malaise, 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3)
asthenia)*
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)

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 Grades 1-4 Grades 3-4
Femara Tamoxifen Femara Tamoxifen
Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447
n (%) n (%) n (%) n (%)
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)
1
Myocardial infarction 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 14 (0.6) 86 (3.5) 0 - 14 (0.6)
disorders*
Ovarian cyst* 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2)
Endometrial 11 (0.4) 72 (2.9) - - - -
hyperplasia/cancer**1
Endometrial 6/1909 (0.3) 57/194 (2.9) - - - -
hyperplasia/cancer**,3 3
Other endometrial disorders* 2 (< 0.1) 3 (0.1) 0 - 0 -
2
Myocardial infarction** 24 (1.0) 12 (0.5) - - - -
Myocardial ischemia 6 (0.2) 9 (0.4) - - - -
Cerebrovascular 74 (3.0) 68 (2.8) - - - -
accident/TIA**1
Cerebrovascular 51 (2.1) 47 (1.9) - - - -
accident/TIA**2
Angina requiring surgery**1 35 (1.4) 33 (1.3) - - - -
2
Angina requiring surgery** 25 (1.0) 25 (1.0) - - - -
1
Thromboembolic event** 79 (3.2) 113 (4.6) - - - -
2
Thromboembolic event** 51 (2.1) 89 (3.6) - - - -
1
Cardiac failure 39 (1.6) 34 (1.4) - - - -
2
Cardiac failure 27 (1.1) 15 (0.6) - - - -
1
Hypertension 160 (6.5) 175 (7.2) - - - -
2
Hypertension 138 (5.6) 139 (5.7) - - - -
1
Other cardiovascular** 172 (7.0) 174 (7.1) - - - -
2
Other cardiovascular** 120 (4.9) 119 (4.9) - - - -
1
Second primary malignancy 129 (5.3) 150 (6.1) - - - -
Second primary malignancy2 54 (2.2) 79 (3.2) - - - -
*Target events pre-specified for analysis

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 Grades 1-4 Grades 3-4
Femara Tamoxifen Femara Tamoxifen
Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447
n (%) n (%) n (%) n (%)
**Events pre-printed on CRF
1At median follow-up of 96 months (i.e., any time after randomization) for Femara (range up to 144 months) and 95 months for

tamoxifen (range up to 143 months).

2At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for Femara and

tamoxifen (range up to 68 months).

3Excluding women who had undergone hysterectomy before study entry.

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.

When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding
fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Femara vs
tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%),
endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Femara vs
tamoxifen respectively).
At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen
(11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic
events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).
Bone Study: Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer
in the adjuvant setting comparing the effect on lumbar spine (L2-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). No patients with a normal BMD at
baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) developed
osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar,
although the differences between the two treatments were less pronounced. During the 2 year period, fractures were
reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm.
Lipid Study: In a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer at 24
months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at
least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen.
In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment
of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median
duration of treatment was 60 months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and
Grades 3-4) irrespective of relationship to study treatment in the adjuvant study (safety population).
Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at Least 5% of Patients in Either Treatment Arm, by
Preferred Term (Safety set)
Letrozole Anastrozole
N = 2049 N = 2062
Adverse Reactions n (%) n (%)
Grade 3/4 All Grades Grade 3/4 All Grades
n (%) n (%) n (%) n (%)
Patients with at least one AR 628 (30.6) 2049 (100.0) 591 (28.7) 2062 (100.0)
Arthralgia 80 (3.9) 987 (48.2) 69 (3.3) 987 (47.9)
Hot flush 17 (0.8) 666 (32.5) 9 (0.4) 666 (32.3)
Fatigue 8 (0.4) 345 (16.8) 10 (0.5) 343 (16.6)
Osteoporosis 5 (0.2) 223 (10.9) 11 (0.5) 225 (10.9)
Myalgia 16 (0.8) 233 (11.4) 15 (0.7) 212 (10.3)
Back pain 11 (0.5) 212 (10.3) 17 (0.8) 193 (9.4)
Osteopenia 4 (0.2) 203 (9.9) 1 (0.0) 173 (8.4)

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 Pain in extremity 9 (0.4) 168 (8.2) 3 (0.1) 174 (8.4)
Lymphoedema 5 (0.2) 159 (7.8) 2 (0.1) 179 (8.7)
Insomnia 7 (0.3) 160 (7.8) 3 (0.1) 149 (7.2)
Hypercholesterolaemia 2 (0.1) 155 (7.6) 1 (0.0) 151 (7.3)
Hypertension 25 (1.2) 156 (7.6) 20 (1.0) 149 (7.2)
Depression 16 (0.8) 147 (7.2) 13 (0.6) 137 (6.6)
Bone pain 10 (0.5) 138 (6.7) 9 (0.4) 122 (5.9)
Nausea 6 (0.3) 137 (6.7) 5 (0.2) 152 (7.4)
Headache 3 (0.1) 130 (6.3) 5 (0.2) 168 (8.1)
Alopecia 2 (0.1) 127 (6.2) 0 (0.0) 134 (6.5)
Musculoskeletal pain 6 (0.3) 123 (6.0) 9 (0.4) 147 (7.1)
Radiation skin injury 11 (0.5) 120 (5.9) 6 (0.3) 88 (4.3)
Dyspnea 16 (0.8) 118 (5.8) 10 (0.5) 96 (4.7)
Cough 1 (0.0) 106 (5.2) 1 (0.0) 120 (5.8)
Musculoskeletal stiffness 2 (0.1) 102 (5.0) 2 (0.1) 84 (4.1)
Dizziness 2 (0.2) 94 (4.6) 7 (0.3) 109 (5.3)
The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not
included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain.
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
In study MA-17, the median duration of extended adjuvant treatment was 24 months and the median duration of follow-
up for safety was 28 months for patients receiving Femara and placebo.
Table 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment.
Most adverse reactions reported were Grade 1 and Grade 2 based on the CTC Version 2.0. In the extended adjuvant
setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes,
arthralgia/arthritis, and myalgia.
Table 3: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm
Number (%) of Patients with Grade 1-4 Number (%) of Patients with Grade 3-4
Adverse Reactions Adverse Reactions
Femara Placebo Femara Placebo
N = 2563 N = 2573 N = 2563 N = 2573
Any Adverse Reactions 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1)
Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9)
Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0
General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1)
Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3)
Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1)
Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9)
Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8)
Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2)
Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2)
Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3)
Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3)
Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7)
Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2)
Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6)
Sweating Increased 619 (24.2) 577 (22.4) 1 (< 0.1) 0
Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6)
Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 (< 0.1)
Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4)
Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3)
Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2)
Hypercholesterolemia 401 (15.6) 398 (15.5) 2 (< 0.1) 5 (0.2)

Reference ID: 5496852

 Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3)
Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 (< 0.1) 5 (0.2)
Vulvovaginal Dryness 137 (5.3) 127 (4.9) 0 0
Psychiatric Disorders 320 (12.5) 276 (10.7) 21 (0.8) 16 (0.6)
Insomnia 149 (5.8) 120 (4.7) 2 (< 0.1) 2 (< 0.1)
Respiratory Disorders 279 (10.9) 260 (10.1) 30 (1.2) 28 (1.1)
Dyspnea 140 (5.5) 137 (5.3) 21 (0.8) 18 (0.7)
Investigations 184 (7.2) 147 (5.7) 13 (0.5) 13 (0.5)
Infections and Infestations 166 (6.5) 163 (6.3) 40 (1.6) 33 (1.3)
Renal Disorders 130 (5.1) 100 (3.9) 12 (0.5) 6 (0.2)

Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized
study in patients who received Femara was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported
osteoporosis was higher in patients who received Femara 6.9% (176) than in patients who received placebo 5.5% (141).
Bisphosphonates were administered to 21.1% of the patients who received Femara and 18.7% of the patients who
received placebo.
The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who
received Femara 6.8% (175) and placebo 6.5% (167).
A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency
demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains.
Bone Substudy: [see Warnings and Precautions (5.1)]
Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no
significant difference between Femara and placebo in total cholesterol or in any lipid fraction at any time over 5 years.
Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].
Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months
The extended adjuvant treatment trial (MA-17) was unblinded early [see Adverse Reactions (6)]. At the updated (final
analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months.
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of
fractures was observed for Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara
12.2% vs placebo 6.4%).
Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the
incidence of new 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.
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months), the incidence of
cardiovascular events was 9.8% for Femara and 7.0% for placebo.
Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the
incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo.
Lipid Substudy: In the extended adjuvant setting (MA-17), based on a median duration of follow-up of 62 months, there
was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction over 5 years. Use
of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].
First-Line Treatment of Advanced Breast Cancer
In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm (median
6 months in the tamoxifen arm). The incidence of adverse reactions was similar for Femara and tamoxifen. The most
frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea.
Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on Femara and
in 15/455 (3%) of patients on tamoxifen.
Adverse reactions that were reported in at least 5% of the patients treated with Femara 2.5 mg or tamoxifen 20 mg in the
first-line treatment study are shown in Table 4.
Table 4: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm

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 Adverse Reactions Femara Tamoxifen
2.5 mg 20 mg
(N = 455) (N = 455)
% %
General Disorders
Fatigue 13 13
Chest Pain 8 9
Edema Peripheral 5 6
Pain NOS 5 7
Weakness 6 4
Investigations
Weight Decreased 7 5
Vascular Disorders
Hot Flushes 19 16
Hypertension 8 4
Gastrointestinal Disorders
Nausea 17 17
Constipation 10 11
Diarrhea 8 4
Vomiting 7 8
Infections/Infestations
Influenza 6 4
Urinary Tract Infection NOS 6 3
Injury, Poisoning and Procedural Complications
Post-Mastectomy Lymphedema 7 7
Metabolism and Nutrition Disorders
Anorexia 4 6
Musculoskeletal and Connective Tissue Disorders
Bone Pain 22 21
Back Pain 18 19
Arthralgia 16 15
Pain in Limb 10 8
Nervous System Disorders
Headache NOS 8 7
Psychiatric Disorders
Insomnia 7 4
Reproductive System and Breast Disorders
Breast Pain 7 7
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea 18 17
Cough 13 13
Chest Wall Pain 6 6

Other less frequent (less than or equal to 2%) adverse reactions considered consequential for both treatment groups,
included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral
thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary
embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart
disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes, and
development of hemiparesis.
Second-Line Treatment of Advanced Breast Cancer
Study discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than progression
of tumor were 5/188 (2.7%) on Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol
acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (0.6% vs
4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara than on megestrol acetate. In the
aminoglutethimide comparison study (AR/BC3), discontinuations for reasons other than progression occurred in 6/193
(3.1%) on 0.5 mg Femara, 7/185 (3.8%) on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide.

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 Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose
Femara groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in
severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the
patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness.
Adverse reactions that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol
acetate, or aminoglutethimide in the two controlled trials AR/BC2 and AR/BC3 are shown in Table 5.
Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm
Adverse Reactions Pooled Pooled Megestrol
Femara Femara Acetate Aminoglutethimide
2.5 mg 0.5 mg 160 mg 500 mg
(N = 359) (N = 380) (N = 189) (N = 178)
% % % %
Body as a Whole

Chest Pain 6 3 7 3
Peripheral Edema1 5 5 8 3
Asthenia 4 5 4 5
Weight Increase 2 2 9 3
Cardiovascular
Hypertension 5 7 5 6
Digestive System
Nausea 13 15 9 14
Vomiting 7 7 5 9
Constipation 6 7 9 7
Diarrhea 6 5 3 4
Pain-Abdominal 6 5 9 8
Anorexia 5 3 5 5
Dyspepsia 3 4 6 5
Infections/Infestations
Viral Infection 6 5 6 3
Lab Abnormality
Hypercholesterolemia 3 3 0 6
Musculoskeletal System
Musculoskeletal2 21 22 30 14
Arthralgia 8 8 8 3
Nervous System
Headache 9 12 9 7
Somnolence 3 2 2 9
Dizziness 3 5 7 3
Respiratory System
Dyspnea 7 9 16 5
Coughing 6 5 7 5
Skin and Appendages
Hot Flushes 6 5 4 3
Rash3 5 4 3 12
Pruritus 1 2 5 3
1Includes peripheral edema, leg edema, dependent edema, edema.
2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain.
3Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash.

Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients treated
with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and
vertigo.
First and Second-Line Treatment of Advanced Breast Cancer
In the combined analysis of the first- and second-line metastatic trials and postmarketing experiences other adverse
reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia
(including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria,
increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of
skin and mucosa (including dry mouth), and disturbances of taste and thirst.

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 6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Femara. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
• Eye Disorders: blurred vision
• Hepatobiliary Disorders: increased hepatic enzymes, hepatitis
• Immune System Disorders: anaphylactic reactions, hypersensitivity reactions
• Nervous System Disorders: carpal tunnel syndrome
• Pregnancy: spontaneous abortions, congenital birth defects
• Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme
• Musculoskeletal and connective tissue disorders: tendon disorders including tendon rupture, tendonitis,
tenosynovitis, and tenosynovitis stenosans (trigger finger)

7 DRUG INTERACTIONS
Tamoxifen
Coadministration of Femara 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 Femara therapy is not impaired if Femara 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 Femara in combination with other anticancer agents.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
Based on postmarketing reports, findings from animal studies and the mechanism of action, Femara 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/m2 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

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 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/m2 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/m2
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/m2 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/m2
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 Femara, advise lactating
women not to breastfeed while taking Femara 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/m2
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, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with
Femara.
Contraception
Females
Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Femara
and for at least 3 weeks after the last dose.
Infertility
Females
Based on studies in female animals, Femara may impair fertility in females of reproductive potential [see Nonclinical
Toxicology (13.1)].
Males
Based on studies in male animals, Femara may impair fertility in males of reproductive potential [see Nonclinical
Toxicology (13.1)].

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 8.4 Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral
gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and
reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in
AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased
fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the
seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to
recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at
clinically relevant exposures.
8.5 Geriatric Use
The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65
years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or
equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.
For the extended adjuvant setting (MA-17), 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 (BIG 1-98), 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.

10 OVERDOSAGE
Isolated cases of Femara 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.

11 DESCRIPTION
Femara 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

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 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
C17H11N5, and a melting range of 184°C to 185°C.
Femara 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.

12 CLINICAL PHARMACOLOGY
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.
12.2 Pharmacodynamics
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress
plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% 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.
12.3 Pharmacokinetics
Absorption and Distribution: 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

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 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).
Elimination
Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol-
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 inhibited
CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown.
Specific Populations
Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 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 Impairment: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min),
no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study
(AR/BC2) 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 to 50 mL/min) did not affect steady-state plasma letrozole
concentrations.
Hepatic Impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis,
Child-Pugh classification A and B), the mean area under curve (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 pharmacokinetic 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 (2.5)].

13 NONCLINICAL TOXICOLOGY
13.1 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 produced an increase in the
incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal
to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in
breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were
considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing
hormone resulting from the decrease in circulating estrogen.
Femara (letrozole) was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential
clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo
(micronucleus test in rats).
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 ≥ 0.03 mg/kg/day
(approximately 0.1 times the maximum recommended human dose on a mg/m2 basis). In repeat-dose toxicity studies,

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 administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females
at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4, and 0.4 times the daily
maximum recommended human dose on a mg/m2 basis, respectively).

14 CLINICAL STUDIES
14.1 Updated Adjuvant Treatment of Early Breast Cancer
In a multicenter study (BIG 1-98, NCT00004205) 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. 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
Option 2:
A. Tamoxifen for 5 years
B. Femara for 5 years
The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara 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 6.
The primary endpoint of this trial was 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. Femara 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 Femara (if they had received tamoxifen for at least 2
years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they
remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately
70% (448) of these 632 patients crossed to Femara 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 Femara (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 MAA.
The PCA allowed the results of Femara 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 Femara after a longer
time (because follow-up was truncated in two arms at around 25 months). The MAA (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 Femara. The updated
results for the MAA are summarized in Table 7. 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 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 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population)

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 Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA)
Femara Tamoxifen Femara Tamoxifen
N = 4003 N = 4007 N = 2463 N = 2459
Characteristic n (%) n (%) n (%) n (%)
Age (median, years) 61 61 61 61
Age range (years) 38-89 39-90 38-88 39-90
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 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)
Femara Tamoxifen Hazard ratio
N = 2463 N = 2459
Events 5-year Events 5-year (95% CI) P
(%) rate (%) rate
Disease-free survival1 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)
1-3 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 DFS2 ITT 401 88.5 446 86.6 0.88 (0.77,1.01)
Time to distant metastasis3 ITT 257 92.4 298 90.1 0.85 (0.72, 1.00)
Adjuvant chemotherapy ITT 84 - 109 - 0.75 (0.56-1.00)
No chemotherapy ITT 173 - 189 - 0.90 (0.73,1.11)
Distant DFS4 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)
1-3 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:
1
Disease-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.
2
Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event.
3
Time to distant metastasis: Interval from randomization to distant metastasis.
4
Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause.
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 Femara 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.

Reference ID: 5496852

 Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT Approach)
1.0
-- - ---
0.9
---
0.8

Letrozole Tsmoxifen
0.7 No. of Patients 2469 2459
Events 445 (18 . 1%) 500 (20.3%)
0.6 Censored 2018 (81.9%) 1959 (79.7%)

0.5

Treatment: Letrozole
0.4
Tunoxifen

0.3

0.2

0.1

0.0

12 18 24 30 36 42 48 54 60 66 72

Patitm.b at ri■k:
Letrozole
Tamoxi:f'en
2'39
2430
2376
2300
233B
2302
....
2249
Months

2249
2203
220B
2159
2176
2 116
2130
2087
1927
1B08
1483
1448
1290
1245

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 MAA. There was no statistically significant
difference in overall survival. The hazard ratio for survival in the Femara arm compared to the tamoxifen arm was 0.87,
with 95% CI (0.75, 1.02) (see Table 7).
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] Femara 3 years versus tamoxifen
beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara
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 (MA-17, NCT00003140) of Femara 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 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 8.
Table 8: Selected Study Population Demographics (Modified ITT Population)
Baseline Status Femara Placebo

N = 2582 N = 2586

Hormone Receptor Status (%)

ER+ and/or PgR+ 98 98

Both Unknown 2 2

Nodal Status (%)

Node Negative 50 50

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 Node Positive 46 46

Nodal Status Unknown 4 4

Chemotherapy 46 46

Table 9 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.
Disease-free survival by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall
results. Data were premature for an analysis of survival.
Table 9: Extended Adjuvant Study Results
Femara Placebo Hazard Ratio P-Value
N = 2582 N = 2586 (95% CI)

Disease Free Survival (DFS)1 Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)2 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 - 0.84) 0.003

Contralateral Breast Cancer 19 29

Deaths Without Recurrence or Contralateral Breast 30 38

Cancer

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).
1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause.
2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on

stratified log-rank test.

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of
60 Months
Table 10: Update of Extended Adjuvant Study Results
Femara Placebo Hazard Ratio1 P-Value2
N = 2582 N = 2586 (95% CI)
(%) (%)

Disease Free Survival (DFS) events3

344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12
Breast cancer recurrence 209 286 0.75 (0.63, 0.89) 0.001
(Protocol definition of DFS events4)

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 135 116
Breast Cancer
1Adjusted by receptor status, nodal status and prior chemotherapy.
2Stratifiedlog-rank test, stratified by receptor status, nodal status and prior chemotherapy.
3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring

switches to Femara in 60% of the placebo arm.

4Protocol definition does not include deaths from any cause.

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 Updated analyses were conducted at a median follow-up of 62 months. In the Femara 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 Femara.
In this updated analysis shown in Table 10 Femara 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 Femara 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 DFS or overall survival.
14.4 First-Line Treatment of Advanced Breast Cancer
A randomized, double-blind, multinational trial (P025) 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 11.
Table 11: Selected Study Population Demographics
Baseline Status Femara Tamoxifen
N = 458 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%

Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12).
Table 12 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 12: Results of First-Line Treatment of Advanced Breast Cancer
Femara Tamoxifen Hazard or Odds
2.5 mg 20 mg Ratio (95% CI)
N = 453 N = 454 P-Value (2-sided)

Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)1
P < 0.0001
Objective Response Rate
(CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)2

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 P = 0.0002
(CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47)2
P = 0.0004
Duration of Objective Response
Median 18 months 16 months
(N = 145) (N = 95)
Overall Survival 35 months 32 months
(N = 458) (N = 458) P = 0.51363
1Hazard ratio.
2Odds ratio.
3Overall log-rank test.

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2: Kaplan-Meier Estimates of Time to Progression (Study P025)

1.0
0.9
0.8
0.7 '
.
I'
":"
''
1
0.6
•
a
' -..,,._l
---~- ----------------------------------
-
0.5
' .... ,!-,,,
0.4
E 0.3
'...... .
1 ... . ,.

D.2
. ,.. ............. __ ...
.........
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60
M~s
Femarae 2.5 mg ----- tamoxifen 20 mg

Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14, results
by disease site and Table 15, the results by receptor status.

Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy

Variable Femara Tamoxifen
2.5 mg 20 mg
N = 84 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 Femara; hazard ratio greater than 1 or odds ratio less than 1
favors tamoxifen.

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 Table 14: Efficacy by Disease Site
Femara Tamoxifen
2.5 mg 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 15: Efficacy by Receptor Status

Variable Femara Tamoxifen
2.5 mg 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 Femara; hazard ratio greater than 1 or odds ratio less than 1
favors tamoxifen.
Figure 3 shows the Kaplan-Meier curves for survival.

Reference ID: 5496852

 Figure 3: Survival by Randomized Treatment Arm

1.0 1.0
0.9 0.9
0.8 0.8
0.7 0.7
0.6 0.6
.z:• 0.5 o.s ;i!!:
c
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0.0 0.0
0 6 12 18 24 30 36 42 48 54 60
Months
letrozole 1st tarnoxHen 1st

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 log-rank 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 crossover 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% 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
Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six noncomparative trials (AR/BC1, P01, AR/ST1,
AR/PS1, AR/ES1, and NJO-03) 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 trials
achieved an objective tumor response (complete or partial response).
Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, AR/BC3) 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 (AR/BC2); and
aminoglutethimide 250 mg twice a day with corticosteroid supplementation in the other study (AR/BC3)]. In each study
over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients 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 16.

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 Table 16: Selected Study Population Demographics
Parameter Megestrol Acetate Aminoglutethimide
Study 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 17 shows the results for the first trial (AR/BC2), 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 17: Megestrol Acetate Study Results
Femara Femara Megestrol
0.5 mg 2.5 mg Acetate
N = 188 N = 174 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 Femara 2.5: Femara 0.5 = 2.33 Femara 2.5: megestrol = 1.58
(95% CI: 1.32, 4.17); P = 0.004* (95% CI: 0.94, 2.66); P = 0.08*
Relative Risk of Progression Femara 2.5: Femara 0.5 = 0.81 Femara 2.5: megestrol = 0.77
(95% CI: 0.63, 1.03); P = 0.09* (95% CI: 0.60, 0.98); P = 0.03*
*Two-sided P-value.

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 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)

1,1!

..7

-~
...,_""\-- L.~
. "'"' .....-----
~ ..."'-.,_ __ _L..-,,
-i ________ _

., ---i__ ____ _

T~Gtour;: - - ~ 0..fii ll'lgl - -- -- -- Fe!ud 25 mg- - 1M

The results for the study comparing Femara to aminoglutethimide (AR/BC3), with a minimum follow-up of 9 months, are
shown in Table 18 (Unadjusted analyses are used).
Table 18: Aminoglutethimide Study Results
Femara Femara
0.5 mg 2.5 mg Aminoglutethimide
N = 193 N = 185 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 Femara 2.5: Femara 2.5:
Femara 0.5 = 1.05 Aminoglutethimide = 1.61
(95% CI: 0.62, 1.79); P = 0.85* (95% CI: 0.90, 2.87); P = 0.11*
Relative Risk of Progression Femara 2.5: Femara 2.5:
Femara 0.5 = 0.86 Aminoglutethimide = 0.74
(95% CI: 0.68, 1.11); P = 0.25* (95% CI: 0.57, 0.94); P = 0.02*
*Two-sided P-value.
The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.

Reference ID: 5496852

 Figure 5: Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

l.
~-,
••••••••••••....
···-----,
i
L .. _....
' -7
,...,_ _ - - - - - ' - ~ - --_- _ -_·_--_-_··_-_
- -_
-

200 300 400 500 600 700 800 900 1000

TIME TO PROGRESSION (IN DAYS)

Treatment Group: - - - Femara ® 0.5 mg Femara ® 2.5 mg - - - AG

16 HOW SUPPLIED/STORAGE AND HANDLING

Packaged in HDPE bottles with a safety screw cap.
2.5 mg tablets
Bottles of 30 tablets NDC 0078-0249-15
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP
Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during Femara
therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become
pregnant, or if pregnancy is suspected, during treatment with Femara [see Warnings and Precautions (5.6) and Use in
Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during Femara treatment and for at least 3 weeks after the last dose [see Use in Specific
Populations (8.2)].
Infertility
Advise females and males of reproductive potential of the potential for reduced fertility from Femara [see Use in Specific
Populations (8.3)].
Fatigue and Dizziness
Since fatigue and dizziness have been observed with the use of Femara and somnolence was uncommonly reported,
caution is advised when driving or using machinery [see Warnings and Precautions (5.4)].
Bone Effects
Consideration should be given to monitoring bone mineral density [see Warnings and Precautions (5.1)].
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey, 07936
© Novartis

Reference ID: 5496852