HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`--------------------------------CONTRAINDICATIONS-----------------------------
`
`Women of premenopausal endocrine status, including pregnant women (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
` Decreases in bone mineral density may occur. Consider bone mineral
`density monitoring (5.1)
` Increases in total cholesterol may occur. Consider cholesterol monitoring.
`(5.2)
` Fatigue, dizziness and somnolence may occur. Exercise caution when
`operating machinery (5.4)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`The most common adverse reactions (>20%) were hot flashes, arthralgia (6.1);
`flushing, asthenia, edema, arthralgia, headache, dizziness,
`hypercholesterolemia, sweating increased, bone pain (6.2, 6.3); and
`musculoskeletal (6.4).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: 1/2014
`
`
`
`Postmarketing Experience
`6.7
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Updated Adjuvant Treatment of Early Breast Cancer
`14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median
`Treatment Duration of 24 Months
`14.3 Updated Analyses of Extended Adjuvant Treatment of Early
`Breast Cancer, Median Treatment Duration of 60 Months
`14.4 First-Line Treatment of Advanced Breast Cancer
`14.5 Second-Line Treatment of Advanced Breast Cancer
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
` *
`
` Sections or subsections omitted from the full prescribing information are not
`listed
`
`These highlights do not include all the information needed to use
`FEMARA safely and effectively. See full prescribing information for
`FEMARA.
`
`Femara (letrozole) tablets
`Initial U.S. Approval: 1997
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`Femara is an aromatase inhibitor indicated for:
` Adjuvant treatment of postmenopausal women with hormone receptor
`positive early breast cancer (1.1)
` Extended adjuvant treatment of postmenopausal women with early breast
`cancer who have received prior standard adjuvant tamoxifen therapy (1.2)
` First and second-line treatment of postmenopausal women with hormone
`receptor positive or unknown advanced breast cancer (1.3)
`
`-------------------------DOSAGE AND ADMINISTRATION---------------------
`
`Femara tablets are taken orally without regard to meals (2):
` Recommended dose: 2.5.mg once daily (2.1)
` Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other
`day (2.5, 5.3)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`
`2.5 milligram tablets (3)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Adjuvant Treatment of Early Breast Cancer
`1.2
`Extended Adjuvant Treatment of Early Breast Cancer
`1.3
`First and Second-Line Treatment of Advanced Breast Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`2.2 Use in Adjuvant Treatment of Early Breast Cancer
`2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer
`2.4 Use in First and Second-Line Treatment of Advanced Breast
`Cancer
`2.5 Use in Hepatic Impairment
`2.6 Use in Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Bone Effects
`5.2 Cholesterol
`5.3 Hepatic Impairment
`5.4
`Fatigue and Dizziness
`5.5
`Laboratory Test Abnormalities
`6 ADVERSE REACTIONS
`6.1 Adjuvant Treatment of Early Breast Cancer
`6.2
`Extended Adjuvant Treatment of Early Breast Cancer, Median
`Treatment Duration of 24 Months
`6.3 Updated Analysis, Extended Adjuvant Treatment of Early
`Breast Cancer, Median Treatment Duration of 60 Months
`First-Line Treatment of Advanced Breast Cancer
`Second- Line Treatment of Advanced Breast Cancer
`First and Second-Line Treatment of Advanced Breast Cancer
`
`6.4
`6.5
`6.6
`
`Ex. 1075-0001
`
`

`
`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 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. The planned duration of
`treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should
`be discontinued at relapse [see Clinical Studies (14.1)].
`
`2.3
`
`Use in Extended Adjuvant Treatment of Early Breast Cancer
`
`In the extended adjuvant setting, the optimal treatment duration with 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 was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58%
`of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at
`tumor relapse [see Clinical Studies (14.2)].
`
`2.4
`
`Use in First and Second-Line Treatment of Advanced Breast Cancer
`
`In patients with advanced disease, treatment with 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 ≥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).
`
`Ex. 1075-0002
`
`

`
`4
`
`CONTRAINDICATIONS
`
`Femara may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal
`women with breast cancer has not been demonstrated. Femara is contraindicated in women who are or may become
`pregnant. If Femara is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
`should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
`
`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 substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-
`L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months
`a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in
`the tamoxifen arm (difference = 4.4%) (P<0.0001) [see Adverse reactions (6.1)]. Updated results from the BMD
`substudy in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median
`decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The
`changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly
`different [see Adverse Reactions (6.2)].
`
`In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and
`10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse
`Reactions (6.1)]. In the extended adjuvant trial the incidence of bone fractures at any time after randomization
`was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and
`7.8% for placebo [see Adverse Reactions (6.3)].
`
`5.2
`
`Cholesterol
`
`Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was
`reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3-4 hypercholesterolemia was
`reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of
`≥1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline
`total serum cholesterol within the normal range (i.e., <=1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840
`(3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see
`Adverse Reactions (6.1)].
`
`5.3
`
`Hepatic Impairment
`
`Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of 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 (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.
`
`6
`
`ADVERSE REACTIONS
`
`The most serious adverse reactions from the use of Femara are:
`
` Bone effects [see Warnings and Precautions (5.1)]
`
`
`
`Increases in cholesterol [see Warnings and Precautions (5.2)]
`
`Ex. 1075-0003
`
`

`
`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.
`
`6.1
`
`Adjuvant Treatment of Early Breast Cancer
`
`The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for
`safety was 73 months for patients receiving Femara and tamoxifen.
`
`Certain adverse reactions were prospectively specified for analysis, 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 reporting 1 or more AE) were Grade 1 or Grade 2
`applying the Common Toxicity Criteria Version 2.0/ Common Terminology Criteria for Adverse Events, version
`3.0. Table 1 describes adverse reactions (Grades 1-4) 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, Irrespective of Relationship to Study Drug) in
`the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 73 Months; Median Treatment 60
`Months)
`
`
`
`Adverse Reaction
`
`Pts with any adverse event
`
`Hypercholesterolemia
`
`Hot Flashes/Flushes
`
`Grades 1-4
`
`Grades 3-4
`
`Femara
`N=2448
`n (%)
`
`tamoxifen
`N=2447
`n (%)
`
`Femara
`N=2448
`n (%)
`
`tamoxifen
`N=2447
`n (%)
`
`2310
`
`1280
`
`821
`
`618
`357
`338
`317
`283
`247
`235
`
`(94.4)
`
`(52.3)
`
`(33.5)
`
`(25.2)
`(14.6)
`(13.8)
`(12.9)
`(11.6)
`(10.1)
`( 9.6)
`
`2214
`
`700
`
`929
`
`501
`426
`257
`378
`277
`174
`250
`
`(90.5)
`
`(28.6)
`
`(38.0)
`
`(20.4)
`(17.4)
`(10.5)
`(15.4)
`(11.3)
`( 7.1)
`(10.2)
`
`212
`
`( 8.7)
`
`635
`
`11
`
`0
`
`85
`0
`-
`27
`6
`-
`6
`
`18
`
`(25.9)
`
`( 0.4)
`
`-
`
`( 3.5)
`-
`-
`( 1.1)
`( 0.2)
`-
`( 0.2)
`
`( 0.7)
`
`604
`
`6
`
`0
`
`50
`0
`-
`39
`9
`-
`7
`
`14
`
`(24.7)
`
`( 0.2)
`
`-
`
`( 2.0)
`-
`-
`( 1.6)
`( 0.4)
`-
`( 0.3)
`
`( 0.6)
`
`Arthralgia/Arthritis
`Night Sweats
`Bone Fractures2
`Weight Increase
`Nausea
`Bone Fractures1
`Fatigue (Lethargy, Malaise,
`Asthenia)
`Myalgia
`
`Edema
`
`Weight Decrease
`
`Vaginal Bleeding
`Back Pain
`Osteoporosis NOS
`Bone pain
`Depression
`Vaginal Irritation
`Headache
`
`Pain in extremity
`
`Osteopenia
`Dizziness/Light-Headedness
`Alopecia
`Vomiting
`Cataract
`Constipation
`Breast pain
`Anorexia
`Endometrial Hyperplasia/ Cancer2,
`
`217
`
`164
`
`140
`
`128
`125
`124
`123
`119
`111
`105
`
`103
`
`87
`84
`83
`80
`49
`49
`37
`20
`
`11/1909
`
`( 8.9)
`
`( 6.7)
`
`( 5.7)
`
`( 5.2)
`( 5.1)
`( 5.1)
`( 5.0)
`( 4.9)
`( 4.5)
`( 4.3)
`
`( 4.2)
`
`( 3.6)
`( 3.4)
`( 3.4)
`( 3.3)
`( 2.0)
`( 2.0)
`( 1.5)
`( 0.8)
`
`( 0.6)
`
`160
`
`129
`
`320
`136
`66
`109
`114
`77
`94
`
`79
`
`74
`84
`84
`80
`54
`71
`43
`20
`
`70/1943
`
`( 6.5)
`
`( 5.3)
`
`(13.1)
`( 5.6)
`( 2.7)
`( 4.5)
`( 4.7)
`( 3.1)
`( 3.8)
`
`( 3.2)
`
`( 3.0)
`( 3.4)
`( 3.4)
`( 3.3)
`( 2.2)
`( 2.9)
`( 1.8)
`( 0.8)
`
`( 3.6)
`
`3
`
`8
`
`1
`7
`10
`6
`16
`2
`9
`
`6
`
`0
`1
`0
`3
`16
`3
`1
`1
`
`-
`
`( 0.1)
`
`( 0.3)
`
`(<0.1)
`( 0.3)
`( 0.4)
`( 0.2)
`( 0.7)
`(<0.1)
`( 0.4)
`
`( 0.2)
`
`-
`(<0.1)
`-
`( 0.1)
`( 0.7)
`( 0.1)
`(<0.1)
`(<0.1)
`
`-
`
`1
`
`5
`
`8
`11
`5
`4
`14
`2
`5
`
`4
`
`2
`6
`0
`5
`17
`1
`0
`1
`
`-
`
`(<0.1)
`
`( 0.2)
`
`( 0.3)
`( 0.4)
`( 0.2)
`( 0.2)
`( 0.6)
`(<0.1)
`( 0.2)
`
`( 0.2)
`
`(<0.1)
`(0.2)
`-
`(0.2)
`( 0.7)
`(<0.1)
`-
`(<0.1)
`
`-
`
`Ex. 1075-0004
`
`

`
`3
`Endometrial Proliferation
`Disorders
`Endometrial Hyperplasia/ Cancer1,
`3
`Other Endometrial Disorders
`Myocardial Infarction1
`Myocardial Infarction2
`Myocardial Ischemia
`Cerebrovascular Accident1
`Cerebrovascular Accident2
`Angina1
`Angina2
`Thromboembolic Event1
`Thromboembolic Event2
`Other Cardiovascular1
`Other Cardiovascular2
`Second Malignancies1
`Second Malignancies2
`
`10
`
`(0.3)
`
`71
`
`(1.8)
`
`6/1909
`
`( 0.3)
`
`57/1943
`
`(2.9)
`
`2
`24
`37
`6
`52
`70
`
`26
`
`32
`51
`71
`260
`312
`53
`102
`
`(<0.1)
`( 1.0)
`( 1.5)
`( 0.2)
`( 2.1)
`( 2.9)
`
`( 1.1)
`
`( 1.3)
`( 2.1)
`( 2.9)
`(10.6)
`(12.7)
`( 2.2)
`( 4.2)
`
`3
`12
`25
`9
`46
`63
`
`24
`
`31
`89
`111
`256
`337
`78
`119
`
`( 0.1)
`( 0.5)
`(1.0)
`( 0.4)
`( 1.9)
`( 2.6)
`
`( 1.0)
`
`( 1.3)
`( 3.6)
`( 4.5)
`(10.5)
`(13.8)
`( 3.2)
`( 4.9)
`
`0
`
`-
`
`0
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`
`14
`
`(0.6)
`
`-
`
`0
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`
`1 During study treatment, based on Safety Monotherapy population
`2 Any time after randomization, including post treatment follow-up
`3 Excluding women who had undergone hysterectomy before study entry
`Note: Cardiovascular (including cerebrovascular and thromboembolic), skeletal and urogenital/endometrial events and second
`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 73 months, a higher incidence of events was seen for Femara (13.8%) than for
`tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding
`thromboembolic events (4.5% vs 2.9%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs
`Femara, respectively).
`
`Bone Study: Results of a phase 3 safety trial in 262 postmenopausal women with resected receptor positive early
`breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (BMD)
`of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar
`spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference
`= 4.4%) (P<0.0001). 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 phase 3 safety trial in 262 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.
`
`6.2
`
`Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
`
`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 2 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 Common Toxicity Criteria
`
`Ex. 1075-0005
`
`

`
`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 2: Percentage of Patients with Adverse Reactions
`
`
`
`
`
`
`
`Any Adverse Reaction
`
`Vascular Disorders
`
`Flushing
`
`General Disorders
`
`Asthenia
`
`Edema NOS
`
`Musculoskeletal Disorders
`
`Arthralgia
`
`Arthritis NOS
`
`Myalgia
`
`Back Pain
`
`Nervous System Disorders
`
`Headache
`
`Dizziness
`
`Skin Disorders
`
`Sweating Increased
`
`Gastrointestinal Disorders
`
`Constipation
`
`Nausea
`
`Diarrhea NOS
`
`Metabolic Disorders
`
`Hypercholesterolemia
`
`Reproductive Disorders
`
`Vaginal Hemorrhage
`
`Vulvovaginal Dryness
`
`Psychiatric Disorders
`
`Insomnia
`
`Respiratory Disorders
`
`Dyspnea
`
`Investigations
`
`Infections and Infestations
`
`Number (%) of Patients with
`Grade 1-4 Adverse Reaction
`
`Number (%) of Patients with
`Grade 3-4 Adverse Reaction
`
`Femara
`
`N=2563
`
`2232 (87.1)
`1375 (53.6)
`1273 (49.7)
`1154 (45)
`862 (33.6)
`471 (18.4)
`978 (38.2)
`565 (22)
`173 (6.7)
`171 (6.7)
`129 (5)
`863 (33.7)
`516 (20.1)
`363 (14.2)
`830 (32.4)
`619 (24.2)
`725 (28.3)
`290 (11.3)
`221 (8.6)
`128 (5)
`551 (21.5)
`401 (15.6)
`303 (11.8)
`123 (4.8)
`137 (5.3)
`320 (12.5)
`149 (5.8)
`279 (10.9)
`140 (5.5)
`184 (7.2)
`166 (6.5)
`
`Placebo
`
`N=2573
`
`2174 (84.5)
`1230 (47.8)
`1114 (43.3)
`1090 (42.4)
`826 (32.1)
`416 (16.2)
`836 (32.5)
`465 (18.1)
`124 (4.8)
`122 (4.7)
`112 (4.4)
`819 (31.8)
`508 (19.7)
`342 (13.3)
`787 (30.6)
`577 (22.4)
`731 (28.4)
`304 (11.8)
`212 (8.2)
`143 (5.6)
`537 (20.9)
`398 (15.5)
`357 (13.9)
`171 (6.6)
`127 (4.9)
`276 (10.7)
`120 (4.7)
`260 (10.1)
`137 (5.3)
`147 (5.7)
`163 (6.3)
`
`Femara
`
`N=2563
`
`419 (16.3)
`59 (2.3)
`3 (0.1)
`30 (1.2)
`16 (0.6)
`4 (0.2)
`71 (2.8)
`25 (1)
`10 (0.4)
`8 (0.3)
`8 (0.3)
`65 (2.5)
`18 (0.7)
`9 (0.4)
`17 (0.7)
`1 (<0.1)
`43 (1.7)
`6 (0.2)
`3 (0.1)
`12 (0.5)
`24 (0.9)
`2 (<0.1)
`9 (0.4)
`2 (<0.1)
`0
`21 (0.8)
`2 (<0.1)
`30 (1.2)
`21 (0.8)
`13 (0.5)
`40 (1.6)
`
`Placebo
`
`N=2573
`
`389 (15.1)
`74 (2.9)
`0
`28 (1.1)
`7 (0.3)
`3 (0.1)
`50 (1.9)
`20 (0.8)
`5 (0.2)
`6 (0.2)
`7 (0.3)
`58 (2.3)
`17 (0.7)
`6 (0.2)
`16 (0.6)
`0
`42 (1.6)
`2 (<0.1)
`10 (0.4)
`8 (0.3)
`32 (1.2)
`5 (0.2)
`8 (0.3)
`5 (0.2)
`0
`16 (0.6)
`2 (<0.1)
`28 (1.1)
`18 (0.7)
`13 (0.5)
`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 Sub-study: [see Warnings and Precautions (5.1)].
`
`Ex. 1075-0006
`
`

`
`Lipid Sub-study: 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
`6.3
`Duration of 60 Months
`
`The extended adjuvant treatment trial was unblinded early [see Adverse Reactions (6.2)]. 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 sub-study: 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 over 5
`years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and
`Precautions (5.2)].
`
`6.4
`
`First-Line Treatment of Advanced Breast Cancer
`
`A total of 455 patients were treated for a median time of exposure of 11 months. 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, regardless of relationship to study drug, 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 3.
`
`Table 3: Percentage (%) of Patients with Adverse Reactions
`
`Adverse
`Reaction
`
`
`General Disorders
`
`Fatigue
`
`Chest Pain
`
`Edema Peripheral
`
`Pain NOS
`
`Weakness
`Investigations
`Weight Decreased
`
`Vascular Disorders
`
`Hot Flushes
`
`Hypertension
`Gastrointestinal Disorders
`
`Nausea
`
`Constipation
`
`Diarrhea
`
`Vomiting
`
`Femara
`2.5 mg
`(N=455)
`%
`
`13
`8
`5
`5
`6
`
`7
`
`19
`8
`
`17
`10
`8
`7
`
`tamoxifen
`20 mg
`(N=455)
`%
`
`13
`9
`6
`7
`4
`
`5
`
`16
`4
`
`17
`11
`4
`8
`
`Ex. 1075-0007
`
`

`
`Infections/Infestations
`
`Influenza
`
`Urinary Tract Infection NOS
`Injury, Poisoning and Procedural Complications
`
`Post-Mastectomy Lymphedema
`Metabolism and Nutrition Disorders
`
`Anorexia
`Musculoskeletal and Connective Tissue Disorders
`
`Bone Pain
`
`Back Pain
`
`Arthralgia
`
`Pain in Limb
`Nervous System Disorders
`
`Headache NOS
`Psychiatric Disorders
`
`Insomnia
`Reproductive System and Breast Disorders
`
`Breast Pain
`Respiratory, Thoracic and Mediastinal Disorders
`
`Dyspnea
`
`Cough
`
`Chest Wall Pain
`
`
`6
`6
`
`7
`
`4
`
`22
`18
`16
`10
`
`8
`
`7
`
`7
`
`18
`13
`6
`
`
`4
`3
`
`7
`
`6
`
`21
`19
`15
`8
`
`7
`
`4
`
`7
`
`17
`13
`6
`
`Other less frequent (≤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.
`
`6.5
`
`Second- Line Treatment of Advanced Breast Cancer
`
`Study discontinuations in the megestrol acetate comparison study 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, 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.
`
`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, regardless of relationship to study drug, 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 are shown
`in Table 4.
`
`Table 4: Percentage (%) of Patients with Adverse Reactions
`
`Adverse
`Reaction
`
`
`
`Body as a Whole
`
`Fatigue
` Chest Pain
`Peripheral Edema1
`
` Asthenia
` Weight Increase
`Cardiovascular
`
`Pooled
`Femara
`2.5 mg
`(N=359)
`%
`
`8
`6
`5
`4
`2
`
`
`Pooled
`Femara
`0.5 mg
`(N=380)
`%
`
`6
`3
`5
`5
`2
`
`
`megestrol
`acetate
`160 mg
`(N=189)
`%
`
`11
`7
`8
`4
`9
`
`
`
`aminoglutethimide
`500 mg
`(N=178)
`%
`
`3
`3
`3
`5
`3
`
`
`Ex. 1075-0008
`
`

`
`5
`
`13
`7
`6
`6
`6
`5
`3
`
`6
`
`
`
`7
`
`15
`7
`7
`5
`5
`3
`4
`
`5
`
`3
`
`22
`8
`
`12
`2
`5
`
`9
`5
`
`5
`4
`2
`
`5
`
`9
`5
`9
`3
`9
`5
`6
`
`6
`
`0
`
`30
`8
`
`9
`2
`7
`
`16
`7
`
`4
`3
`5
`
`6
`
`14
`9
`7
`4
`8
`5
`5
`
`3
`
`6
`
`14
`3
`
`7
`9
`3
`
`5
`5
`
`3
`12
`3
`
` Hypertension
`Digestive System
` Nausea
` Vomiting
` Constipation
` Diarrhea
`
`Pain-Abdominal
` Anorexia
` Dyspepsia
`Infections/Infestations
` Viral Infection
`Lab Abnormality
`3
` Hypercholesterolemia
`
`Musculoskeletal System
` Musculoskeletal2
`21
`8
` Arthralgia
`
`Nervous System
`9
` Headache
`3
`
`Somnolence
`3
` Dizziness
`
`Respiratory System
`7
` Dyspnea
`6
` Coughing
`
`Skin and Appendages
`6
` Hot Flushes
` Rash3
`5
`1
`
`Pruritus
`Includes peripheral edema, leg edema, dependent edema, edema
`Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
`Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash
`
`1
`2
`3
`
`Other less frequent (<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.
`
`6.6
`
`First and Second-Line Treatment of Advanced Breast Cancer
`
`In the combined analysis of the first- and second-line metastatic trials and post-marketing 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.
`
`6.7
`
`Postmarketing Experience
`
`Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis,
`erythema multiforme, and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger finger have
`been identified during post approval use of Femara.
`
`7
`
`DRUG INTERACTIONS
`
`Tamoxifen
`
`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 trials 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 showed no clinically significant effect on letrozole
`pharmacokinetics.
`
`Warfarin
`
`Ex. 1075-0009
`
`

`
`An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin
`pharmacokinetics.
`
`Other anticancer agents
`
`There is no clinical experience to date on the use of Femara in combination with other anticancer agents.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Category X [see Contraindications (4)]. Femara may cause fetal harm when administered to a pregnant
`woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Femara is
`contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient
`becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
`
`Femara caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at d