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LETROZOLE

Sun Pharmaceutical Industries Limited

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use letrozole safely and effectively. See full prescribing information for letrozole tablets. Letrozole Tablets, USPInitial U.S. Approval: 1997 RECENT MAJOR CHANGES1.12.2INDICATIONS AND USAGELetrozole tablets are aromatase inhibitors 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 ADMINISTRATIONLetrozole 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 STRENGTHS3CONTRAINDICATIONS4WARNINGS 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) Side Effects6.16.26.36.4To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Early Breast Cancer


Letrozole

1.2 Extended Adjuvant Treatment of Early Breast Cancer


see Clinical Studies (14.2, 14.3)

1.3 First and Second-Line Treatment of Advanced Breast Cancer


see Clinical Studies (14.4, 14.5)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose


2.2 Use in Adjuvant Treatment of Early Breast Cancer


In see Clinical Studies (14.1)

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer


see Clinical Studies (14.2)

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer


see Clinical Studies (14.4, 14.5)

2.5 Use in Hepatic Impairment


see Warnings and Precautions (5.3)

2.6 Use in Renal Impairment


see Clinical Pharmacology (12.3)

3 DOSAGE FORMS AND STRENGTHS


4 CONTRAINDICATIONS


see Use in Specific Populations (8.1)

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects


PSee Adverse reactions (6.1)[see Adverse Reactions (6.2)].
 
See Adverse Reactions (6.1)[see Adverse Reactions (6.3)].

5.2 Cholesterol


[see Adverse Reactions (6.1)]

5.3 Hepatic Impairment


[see Dosage and Administration (2.5)]

5.4 Fatigue and Dizziness


5.5 Laboratory Test Abnormalities


6 ADVERSE REACTIONS


The most serious adverse reactions from the use of letrozole are:

  • Bone effects [see Warnings and Precautions (5.1)]
  • Increases in cholesterol [see Warnings and Precautions (5.2)]

6.1 Adjuvant Treatment of Early Breast Cancer






Table 1: Patients with Adverse Reactions (CTC Grades 1 to 4, Irrespective of Relationship to Study Drug) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 73 Months; Median Treatment 60 Months)
  Grades 1 to 4 Grades 3 to 4
Adverse Reaction Letrozole
N=2448
n (%)		 Tamoxifen
N=2447
n (%)		 Letrozole N=2448
n (%)		 Tamoxifen
N=2447
n (%)
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.
Pts with any adverse event
2310
 (94.4)
2214
 (90.5)
635
(25.9)
 604
(24.7)
Hypercholesterolemia
1280
 (52.3)
700
 (28.6)
11
(0.4)
 6
 (0.2)
Hot Flashes/Flushes
821
 (33.5)
929
 (38)
0
 -
 0
 -
Arthralgia/Arthritis
618
 (25.2)
501
 (20.4)
85
(3.5)
 50
 (2)
Night Sweats
357
 (14.6)
426
 (17.4)
0
 -
 0
 -
Bone FracturesAny time after randomization, including post treatment follow-up
338
 (13.8)
257
 (10.5)
-
 -
 -
 -
Weight Increase
317
 (12.9)
378
 (15.4)
27
(1.1)
 39
 (1.6)
Nausea
283
 (11.6)
277
 (11.3)
6
 (0.2)
9
 (0.4)
Bone FracturesDuring study treatment, based on Safety Monotherapy population
247
 (10.1)
174
 (7.1)
-
 -
 -
 -
Fatigue (Lethargy, Malaise, Asthenia)
 235
 ( 9.6)
250
 (10.2)
6
 (0.2)
7
 (0.3)
Myalgia
217
 (8.9)
212
 (8.7)
18
(0.7)
 14
 (0.6)
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)
Vaginal Bleeding
128
 (5.2)
320
 (13.1)
1
 (<0.1)
8
 (0.3)
Back Pain
125
 (5.1)
136
 (5.6)
7
 (0.3)
11
 (0.4)
Osteoporosis NOS
124
 (5.1)
66
 (2.7)
10
(0.4)
 5
 (0.2)
Bone pain
123
(5)
 109
 (4.5)
6
 (0.2)
4
 (0.2)
Depression
119
 (4.9)
114
 (4.7)
16
(0.7)
 14
 (0.6)
Vaginal Irritation
111
 (4.5)
77
 (3.1)
2
 (<0.1)
2
 (<0.1)
Headache
105
 (4.3)
94
 (3.8)
9
 (0.4)
5
 (0.2)
Pain in extremity
103
 (4.2)
79
 (3.2)
6
 (0.2)
4
 (0.2)
Osteopenia
87
 (3.6)
74
 (3)
0
 -
 2
 (<0.1)
Dizziness/Light-Headedness
84
 (3.4)
84
 (3.4)
1
 (<0.1)
6
 (0.2)
Alopecia
83
 (3.4)
84
 (3.4)
0
 -
 0
 -
Vomiting
80
 (3.3)
80
 (3.3)
3
 (0.1)
5
 (0.2)
Cataract
49
 (2)
54
 (2.2)
16
(0.7)
 17
 (0.7)
Constipation
49
 (2)
71
 (2.9)
3
 (0.1)
1
 (<0.1)
Breast pain
37
 (1.5)
43
 (1.8)
1
 (<0.1)
0
 -
Anorexia
20
 (0.8)
20
 (0.8)
1
 (<0.1)
1
 (<0.1)
Endometrial Hyperplasia/CancerAny time after randomization, including post treatment follow-up , Excluding women who had undergone hysterectomy before study entry
11/1909
(0.6)
 70/1943
(3.6)
 -
 -
 -
 -

Endometrial Proliferation Disorders 		10
 (0.3)
 71
 (1.8)
 0
 -
 14
(0.6)
Endometrial Hyperplasia/CancerDuring study treatment, based on Safety Monotherapy population , Excluding women who had undergone hysterectomy before study entry
6/1909
( 0.3)
 57/1943
(2.9)
 -
 -
 -
 -
Other Endometrial Disorders
2
(<0.1)
 3
(0.1)
 0
 -
 -
 -
Myocardial InfarctionDuring study treatment, based on Safety Monotherapy population
24
 (1)
12
 (0.5)
 -
 -
 -
 -
Myocardial InfarctionAny time after randomization, including post treatment follow-up
37
 (1.5)
25
(1)
 -
 -
 -
 -
Myocardial Ischemia
6
(0.2)
 9
(0.4)
 -
 -
 -
 -
Cerebrovascular AccidentDuring study treatment, based on Safety Monotherapy population
52
 (2.1)
46
 (1.9)
-
 -
 -
 -
Cerebrovascular AccidentAny time after randomization, including post treatment follow-up
70
 (2.9)
 63
 (2.6)
 -
 -
 -
 -
AnginaDuring study treatment, based on Safety Monotherapy population
26
 (1.1)
24
(1)
 -
 -
 -
 -
AnginaAny time after randomization, including post treatment follow-up
32
 (1.3)
31
 (1.3)
 -
 -
 -
 -
Thromboembolic EventDuring study treatment, based on Safety Monotherapy population
51
 (2.1)
89
 (3.6)
-
 -
 -
 -
Thromboembolic EventAny time after randomization, including post treatment follow-up
71
 (2.9)
111
 (4.5)
-
 -
 -
 -
Other CardiovascularDuring study treatment, based on Safety Monotherapy population
260
 (10.6)
256
 (10.5)
-
 -
 -
 -
Other CardiovascularAny time after randomization, including post treatment follow-up
312
 (12.7)
337
 (13.8)
-
 -
 -
 -
Second MalignanciesDuring study treatment, based on Safety Monotherapy population
53
 (2.2)
78
 (3.2)
-
 -
 -
 -
Second MalignanciesAny time after randomization, including post treatment follow-up
102
 (4.2)
119
 (4.9)
-
 -
 -
 -






P

6.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months




Table 2: Percentage of Patients with Adverse Reactions
  Number (%) of Patients with Grade 1 to 4 Adverse Reaction Number (%) of Patients with Grade 3 to 4 Adverse Reaction
  Letrozole N=2563 Placebo
N=2573		 Letrozole N=2563 Placebo
N=2573
Any Adverse Reaction
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)
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)







Bone Sub-study: see Warnings and Precautions (5.1)

Lipid Sub-study: [see Warnings and Precautions (5.2)]

6.3 Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months


see Adverse Reactions (6.2)







[see Warnings and Precautions (5.2)]

6.4 First-Line Treatment of Advanced Breast Cancer




Table 3: Percentage (%) of Patients with Adverse Reactions
Adverse Reaction Letrozole 2.5 mg
(N=455)
%		 Tamoxifen
20 mg
(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

6.5 Second- Line Treatment of Advanced Breast Cancer





Table 4: Percentage (%) of Patients with Adverse Reactions
Adverse
Reaction		 Pooled
Letrozole 2.5 mg (N=359) %		 Pooled
Letrozole 0.5 mg (N=380) %		 Megestrol
Acetate
160 mg (N=189) %		 Aminoglutethimide
 
500 mg
(N=178) %
Body as a Whole
Fatigue
8
 6
 11
 3
Chest Pain
6
 3
 7
 3
Peripheral EdemaIncludes peripheral edema, leg edema, dependent edema, edema
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
MusculoskeletalIncludes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
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
RashIncludes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash
5
 4
 3
 12
Pruritus
1
 2
 5
 3

6.6 First and Second-Line Treatment of Advanced Breast Cancer


6.7 Postmarketing Experience


7 DRUG INTERACTIONS


Tamoxifen



Cimetidine



Warfarin



Other anticancer agents

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


Pregnancy Category Xsee Contraindications (4)



2

2 2 2 see Nonclinical Toxicology (13.2)

8.3 Nursing Mothers


8.4 Pediatric Use


8.5 Geriatric Use






10 OVERDOSAGE




2 2

11 DESCRIPTION



LETROZOLE
17115



12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action








12.2 Pharmacodynamics






12.3 Pharmacokinetics


Absorption and Distribution:

Metabolism and Excretion:



Pediatric, Geriatric and Race:

Renal Impairment:

Hepatic Impairment:

see Dosage and Administration (2.5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


2 0-12hr0-24hr 2 0-24hr

in vitro testsE.coliin vitroin vivo



2

Letrozole

13.2 Animal Toxicology and/or Pharmacology


Reproductive Toxicology: 2 2

2

14 CLINICAL STUDIES

14.1 Updated Adjuvant Treatment of Early Breast Cancer














P



Table 5: Adjuvant Study - Patient and Disease Characteristics (ITT Population)
Characteristic Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA)
Letrozole
N=4003
n (%)		 Tamoxifen
N=4007
n (%)		 Letrozole
N=2463
n (%)		 Tamoxifen
N=2459
n (%)
Age (median, years)
 61
 61
 61
 61
Age range (years)
 38 to 89
 39 to 90
 38 to 88
 39 to 90
Hormone receptor status (%)
ER+ and/or PgR+
 99.7
 99.7
 99.7
 99.7
Both unknown
 0.3
 0.3
 0.3
 0.3
Nodal status (%)
Node negative
 52
 52
 50
 52
Node positive
 41
 41
 43
 41
Nodal status unknown
 7
 7
 7
 7
Prior adjuvant chemotherapy (%)
 24
 24
 24
 24

Table 6: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)
    Letrozole
N=2463		 Tamoxifen
N=2459		 Hazard
ratio
(95% CI)		 P
 
  Events (%) 5-year rate Events (%) 5-year rate
Definition of:
Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event
ITT
445 (18.1)
87.4
500 (20.3)
84.7
0.87 (0.76, 0.99)
0.03
 
 Censor
445
87.4
483
84.2
0.84 (0.73, 0.95)
 
0 positive nodes
ITT
165
92.2
189
90.3
0.88 (0.72, 1.09)
 
1 to 3 positive nodes
ITT
151
85.6
163
83
0.85 (0.68, 1.06)
 
>=4 positive nodes
ITT
123
71.2
142
62.6
0.81 (0.64, 1.03)
 
Adjuvant chemotherapy
ITT
119
86.4
150
80.6
0.77 (0.60, 0.98)
 
No chemotherapy
ITT
326
87.8
350
86.1
0.91 (0.78, 1.06)
 
Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event
ITT
401
88.5
446
86.6
0.88 (0.77,1.01)
 
Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis
ITT
257
92.4
298
90.1
0.85 (0.72, 1)
 
Adjuvant chemotherapy
ITT
84
-
 109
-
 0.75 (0.56-1)
 
No chemotherapy
ITT
173
-
 189
-
 0.90 (0.73,1.11)
 
Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause
ITT
385
89
 432
87.1
0.87 (0.76,1)
 
Contralateral breast cancer
ITT
34
99.2
44
98.6
0.76 (0.49, 1.19)
 
Overall survival
ITT
303
91.8
343
90.9
0.87 (0.75, 1.02)
 
 
 Censor
303
91.8
338
90.1
0.82 (0.70, 0.96)
 
0 positive nodes
ITT
107
95.2
121
94.8
0.90 (0.69.1.16)
 
1 to 3 positive nodes
ITT
99
90.8
114
90.6
0.81(0.62,1.06)
 
>=4 positive nodes
ITT
92
80.2
104
73.6
0.86 (0.65, 1.14)
 
Adjuvant chemotherapy
ITT
76
91.5
96
88.4
0.79 (0.58, 1.06)
 
No chemotherapy
ITT
227
91.9
247
91.8
0.91 (0.76, 1.08)
 





LETROZOLE


14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months






Table 7: Selected Study Population Demographics (Modified ITT Population)
Baseline Status Letrozole N=2582 Placebo
N=2586
Hormone Receptor Status (%)
ER+ and/or PgR+
98
 98
Both Unknown
2
 2
Nodal Status (%)
Node Negative
50
 50
Node Positive
46
 46
Nodal Status Unknown
4
 4
Chemotherapy
46
 46
Table 8: Extended Adjuvant Study Results
  Letrozole
N = 2582		 Placebo
N = 2586		 Hazard Ratio (95% CI) P-Value
CI = confidence interval for hazard ratio. Hazard ratio of less than 1 indicates difference in favor of letrozole (lesser risk of recurrence); hazard ratio greater than 1 indicates difference in favor of placebo (higher risk of recurrence with letrozole).
Disease Free Survival (DFS)First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause Events
122 (4.7%)
 193 (7.5%)
 0.62 (0.49, 0.78)Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified logrank test.
0.00003
Local Breast Recurrence
 9
 22
Local Chest Wall Recurrence
2
 8
Regional Recurrence
7
 4
Distant Recurrence
 55
 92
 0.61 (0.44 to 0.84)
 0.003
Contralateral Breast Cancer
19
 29
Deaths Without Recurrence or Contralateral Breast Cancer
30
 38

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 9: Update of Extended Adjuvant Study Results
  Letrozole
N = 2582
(%)		 Placebo
N = 2586
(%)		 Hazard RatioAdjusted by receptor status, nodal status and prior chemotherapy
(95% CI)		 P-ValueStratified logrank test, stratified by receptor status, nodal status and prior chemotherapy
Disease Free Survival (DFS) eventsDFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole in 60% of the placebo arm.
344 (13.3)
 402 (15.5)
 0.89 (0.77, 1.03)
 0.12
Breast cancer recurrence
(Protocol definition of DFS eventsProtocol definition does not include deaths from any cause)
209
 286
 0.75 (0.63, 0.89)
 0.001
Local Breast Recurrence
 15
 44
Local Chest Wall Recurrence
 6
 14
Regional Recurrence
 10
 8
Distant Recurrence
 140
 167
Distant recurrence (first or subsequent events)
 142
 169
 0.88 (0.7,1.1)
 0.246
Contralateral Breast Cancer
 37
 53
Deaths Without Recurrence or Contralateral Breast Cancer
 135
 116


14.4 First-Line Treatment of Advanced Breast Cancer


Table 10: Selected Study Population Demographics
Baseline Status Letrozole
N=458		 Tamoxifen
N=458
Stage of Disease
IIIB
 6%
 7%
IV
 93%
 92%
Receptor Status
ER and PgR Positive
 38%
 41%
ER or PgR Positive
 26%
 26%
Both Unknown
 34%
 33%
ER- or PgR- / Other Unknown
 <1%
 0
Previous Antiestrogen Therapy
Adjuvant
 19%
 18%
None
 81%
 82%
Dominant Site of Disease
Soft Tissue
 25%
 25%
Bone
 32%
 29%
Viscera
 43%
 46%


Table 11: Results of First-Line Treatment of Advanced Breast Cancer
 
 Letrozole
2.5 mg
N=453
Tamoxifen
20 mg
N=454
Hazard or Odds
Ratio (95% CI)
P-Value (2-Sided)
Median Time to Progression
9.4 months
 6 months
 0.72 (0.62, 0.83)Hazard ratio
P<0.0001
Objective Response Rate
(CR + PR)
 145 (32%)
 95 (21%)
 1.77 (1.31, 2.39)Odds ratio
P=0.0002
(CR)
 42 (9%)
 15 (3%)
 2.99 (1.63, 5.47)Odds ratio
P=0.0004
Duration of Objective Response
Median
 18 months
(N=145)
 16 months
(N=95)
Overall Survival
35 months
(N=458)
 32 months
(N=458)
 P=0.5136Overall logrank test


Figure 2 Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)
LETROZOLE
Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy
Variable Letrozole 2.5 mg
N=84 		Tamoxifen 20 mg N=83
Median Time to Progression
(95% CI)
8.9 months
(6.2, 12.5)
 5.9 months
(3.2, 6.2)
Hazard Ratio for TTP (95% CI)
0.6 (0.43, 0.84)
Objective Response Rate
(CR + PR)
22 (26%)
 7 (8%)
Odds Ratio for Response (95% CI)
3.85 (1.5, 9.6)
Table 13: Efficacy by Disease Site
Letrozole 2.5 mg Tamoxifen 20 mg
Dominant Disease Site
Soft Tissue:
N=113
 N=115
Median TTP
12.1 months
 6.4 months
Objective Response Rate
50%
34%
Bone:
N=145
 N=131
Median TTP
9.5 months
 6.3 months
Objective Response Rate
23%
15%
Viscera:
N=195
 N=208
Median TTP
8.3 months
 4.6 months
Objective Response Rate
28%
 17%

Table 14: Efficacy by Receptor Status
Variable Letrozole 2.5 mg Tamoxifen 20 mg
Receptor Positive
N=294
 N=305
Median Time to Progression (95% CI)
9.4 months (8.9, 11.8)
 6 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 (1.2, 2.6)
Receptor Unknown
N=159
 N=149
Median Time to Progression (95% CI)
9.2 months (6.1, 12.3)
 6 months (4.1, 6.4)
Hazard Ratio for TTP (95% CI)
0.77 (0.6, 0.99)
Objective Response Rate (CR+PR)
48 (30%)
 29 (20%)
Odds Ratio for Response (95% CI)
1.79 (1.1, 3)




Figure 3 Survival by Randomized Treatment Arm
LETROZOLE
Legend:





14.5 Second-Line Treatment of Advanced Breast Cancer




Table 15: Selected Study Population Demographics
Parameter Megestrol Acetate Study Aminoglutethimide Study
No. of Participants
552
 557
Receptor Status
ER/PR Positive
57%
 56%
ER/PR Unknown
43%
 44%
Previous Therapy
Adjuvant Only
33%
 38%
Therapeutic +/- Adj.
66%
 62%
Sites of Disease
Soft Tissue
56%
 50%
Bone
50%
 55%
Viscera
40%
 44%


Table 16: Megestrol Acetate Study Results
Letrozole
0.5 mg
N=188		 Letrozole
2.5 mg
N=174		 Megestrol
Acetate
N=190
Objective Response (CR + PR)
22 (11.7%)
 41 (23.6%)
 31 (16.3%)
Median Duration of Response
552 days
 (Not reached)
 561 days
Median Time to Progression
154 days
 170 days
 168 days
Median Survival
633 days
 730 days
 659 days
Odds Ratio for Response
letrozole 2.5: letrozole 0.5=2.33
(95% CI: 1.32, 4.17); P=0.004two-sided P-value
letrozole 2.5: megestrol=1.58
(95% CI: 0.94, 2.66); P=0.08two-sided P-value
Relative Risk of Progression
letrozole 2.5: letrozole 0.5=0.81
(95% CI: 0.63, 1.03); P=0.09two-sided P-value
letrozole 2.5: megestrol=0.77
(95% CI: 0.6, 0.98); P=0.03two-sided P-value


Figure 4 Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)
LETROZOLE
Table 17: Aminoglutethimide Study Results
 
 Letrozole
0.5 mg
N=193
Letrozole
2.5 mg
N=185
Aminoglutethimide
N=179
Objective Response (CR + PR)
34 (17.6%)
 34 (18.4%)
 22 (12.3%)
Median Duration of Response
619 days
 706 days
 450 days
Median Time to Progression
103 days
 123 days
 112 days
Median Survival
636 days
 792 days
 592 days
Odds Ratio for
Response
letrozole 2.5: letrozole 0.5=1.05 (95% CI: 0.62, 1.79); P=0.85two-sided P-value
letrozole 2.5: aminoglutethimide=1.61
(95% CI: 0.9, 2.87); P=0.11two-sided P-value
Relative Risk of Progression
letrozole 2.5: letrozole 0.5=0.86 (95% CI: 0.68, 1.11); P=0.25two-sided P-value
letrozole 2.5: aminoglutethimide=0.74
(95% CI: 0.57, 0.94); P=0.02two-sided P-value


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

16 HOW SUPPLIED/STORAGE AND HANDLING











17 PATIENT COUNSELING INFORMATION


Information for Patients









Caraco Pharmaceutical Laboratories, Ltd.




Sun Pharmaceutical Industries Ltd.




PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


NDC 62756-511-83
Letrozole Tablets USP
2.5 mg
Rx only
30 TABLETS
SUN PHARMACEUTICAL INDUSTRIES LTD.
LETROZOLE

LETROZOLE

LETROZOLE TABLET, FILM COATED

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:62756-511
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
LETROZOLE LETROZOLE 2.5 mg

Inactive Ingredients

Ingredient Name Strength
lactose monohydrate
cellulose, microcrystalline
STARCH, CORN
POVIDONE K30
SODIUM STARCH GLYCOLATE TYPE A POTATO
SILICON DIOXIDE
MAGNESIUM STEARATE
HYPROMELLOSES
FERRIC OXIDE YELLOW
titanium dioxide
POLYETHYLENE GLYCOLS
talc

Product Characteristics

Color Size Imprint Code Shape
YELLOW (dark yellow) 6 mm 511 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:62756-511-83 30 in 1 BOTTLE
2 NDC:62756-511-88 100 in 1 BOTTLE
3 NDC:62756-511-08 100 in 1 BOTTLE
4 NDC:62756-511-18 1000 in 1 BOTTLE

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA091466 2011-06-03


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