Letrozole
These highlights do not include all the information needed to use letrozole tablets safely and effectively. See full prescribing information for letrozole tablets. LETROZOLE tablets, for oral use Initial U.S. Approval: 1997
26dcb6ee-74d8-4804-b151-79a41484979b
HUMAN PRESCRIPTION DRUG LABEL
Nov 14, 2023
Bryant Ranch Prepack
DUNS: 171714327
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letrozole
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ADVERSE REACTIONS SECTION
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 letrozole 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 | |||||||
|
Adverse Reactions |
Letrozole Tablets |
Tamoxifen |
Letrozole Tablets |
Tamoxifen | ||||
|
Patients with any adverse reaction |
2309 |
(93.4) |
2212 |
(90.4) |
636 |
(26.0) |
606 |
(24.8) |
|
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) |
|
Bone fractures 1 |
361 |
(14.7) |
280 |
(11.4) |
|
|
|
|
|
Night sweats * |
356 |
(14.6) |
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) |
|
Bone Fractures**2 |
249 |
(10.2) |
175 |
( 7.2) |
|
|
|
|
|
Fatigue (lethargy, malaise, asthenia)**2 |
235 |
( 9.6) |
250 |
(10.2) |
6 |
( 0.2) |
7 |
( 0.3) |
|
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) |
66 |
( 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) |
|
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) |
|
Myocardial infarction 1 |
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 disorders * |
14 |
(0.6) |
86 |
(3.5) |
0 |
|
14 |
(0.6) |
|
Ovarian cyst * |
11 |
(0.4) |
18 |
(0.7) |
4 |
(0.2) |
4 |
(0.2) |
|
Endometrial hyperplasia/ Cancer**1 |
11 |
(0.4) |
72 |
(2.9) |
|
|
|
|
|
Endometrial hyperplasia/ Cancer**3 |
6/1909 |
( 0.3) |
57/1943 |
(2.9) |
|
|
|
|
|
Other endometrial disorders** |
2 |
(<0.1) |
3 |
( 0.1) |
0 |
|
0 |
|
|
Myocardial infarction**2 |
24 |
( 1.0) |
12 |
( 0.5) |
|
|
|
|
|
Myocardial ischemia |
6 |
( 0.2) |
9 |
( 0.4) |
|
|
|
|
|
Cerebrovascular accident/TIA**1 |
74 |
(3.0) |
68 |
(2.8) |
|
|
|
|
|
Cerebrovascular accident/TIA**2 |
51 |
( 2.1) |
47 |
( 1.9) |
|
|
|
|
|
Angina requiring surgery**1 |
35 |
( 1.4) |
33 |
( 1.3) |
|
|
|
|
|
Angina requiring surgery**2 |
25 |
( 1.0) |
25 |
( 1.0) |
|
|
|
|
|
Thromboembolic event**1 |
79 |
( 3.2) |
113 |
( 4.6) |
|
|
|
|
|
Thromboembolic event**2 |
51 |
( 2.1) |
89 |
( 3.6) |
|
|
|
|
|
Cardiac failure 1 |
39 |
(1.6) |
34 |
(1.4) |
|
|
|
|
|
Cardiac failure 2 |
27 |
(1.1) |
15 |
(0.6) |
|
|
|
|
|
Hypertension 1 |
160 |
(6.5) |
175 |
(7.2) |
|
|
|
|
|
Hypertension 2 |
138 |
(5.6) |
139 |
(5.7) |
|
|
|
|
|
Other cardiovascular**1 |
172 |
(7.0) |
174 |
(7.1) |
|
|
|
|
|
Other cardiovascular 2 |
120 |
(4.9) |
119 |
(4.9) |
|
|
|
|
|
Second primary malignancy 1 |
129 |
(5.3) |
150 |
(6.1) |
|
|
|
|
|
Second primary malignancy 2 |
54 |
( 2.2) |
79 |
( 3.2) |
|
|
|
|
*Target events pre-specified for analysis
**Events pre-printed on CRF
1 At median follow-up of 96 months (i.e. any time after randomization) for letrozole tablets (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 letrozole tablets 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 letrozole regarding fractures (10.1% vs. 7.1%), myocardial infarctions (1.0% vs. 0.5%), and arthralgia (25.2% vs. 20.4%) (letrozole 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%) (letrozole vs. tamoxifen respectively).
At a median follow up of 96 months, a higher incidence of events was seen for letrozole (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.6% vs. 3.2%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, 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)|
Adverse Reactions |
Letrozole |
Anastrozole | ||
|---|---|---|---|---|
|
Grade 3/4 |
All grades |
Grade 3/4 |
All grades | |
|
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) |
|
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) |
|
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) |
|
Dyspnoea |
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 letrozole tablets 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 Adverse Reactions |
Number (%) of Patients with Grade 3-4 Adverse Reactions | |||
|
Letrozole Tablets |
Placebo |
Letrozole Tablets |
Placebo | |
|
N=2563 |
N=2573 |
N=2563 |
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) |
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 letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self- reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole 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 letrozole 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 letrozole 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 letrozole (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole 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 letrozole 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 letrozole 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 letrozole arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for letrozole 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 letrozole and in 15/455 (3%) of patients on tamoxifen.
Adverse reactions that were reported in at least 5% of the patients treated with letrozole 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|
Adverse |
Letrozole |
Tamoxifen |
|
Reactions |
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 letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on letrozole 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 letrozole, 7/185 (3.8%) on 2.5 mg letrozole, 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 letrozole 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 letrozole 0.5 mg, letrozole 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 |
Pooled |
Pooled |
megestrol | |
|
Reactions |
Letrozole |
Letrozole |
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 Edema 1 |
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 | ||||
|
Musculoskeletal 2 |
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 |
|
Rash 3 |
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 letrozole, 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.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of letrozole. 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, trigger finger
Pregnancy: spontaneous abortions, congenital birth defects
Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme
The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain and musculoskeletal ( 6).
To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
NONCLINICAL TOXICOLOGY SECTION
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/m 2 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 AUC 0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC 0-24hr 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/m 2 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 AUC 0-24hr 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.
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/m 2 basis). In repeat-dose toxicity studies, 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/m 2 basis, respectively).
HOW SUPPLIED SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
Letrozole Tablets, USP
2.5 mg tablets – yellow round, biconvex, film coated tablets imprinted with 'LT' on one side and plain on other side.
NDC: 63629-7819-4: 40 Tablets in a BOTTLE
NDC: 63629-7819-1: 30 Tablets in a BOTTLE
NDC: 63629-7819-2: 10 Tablets in a BOTTLE
NDC: 63629-7819-3: 90 Tablets in a BOTTLE
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Repackaged/Relabeled by:
Bryant Ranch Prepack, Inc.
Burbank, CA 91504
INFORMATION FOR PATIENTS SECTION
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 letrozole 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 letrozole tablets [see Warnings and Precautions ( 5.6), and Use in Specific Populations ( 8.1), ( 8.3)]
Lactation
Advise women not to breastfeed during letrozole tablets 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 letrozole tablets [see Use in Specific Populations ( 8.3) .
Fatigue and Dizziness
Since fatigue and dizziness have been observed with the use of letrozole tablets and somnolence was uncommonly reported, caution is advised when driving or using machinery.
Bone Effects Consideration should be given to monitoring bone mineral density.
Manufactured For:
Accord Healthcare, Inc.,
1009 Slater Road,
Suite 210-B,
Durham, NC 27703,
USA.
Manufactured By:
Intas Pharmaceuticals Limited,
Plot No. : 457, 458,
Village – Matoda,
Bavla Road, Ta.- Sanand,
Dist.- Ahmedabad – 382 210.
India.
10 2293 1 697339
Issued May 2019