Letrozole (Page 2 of 12)

5.4 Fatigue and Dizziness

Because fatigue, dizziness and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use.

5.5 Laboratory Test Abnormalities

No dose related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole 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 letrozole are:

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

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 letrozole 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 one 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 to 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 to 4, Irrespective of Relationship to Study Drug) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 73 Months; Median Treatment 60 Months)
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.
*
Any time after randomization, including post treatment follow-up
During study treatment, based on Safety Monotherapy population
Excluding women who had undergone hysterectomy before study entry

Grades 1 to 4

Grades 3 to 4

Adverse Reaction

Letrozole

N = 2,448

n (%)

Tamoxifen

N = 2,447

n (%)

Letrozole

N = 2,448

n (%)

Tamoxifen

N = 2,447

n (%)

Pts with any adverse event

2,310 (94.4)

2,214 (90.5)

635 (25.9)

604 (24.7)

Hypercholesterolemia

1,280 (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 Fractures *

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 Fractures

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/Cancer *

11/1,909 (0.6)

70/1,943 (3.6)

— -

— -

Endometrial Proliferation Disorders

10 (0.3)

71 (1.8)

0 -

14 (0.6)

Endometrial Hyperplasia/Cancer

6/1,909 (0.3)

57/1,943 (2.9)

— -

— -

Other Endometrial Disorders

2 (< 0.1)

3 (0.1)

0 -

0 -

Myocardial Infarction

24 (1)

12 (0.5)

— -

— -

Myocardial Infarction *

37 (1.5)

25 (1)

— -

— -

Myocardial Ischemia

6 (0.2)

9 ( 0.4)

— -

— -

Cerebrovascular Accident

52 (2.1)

46 (1.9)

— -

— -

Cerebrovascular Accident *

70 (2.9)

63 (2.6)

— -

— -

Angina

26 (1.1)

24 (1)

— -

— -

Angina *

32 (1.3)

31 (1.3)

— -

— -

Thromboembolic Event

51 (2.1)

89 (3.6)

— -

— -

Thromboembolic Event *

71 (2.9)

111 (4.5)

— -

— -

Other Cardiovascular

260 (10.6)

256 (10.5)

— -

— -

Other Cardiovascular *

312 (12.7)

337 (13.8)

— -

— -

Second Malignancies

53 (2.2)

78 (3.2)

— -

— -

Second Malignancies *

102 (4.2)

119 (4.9)

— -

— -

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% 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 73 months, a higher incidence of events was seen for letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.5% vs. 2.9%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, respectively).

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