Femara (Page 2 of 11)

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)]

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)
Grades 1-4 Grades 3-4
Adverse Reaction Femara N=2448 n (%) tamoxifen N=2447 n (%) Femara N=2448 n (%) tamoxifen N=2447 n (%)
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 - 0 -
Arthralgia/Arthritis 618 (25.2) 501 (20.4) 85 ( 3.5) 50 ( 2.0)
Night Sweats 357 (14.6) 426 (17.4) 0 - 0 -
Bone Fractures2 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 Fractures1 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 ( 5.0) 109 ( 4.5) 6 ( 0.2) 4 ( 0.2)
Depression 119 ( 4.9) 114 ( 4.7) 16 ( 0.7) 14 ( 0.6)
Vaginal Irritation 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) 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 ( 2.0) 54 ( 2.2) 16 ( 0.7) 17 ( 0.7)
Constipation 49 ( 2.0) 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/ Cancer2, 3 11/1909 ( 0.6) 70/1943 ( 3.6) - - - -
Endometrial Proliferation Disorders 10 (0.3) 71 (1.8) 0 - 14 (0.6)
Endometrial Hyperplasia/ Cancer1, 3 6/1909 ( 0.3) 57/1943 (2.9) - - - -
Other Endometrial Disorders 2 (<0.1) 3 ( 0.1) 0 - 0 -
Myocardial Infarction1 24 ( 1.0) 12 ( 0.5) - - - -
Myocardial Infarction2 37 ( 1.5) 25 (1.0) - - - -
Myocardial Ischemia 6 ( 0.2) 9 ( 0.4) - - - -
Cerebrovascular Accident1 52 ( 2.1) 46 ( 1.9) - - - -
Cerebrovascular Accident2 70 ( 2.9) 63 ( 2.6) - - - -
Angina1 26 ( 1.1) 24 ( 1.0) - - - -
Angina2 32 ( 1.3) 31 ( 1.3) - - - -
Thromboembolic Event1 51 ( 2.1) 89 ( 3.6) - - - -
Thromboembolic Event2 71 ( 2.9) 111 ( 4.5) - - - -
Other Cardiovascular1 260 (10.6) 256 (10.5) - - - -
Other Cardiovascular2 312 (12.7) 337 (13.8) - - - -
Second Malignancies1 53 ( 2.2) 78 ( 3.2) - - - -
Second Malignancies2 102 ( 4.2) 119 ( 4.9) - - - -

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 3-5 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 post menopausal 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 post menopausal 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.

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