ADVERSE REACTIONS
Femara® (letrozole tablets) was generally well tolerated across all studies in first-line and second-line metastatic breast cancer, adjuvant treatment, as well as extended adjuvant treatment in women who have received prior adjuvant tamoxifen treatment. Generally, the observed adverse reactions are mild or moderate in nature.
Adjuvant Treatment of Early Breast Cancer in Postmenopausal W omen
The median duration of adjuvant treatment was 24 months and the median duration of follow-up for safety was 26 months for patients receiving Femara and tamoxifen.
Certain adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.
Adverse events were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse events reported (82%) were Grade 1 and Grade 2 applying the Common Toxicity Criteria Version 2.0. Table 13 describes adverse events (Grades 1-4) irrespective of relationship to study treatment in the adjuvant BIG 1-98 trial (safety population, during treatment or within 30 days of stopping treatment).
Table 13 : Pa tients with Adverse Events (CTC Grades 1-4, Irrespective of Relationship to Study Drug) in the Adjuvant Study BIG 1-98
| Grades 1-4 | Grades 3-4 |
Adverse E vent | Femara ®
N=3975
n (%) | tamoxifen
N=3988
n (%) | Femara ®
N=3975
n (%) | tamoxifen
N=3988
n (%) |
| Hot Flashes/Flushes | 1338 | (33.7) | 1515 | (38.0) | 0 | - | 0 | - |
| Arthralgia/Arthritis | 840 | (21.1) | 535 | (13.4) | 88 | (2.2) | 49 | (1.2) |
| Night Sweats | 561 | (14.1) | 654 | (16.4) | 0 | - | 0 | - |
| Weight Increase | 425 | (10.7) | 515 | (12.9) | 21 | (0.5) | 44 | (1.1) |
| Nausea | 378 | (9.5) | 416 | (10.4) | 6 | (0.2) | 10 | (0.3) |
| Fatigue (Lethargy, Malaise, Asthenia) | 333 | (8.4) | 345 | (8.7) | 9 | (0.2) | 9 | (0.2) |
| Edema | 286 | (7.2) | 287 | (7.2) | 5 | (0.1) | 2 | (<0.1) |
| Myalgia | 255 | (6.4) | 243 | (6.1) | 26 | (0.7) | 17 | (0.4) |
| Bone Fractures | 223 | (5.6) | 158 | (4.0) | 76 | (1.9) | 45 | (1.1) |
| Vaginal Bleeding | 177 | (4.5) | 411 | (10.3) | 2 | (<0.1) | 7 | (0.2) |
| Headache | 141 | (3.5) | 126 | (3.2) | 12 | (0.3) | 6 | (0.2) |
| Vaginal Irritation | 139 | (3.5) | 122 | (3.1) | 6 | (0.2) | 3 | (<0.1) |
| Vomiting | 109 | (2.7) | 106 | (2.7) | 6 | (0.2) | 8 | (0.2) |
| Dizziness/Light-Headedness | 96 | (2.4) | 110 | (2.8) | 1 | (<0.1) | 8 | (0.2) |
| Osteoporosis | 79 | (2.0) | 44 | (1.1) | 6 | (0.2) | 7 | (0.2) |
| Constipation | 59 | (1.5) | 95 | (2.4) | 4 | (0.1) | 1 | (<0.1) |
| Endometrial Proliferation Disorders | 10 | (0.3) | 71 | (1.8) | 1 | (<0.1) | 12 | (0.3) |
| Endometrial Cancer 1 | 7/3089 | (0.2) | 12/3157 | (0.4) | - | - | - | - |
| Other Endometrial Disorders | 3 | (<0.1) | 4 | (0.1) | 0 | - | 1 | (<0.1) |
| Myocardial Infarction | 17 | (0.4) | 14 | (0.4) | 15 | (0.4) | 11 | (0.3) |
| Cerebrovascular/TIA | 44 | (1.1) | 41 | (1.0) | 43 | (1.1) | 40 | (1.0) |
| Angina | 27 | (0.7) | 24 | (0.6) | 17 | (0.4) | 7 | (0.2) |
| Thromboembolic Event | 44 | (1.1) | 109 | (2.7) | 29 | (0.7) | 79 | (2.0) |
| Other Cardiovascular | 261 | (6.6) | 248 | (6.2) | 97 | (2.4) | 71 | (1.8) |
| Second Malignancies 2 | 76/4003 | (1.9) | 96/4007 | (2.4) | - | - | - | - |
1 Based on safety population excluding patients who had undergone hysterectomy; time frame is any time after randomization; no CTC grades collected (yes/no response)
2 Based on the intent-to-treat population; time frame is any time after randomization; no CTC grades collected (yes/no response) |
When considering all grades, a higher incidence of events were seen for Femara regarding fractures (5.7% vs 4%), myocardial infarctions (0.6% vs 0.4%), and arthralgia (21.2% vs 13.5%) (Femara vs tamoxifen, respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (1.2% vs 2.8%), endometrial cancer (0.2% vs 0.4%), and endometrial proliferative disorders (0.3% vs 1.8%) (Femara vs tamoxifen, respectively).
Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women W ho have Received 5 Years of Adjuvant Tamoxifen Therapy
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 14 describes the adverse events occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse events reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse events that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia.
Table 1 4 : Percentage of P atients with A dverse E vents
| Number (%) of P atients with G rade 1-4 A dverse E vent | Number (%) of P atients with G rade 3-4 A dverse E vent |
| Femara ® | P lacebo | Femara ® | P lacebo |
| N=2563 | N=2573 | N=2563 | N=2573 |
| Any A dverse E vent | 2232 (87.1) | 2174 (84.5) | 419 (16.3) | 389 (15.1) |
| Vascular D isorders | 1375 (53.6) | 1230 (47.8) | 59 (2.3) | 74 (2.9) |
| Flushing | 1273 (49.7) | 1114 (43.3) | 3 (0.1) | 0 - |
| General D isorders | 1154 (45.0) | 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 D isorders | 978 (38.2) | 836 (32.5) | 71 (2.8) | 50 (1.9) |
| Arthralgia | 565 (22.0) | 465 (18.1) | 25 (1.0) | 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 (5.0) | 112 (4.4) | 8 (0.3) | 7 (0.3) |
| Nervous S ystem D isorders | 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 D isorders | 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 D isorders | 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 (5.0) | 143 (5.6) | 12 (0.5) | 8 (0.3) |
| Metabolic D isorders | 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 D isorders | 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 D isorders | 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 D isorders | 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 I nfestations | 166 (6.5) | 163 (6.3) | 40 (1.6) | 33 (1.3) |
| Renal D isorders | 130 (5.1) | 100 (3.9) | 12 (0.5) | 6 (0.2) |
The duration of follow-up for both the main clinical study and the bone study were insufficient to assess fracture risk associated with long-term use of Femara. 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.
Preliminary results (median duration of follow-up was 20 months) from the bone sub-study (Calcium 500 mg and Vitamin D 400 IU per day mandatory; bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to baseline in hip BMD in Femara patients was 3% vs 0.4% for placebo. The mean decrease from baseline BMD results for the lumbar spine at 2 years were Femara 4.6% decrease and placebo 2.2%.
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).
Preliminary results (median duration of follow-up was 30 months) from the lipid sub-study did not show significant differences between the Femara and placebo groups. The HDL:LDL ratio decreased after the first 6 months of therapy but the decrease was similar in both groups and no statistically significant differences were detected.
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.
First-Line Breast Cancer
A total of 455 patients was treated for a median time of exposure of 11 months. The incidence of adverse experiences was similar for Femara and tamoxifen. The most frequently reported adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse experiences other than progression of tumor occurred in 10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen.
Adverse events, 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 15.
Table 15 : Percentage (%) of Patients with Adverse Events
| Adverse | Femara ® | tamoxifen |
| Experience | 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 (≤2%) adverse experiences 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 Breast Cancer
Femara was generally well tolerated in two controlled clinical trials.
Study discontinuations in the megestrol acetate comparison study for adverse events other than progression of tumor 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 events revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse events 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 events, 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 16.
Table 16 : Percentage (%) of Patients with Adverse Events
| Adverse | Pooled | Pooled | megestrol | |
| Experience | Femara ® | Femara ® | acetate | aminoglutethimide |
| 2.5 mg | 0.5 mg | 160 mg | 500 mg |
| (N=359) | (N=380) | (N=189) | (N=178) |
| % | % | % | % |
| Body as a Whole | | | | |
| Fatigue | 8 | 6 | 11 | 3 |
| Chest Pain | 6 | 3 | 7 | 3 |
| Peripheral Edema1 | 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 | | | | |
| Musculoskeletal2 | 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 |
| Rash3 | 5 | 4 | 3 | 12 |
| Pruritus | 1 | 2 | 5 | 3 |
1 Includes peripheral edema, leg edema, dependent edema, edema
2 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
3 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash |
Other less frequent (<5%) adverse experiences considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.
First-Line and Second-Line Breast Cancer
In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse events that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypoesthesia/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.
Post-Marketing Experiences
Cases of blurred vision, increased hepatic enzymes, angioedema and anaphylactic reactions have been reported.
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