Adjuvant Treatment of Early Breast Cancer
Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Extended Adjuvant Treatment of Early Breast Cancer
Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)].
First and Second-Line Treatment of Advanced Breast Cancer
Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)].
DOSAGE AND ADMINISTRATION
Recommended Dose
The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals.
Use in Adjuvant Treatment of Early Breast Cancer
In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see Clinical Studies (14.1)].
Use in Extended Adjuvant Treatment of Early Breast Cancer
In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)].
Use in First and Second-Line Treatment of Advanced Breast Cancer
In patients with advanced disease, treatment with Femara should continue until tumor progression is evident. [see Clinical Studies (14.4, 14.5)]
Use in Hepatic Impairment
No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.
Use in Renal Impairment
No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥10 mL/min. [see Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side).
CONTRAINDICATIONS
Femara may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Femara is contraindicated in women who are or may become pregnant. If Femara is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [see Use in Specific Populations (8.1)]
WARNINGS AND PRECAUTIONS
Bone Effects
Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety 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) [See Adverse reactions (6.1)]. Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6.2)].
In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [See Adverse Reactions (6.1)]. In the extended adjuvant trial the incidence of bone 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 [see Adverse Reactions (6.3)].
Cholesterol
Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., <=1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see Adverse Reactions (6.1)].
Hepatic Impairment
Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been determined. [see Dosage and Administration (2.5)]
Fatigue and Dizziness
Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised when driving or using machinery until it is known how the patient reacts to Femara use.
Laboratory Test Abnormalities
No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.
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.
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).
| 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.
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
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 2 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 Common Toxicity Criteria 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.
| Number (%) of Patients with Grade 1-4 Adverse Reaction | Number (%) of Patients with Grade 3-4 Adverse Reaction | |||
| Femara | Placebo | Femara | 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 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.
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).
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 Sub-study: [see Warnings and Precautions (5.1)].
Lipid Sub-study: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Femara 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 was unblinded early [see Adverse Reactions (6.2)]. 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 Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara 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 Femara 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 sub-study: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Femara 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
A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for Femara 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 Femara and in 15/455 (3%) of patients on tamoxifen.
Adverse reactions, 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 3.
| Adverse | Femara | tamoxifen |
| Reaction | 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 |
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