Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Letrozole tablets USP, 2.5 mg are dark yellow coloured, round, biconvex, film coated tablets with ‘LET’ debossed on one side and ‘2.5’ on other side and is supplied in Bottles of 30’s count and Unit dose package of 100 (10 x 10). Bottles of 30 NDC 55111-646-30 Unit dose Package of 100 (10 x 10) NDC 55111-646-78; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION Letrozole Tablets, 2.5 mg - Container Label; Letrozole Tablets, 2.5 mg - Carton Label
- 16 HOW SUPPLIED/STORAGE AND HANDLING Letrozole tablets USP, 2.5 mg are dark yellow coloured, round, biconvex, film coated tablets with ‘LET’ debossed on one side and ‘2.5’ on other side and is supplied in Bottles of 30’s count and Unit dose package of 100 (10 x 10). Bottles of 30 NDC 55111-646-30 Unit dose Package of 100 (10 x 10) NDC 55111-646-78
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION Letrozole Tablets, 2.5 mg - Container Label
- Letrozole Tablets, 2.5 mg - Carton Label
Overview
Letrozole tablets USP for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile, and its structural formula is Letrozole is a white to yellowish crystalline powder, freely soluble in dichloromethane, slightly soluble in alcohol and practically insoluble in water. It has a molecular weight of 285.31, molecular formula C 17 H 11 N 5 , and a melting range of 184°C-185°C. Letrozole tablets USP are available as 2.5 mg tablets for oral administration. Inactive Ingredients. Colloidal Silicon Dioxide, Croscarmellose Sodium, Hypromellose, Lactose Monohydrate, Magnesium stearate, Polyethylene Glycol, Povidone, Talc, Titanium dioxide, and Yellow iron oxide .
Indications & Usage
Letrozole tablets are an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer (1.1) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy (1.2) First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer (1.3) 1.1 Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. . 1.2 Extended Adjuvant Treatment of Early Breast Cancer Letrozole tablets are 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 letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies ( 14.2 , 14.3 ) ]. 1.3 First and Second-Line Treatment of Advanced Breast Cancer Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are 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 & Administration
Letrozole tablets are taken orally without regard to meals (2) : Recommended dose: 2.5.mg once daily (2.1) Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day ( 2.5 , 5.3 ) 2.1 Recommended Dose The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole tablets 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) ]. 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with letrozole tablets 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) ]. 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer In patients with advanced disease, treatment with letrozole tablets should continue until tumor progression is evident. [see Clinical Studies ( 14.4 , 14.5 ) ] 2.5 Use in Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole tablets blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3) ]. The recommended dose of letrozole tablets for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined. 2.6 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 ) ].
Warnings & Precautions
Decreases in bone mineral density may occur. Consider bone mineral density monitoring (5.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.2) Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery (5.4) 5.1 Bone Effects Use of letrozole 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) ] . 5.2 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) ]. 5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined. [see Dosage and Administration (2.5) ]. 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.
Contraindications
Letrozole tablets may cause fetal harm when administered to a pregnant woman and the clinicl benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole tablets are contraindicated in women who are or may become pregnant. If letrozole tablets are 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) ] Women of premenopausal endocrine status, including pregnant women (4)
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. The most common adverse reactions (>20%) were hot flashes, arthralgia (6.1) ; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain ( 6.2 , 6.3 ); and musculoskeletal (6.4) . To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Limited Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 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 Letrozole N=2448 n (%) tamoxifen N=2447 n (%) Letrozole 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 Fractures 2 338 (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 1 247 (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/ Cancer 2, 3 11/1909 (0.6) 70/1943 (3.6) -- -- Endometrial Proliferation Disorders 10 (0.3) 71 (1.8) 0 - 14 (0.6) Endometrial Hyperplasia/ Cancer 1, 3 6/1909 (0.3) 57/1943 (2.9) -- -- Other endometrial disorders 2 (<0.1) 3 (0.1) 0 - 0 - Myocardial Infarction 1 24 (1.0) 12 (0.5) -- -- Myocardial Infarction 2 37 (1.5) 25 (1.0) -- -- Myocardial ischemia 6 (0.2) 9 (0.4) -- -- Cerebrovascular accident 1 52 (2.1) 46 (1.9) -- -- Cerebrovascular accident 2 70 (2.9) 63 (2.6) -- -- Angina 1 26 (1.1) 24 (1.0) -- -- Angina 2 32 (1.3) 31 (1.3) -- -- Thromboembolic Event 1 51 (2.1) 89 (3.6) -- -- Thromboembolic Event 2 71 (2.9) 111 (4.5) -- -- Other Cardiovascular 1 260 (10.6) 256 (10.5) -- -- Other Cardiovascular 2 312 (12.7) 337 (13.8) -- -- Second Malignancies 1 53 (2.2) 78 (3.2) -- -- Second Malignancies 2 102 (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 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 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). 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. 6.2 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 letrozole 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. Table 2: Percentage of Patients with Adverse Reactions Number (%)of Patients with Grade 1-4 Adverse Reaction Number (%)of Patients with Grade 3-4 Adverse Reaction Letrozole N=2563 Placebo N=2573 Letrozole N=2563 Placebo 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) 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 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 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) ] 6.3 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 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 sub-study: 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 over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. [see Warnings and Precautions (5.2) ]. 6.4 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 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, regardless of relationship to study drug, 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 3. Table 3: Percentage (%) of Patients with Adverse Reactions Adverse Reaction Letrozole 2.5 mg (N=455) % tamoxifen 20 mg (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 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. 6.5 Second- Line Treatment of Advanced Breast Cancer Study discontinuations in the megestrol acetate comparison study 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, 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, regardless of relationship to study drug, 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 are shown in Table 4. Table 4: Percentage (%) of Patients with Adverse Reactions Adverse Reaction Pooled Letrozole 2.5 mg (N=359) % Pooled Letrozole 0.5 mg (N=380) % megestrol acetate 160 mg (N=189) % aminoglutethimide 500 mg (N=178) % Body as a Whole Fatigue 8 6 11 3 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 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 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. 6.6 First and Second-Line Treatment of Advanced Breast Cancer In the combined analysis of the first- and second-line metastatic trials and post-marketing 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. 6.7 Postmarketing Experience Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme, and hepatitis have been reported.
Drug Interactions
Tamoxifen Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. Other Anticancer Agents There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.
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