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)
1.1Adjuvant Treatment of Early Breast Cancer
Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. .
1.2Extended 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 ) ].
1.3First 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 ) ].
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)
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)
5.1Bone 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) ] .
5.2Cholesterol
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) ].
5.3Hepatic 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) ].
5.4Fatigue 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.
5.5Laboratory 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.
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.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category
X [see Contraindications (4) ]. Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug 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.
Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m 2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well.
Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m 2 basis). Adverse effects included: intrauterine mortality; increased resorptions and postimplantation loss; decreased numbers of live fetuses; and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals.
Letrozole doses 1/10 the daily MHRD (mg/m 2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m 2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. [see Nonclinical Toxicology (13.2) ]. Physicians should discuss the need for adequate contraception with women who are recently menopausal.
Contraception should be used until postmenopausal status is clinically well established.
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
6.1Adjuvant 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.
6.2Extended 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) 123
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
LETROZOLE 2.5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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