Femara is 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 Femara
(letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
1.2Extended 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 (DFS) in patients treated with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)] .
1.3First 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)].
Contraindications
Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)] . Pregnancy. ( 4 ) Known hypersensitivity to the active substance, or to any of the excipients. ( 4 )
Warnings and 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 ) Embryo-Fetal Toxicity: Can cause fetal harm when administered to pregnant women. Obtain a pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception.
5.1 Bone Effects Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) 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) [ s ee Adverse Reactions (6)] .
Updated results from the BMD substudy (MA-17B) 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)]. In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months.
The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [ s ee Adver se R eactions (6)] . In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [ s ee Adverse Reactions (6) ] .
5.2Cholesterol
Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. 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 greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than = 1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [ s ee Adverse R eactions (6)].
5.3Hepatic 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 [see Clinical Pharmacology ( 12.3 ) ] . 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 ) ] .
5.4Fatigue 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.
5.5Laboratory 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.
5.6Embryo-Fetal Toxicity Based
on post-marketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m 2 basis.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with Femara and for at least 3 weeks after the last dose [see Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)] .
Interactions
Tamoxifen Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (Study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the therapeutic effect of Femara therapy is not impaired if Femara is administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine (Study P004) showed no clinically significant effect on letrozole pharmacokinetics.
Warfarin An interaction study (P017) 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 Femara in combination with other anticancer agents.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on postmarketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk [see Contraindications (4), Warnings and Precautions (5.6), Adverse Reactions (6.2), and Clinical Pharmacology (12.1)] .
In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m 2 basis (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown.
However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis).
In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal toxicity including 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 was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) and caused fetal domed head and cervical/centrum vertebral fusion. In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal toxicity, including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses.
Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling. Bone effects [see Warnings and Precautions (5.1)] Increases in cholesterol [see Warnings and Precautions (5.2)] Fatigue and Dizziness [see Warnings and Precautions (5.4)] The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain; and musculoskeletal.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
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 In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen.
Certain adverse reactions were prospectively specified for analysis (see Table 1), 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 who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0.
TIA = Transient ischemic attack. Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 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 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).
Bone Study : Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) 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 safety trial in 263 postmenopausal 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. In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatmen
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Composition
Active ingredients
LETROZOLE 2.5MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA020726.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
