Letrozole
Letrozole Tablets · Tablet, Film Coated · Oral
Uses
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 (DFS) 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 and 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 is unknown. In both the adjuvant study and the post approval adjuvant study, median treatment duration was 5 years. 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 for letrozole tablets was 60 months. Seventy-one percent (71%) of patients were treated for at least 3 years and 58% of patients completed at 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 tablets 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 greater than or equal to 10 mL/min [see Clinical Pharmacology (12.3) ] .
Dosage forms and strengths
2.5 mg tablets: Yellow colored, film-coated, round shaped tablets debossed with one side 'N' and other side 'L'. 2.5 mg tablets. ( 3 )
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. ( 5.6 , 8.1 , 8.3 ) 5.1 Bone Effects Use of letrozole tablets 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) [see 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 [see Adverse Reactions (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 [see Adverse Reactions (6) ] . 5.2 Cholesterol 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 × 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 × 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 [see Adverse Reactions (6) ] . 5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets experienced approximately twice the exposure to letrozole tablets 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 letrozole tablets 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 tablets, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole tablets use. 5.5 Laboratory Test Abnormalities No dose-related effect of letrozole tablets 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 tablets 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole tablets developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent. 5.6 Embryo-Fetal Toxicity Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets 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 letrozole tablets 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) ] .
Side effects
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 Breckenridge Pharmaceutical, Inc., at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical 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 letrozole tablets 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. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) 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) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Adverse Reactions Grades 1-4 Grades 3-4 Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) 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. Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia Target events pre-specified for analysis 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2) Hot flashes 819 (33.5) 929 (38.0) - - - - Arthralgia/arthritis 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0) Bone fractures At median follow-up of 96 months (i.e., any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months). 361 (14.7) 280 (11.4) - - - - Night sweats 356 (14.5) 426 (17.4) - - - - Weight increase 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6) Nausea 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4) Bone fractures Events pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months). 249 (10.2) 175 (7.2) - - - - Fatigue (lethargy, malaise, asthenia) 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3) Myalgia 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6) Vaginal bleeding 129 (5.3) 320 (13.1) 1 (<0.1) 8 (0.3) 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) Osteoporosis 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2) Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4) 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 112 (4.6) 77 (3.1) 2 (<0.1) 2 (<0.1) Headache 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2) Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2) Osteopenia 87 (3.6) 76 (3.1) 0 - 3 (0.1) Dizziness/light-headedness 84 (3.4) 80 (3.3) 1 (<0.1) 6 (0.2) Alopecia 83 (3.4) 84 (3.4) - - - - 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) Myocardial infarction 42 (1.7) 28 (1.1) - - - - Breast pain 37 (1.5) 43 (1.8) 1 (<0.1) - - Anorexia 20 (0.8) 20 (0.8) 1 (<0.1) 1 (<0.1) Endometrial proliferation disorders 14 (0.6) 86 (3.5) 0 - 14 (0.6) Ovarian cyst 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2) Endometrial hyperplasia/cancer 11 (0.4) 72 (2.9) - - - - Endometrial hyperplasia/cancer , Excluding women who had undergone hysterectomy before study entry. 6/1909 (0.3) 57/1943 (2.9) - - - - Other endometrial disorders 2 (<0.1) 3 (0.1) 0 - 0 - Myocardial infarction 24 (1.0) 12 (0.5) - - - - Myocardial ischemia 6 (0.2) 9 (0.4) - - - - Cerebrovascular accident/TIA 74 (3.0) 68 (2.8) - - - - Cerebrovascular accident/TIA 51 (2.1) 47 (1.9) - - - - Angina requiring surgery 35 (1.4) 33 (1.3) - - - - Angina requiring surgery 25 (1.0) 25 (1.0) - - - - Thromboembolic event 79 (3.2) 113 (4.6) - - - - Thromboembolic event 51 (2.1) 89 (3.6) - - - - Cardiac failure 39 (1.6) 34 (1.4) - - - - Cardiac failure 27 (1.1) 15 (0.6) - - - - Hypertension 160 (6.5) 175 (7.2) - - - - Hypertension 138 (5.6) 139 (5.7) - - - - Other cardiovascular 172 (7.0) 174 (7.1) - - - - Other cardiovascular 120 (4.9) 119 (4.9) - - - - Second primary malignancy 129 (5.3) 150 (6.1) - - - - Second primary malignancy 54 (2.2) 79 (3.2) - - - - When considering all grades during study treatment, a higher incidence of events was seen for letrozole tablets regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (letrozole tablets vs tamoxifen respectively).
Drug interactions
Tamoxifen Coadministration of letrozole tablets 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 letrozole tablets therapy is not impaired if letrozole tablets are 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 letrozole tablets in combination with other anticancer agents.
Use in specific populations
Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets can cause fetal harm and are 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) , Postmarketing Experience (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 times 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. 8.2 Lactation Risk Summary It is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data ) . Because of the potential for serious adverse reactions in breastfed infants from letrozole, advise lactating women not to breastfeed while taking letrozole and for at least 3 weeks after the last dose. Data Animal Data In a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03, or 0.3 mg/kg/day on Day 0 through Day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, letrozole tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females of reproductive potential should have a pregnancy test prior to starting treatment with letrozole tablets. Contraception Females Based on animal studies, letrozole tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with letrozole tablets and for at least 3 weeks after the last dose. Infertility Females Based on studies in female animals, letrozole tablets may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] . Males Based on studies in male animals, letrozole tablets may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures. 8.5 Geriatric Use The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were greater than or equal to 70 years old.
Pregnancy
8.1 Pregnancy Risk Summary Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole tablets can cause fetal harm and are 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) , Postmarketing Experience (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 times 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.
Geriatric use
8.5 Geriatric Use The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70. For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.
Overdosage
Isolated cases of letrozole tablets overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m 2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m 2 basis); death was preceded by depressed blood pressure and arrhythmias.
Description
Letrozole tablets for oral administration contain 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, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C. Letrozole tablets are available as 2.5 mg tablets for oral administration. Inactive Ingredients: Colloidal silicon dioxide, ferric oxide (yellow), hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide. FDA approved dissolution test specifications differ from USP Chemical Structure
Mechanism of action
12.1 Mechanism of Action The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
How supplied
Packaged in HDPE bottles with a child resistant closure (30 tablets & 90 tablets) and continuous thread closure (1000 tablets). 2.5 milligram tablets Bottles of 30 tablets NDC 51991-759-33 Bottle of 90 tablets NDC 51991-759-90 Bottles of 1000 tablets NDC 51991-759-10 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient information
Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during letrozole tablets therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with letrozole tablets [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1 , 8.3) ] . Lactation Advise women not to breastfeed during letrozole tablets treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2) ] . Infertility Advise females and males of reproductive potential of the potential for reduced fertility from letrozole tablets [see Use in Specific Populations (8.3) ] . Fatigue and Dizziness Since fatigue and dizziness have been observed with the use of letrozole tablets and somnolence was uncommonly reported, caution is advised when driving or using machinery [see Warnings and Precautions (5.4) ] . Bone Effects Consideration should be given to monitoring bone mineral density [see Warnings and Precautions (5.1) ] .
Label text from the FDA structured product label by Breckenridge Pharmaceutical, Inc. (revised Aug 17, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Letrozole in 24 products
Letrozole NDC products (24)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50090-3474 | Letrozole 2.5 mg/1 Tablet, Film Coated | A-S Medication Solutions | ANDA |
| 50090-8002 | Letrozole 2.5 mg/1 Tablet | A-S Medication Solutions | ANDA |
| 16729-034 | Letrozole 2.5 mg/1 Tablet, Film Coated | Accord Healthcare, Inc. | ANDA |
| 17856-0032 | Letrozole 2.5 mg/1 Tablet, Film Coated | ATLANTIC BIOLOGICALS CORP. | ANDA |
| 59651-180 | Letrozole 2.5 mg/1 Tablet, Film Coated | Aurobindo Pharma Limited | ANDA |
| 23155-875 | Letrozole 2.5 mg/1 Tablet, Film Coated | Avet Pharmaceuticals Inc. | ANDA |
| 42291-374 | Letrozole 2.5 mg/1 Tablet, Film Coated | AvKARE | ANDA |
| 50268-476 | Letrozole 2.5 mg/1 Tablet | AvPAK | ANDA |
| 51991-759 | Letrozole 2.5 mg/1 Tablet | Breckenridge Pharmaceutical, Inc. | ANDA |
| 71335-2396 | Letrozole 2.5 mg/1 Tablet, Film Coated | Bryant Ranch Prepack | ANDA |
| 71335-1526 | Letrozole 2.5 mg/1 Tablet | Bryant Ranch Prepack | ANDA |
| 63629-7819 | Letrozole 2.5 mg/1 Tablet, Film Coated | Bryant Ranch Prepack | ANDA |
| 80005-139 | Letrozole 2.5 mg/1 Tablet, Film Coated | Carnegie Pharmaceuticals LLC | ANDA |
| 62135-491 | Letrozole 2.5 mg/1 Tablet, Film Coated | Chartwell RX, LLC | ANDA |
| 55111-646 | Letrozole 2.5 mg/1 Tablet, Film Coated | Dr. Reddy's Laboratories Limited | ANDA |
| 51407-986 | Letrozole 2.5 mg/1 Tablet, Film Coated | Golden State Medical Supply, Inc. | ANDA |
| 63850-0025 | Letrozole 2.5 mg/1 Tablet | Natco Pharma Limited | ANDA |
| 68071-2167 | Letrozole 2.5 mg/1 Tablet, Film Coated | NuCare Pharmaceuticals,Inc. | ANDA |
| 68071-5264 | Letrozole 2.5 mg/1 Tablet, Film Coated | NuCare Pharmaceuticals,Inc. | ANDA |
| 71205-587 | Letrozole 2.5 mg/1 Tablet, Film Coated | Proficient Rx LP | ANDA |
| 0093-7620 | Letrozole 2.5 mg/1 Tablet, Film Coated | Teva Pharmaceuticals USA, Inc. | ANDA |
| 24979-726 | Letrozole 2.5 mg/1 Tablet, Film Coated | Upsher-Smith Laboratories, LLC | ANDA |
| 69117-0004 | Letrozole 2.5 mg/1 Tablet, Film Coated | Yiling Pharmaceutical, Inc. | ANDA |
| 17088-0100 | Letrozole 2.5 mg/1 Tablet, Film Coated | Novartis Pharma Stein AG | DRUG FOR FURTHER PROCESSING |
Frequently asked questions
What is Letrozole used for?
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…
What are the side effects of Letrozole?
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,… See the full label for the complete list.
Who makes Letrozole?
Letrozole is listed by 20 labelers in the FDA NDC directory, including A-S Medication Solutions, Accord Healthcare, Inc., ATLANTIC BIOLOGICALS CORP., Aurobindo Pharma Limited.