Letrozole

FDA Drug Information • Also known as: Femara, Letrozole

Brand Names: Femara, Letrozole
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Letrozole tablet 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, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C. Letrozole is available as 2.5 mg tablets for oral administration. Inactive Ingredients : Colloidal anhydrous silica, hypromellose, iron oxide yellow , lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, starch (corn), talc, and titanium dioxide. Letrozole structural formula

What Is Letrozole Used For?

1 INDICATIONS AND USAGE Letrozole tablet 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 ) 1.1 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 and Administration

2 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 tablet 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 tablet 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 (71%) percent 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 )] .

Side Effects (Adverse Reactions)

6 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 Accord Healthcare Inc. at 1-866-941-7875 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 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) Grades 1-4 Grades 3-4 Adverse Reactions Letrozole Tablets N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole Tablets N=2448 n (%) Tamoxifen N=2447 n (%) Patients with any adverse reaction 2309 (93.4) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia * 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 1 361 (14.7) 280 (11.4) - - - - Night sweats * 356 (14.6) 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 **2 249 (10.2) 175 ( 7.2) - - - - Fatigue (lethargy, malaise, asthenia) **2 235 ( 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) 66 ( 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 1 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 **1 11 (0.4) 72 (2.9) - - - -...

Drug Interactions

7 DRUG INTERACTIONS Tamoxifen Coadministration of letrozole 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 therapy is not impaired if letrozole 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 letrozole in combination with other anticancer agents.

Contraindications

4 CONTRAINDICATIONS Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations ( 8.1 )] . 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 )] . 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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole 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...

Overdosage

10 OVERDOSAGE Isolated cases of letrozole 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-3474 NDC: 50090-3474-0 90 TABLET, FILM COATED in a BOTTLE

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.