Exemestane

1 INDICATIONS AND USAGE Exemestane is an aromatase inhibitor indicated for: adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane tablets, USP for completion of a total of five consecutive years of adjuvant hormonal therapy ( 14.1 ). treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy ( 14.2 ). 1.1 Adjuvant Treatment of Postmenopausal Women Exemestane tablets, USP are indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane tablets, USP for completion of a total of five consecutive years of adjuvant hormonal therapy [see Clinical Studies ( 14.1 )]. 1.2 Advanced Breast Cancer in Postmenopausal Women Exemestane tablets, USP are indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy [see Clinical Studies ( 14.2 )].

2 DOSAGE AND ADMINISTRATION Recommended Dose: One 25 mg tablet once daily after a meal ( 2.1 ). 2.1 Recommended Dose The recommended dose of exemestane tablet in early and advanced breast cancer is one 25 mg tablet once daily after a meal. adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane tablets for completion of a total of five consecutive years of adjuvant hormonal therapy. the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. 2.2 Dose Modifications Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. For patients receiving exemestane tablets with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of exemestane tablet is 50 mg once daily after a meal [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg ( 3 ) Exemestane Tablets USP, 25 mg are white-colored, round-shaped, biconvex, film-coated tablets debossed with '383' on one side and plain on other side.

4 CONTRAINDICATIONS Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients. Patients with a known hypersensitivity to the drug or to any of the excipients ( 4 ).

6 ADVERSE REACTIONS Early breast cancer: Adverse reactions occurring in ≥ 10% of patients in any treatment group (exemestane vs. tamoxifen) were hot flushes (21% vs. 20%), fatigue (16% vs. 15%), arthralgia (15% vs. 9%), headache (13% vs. 11%), insomnia (12% vs. 9%), and increased sweating (12% vs. 10%). Discontinuation rates due to AEs were similar between exemestane and tamoxifen (6% vs. 5%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane 0.4%, tamoxifen 0.3% ( 6 , 6.1 ). Advanced breast cancer: Most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively ( 6 , 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1- 877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in the labeling: • Reductions in Bone Mineral Density (BMD) [see Warnings and Precautions ( 5.1 )] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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 clinical practice. Adjuvant Therapy The data described below reflect exposure to exemestane in 2,325 postmenopausal women with early breast cancer. Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study [See Clinical Studies ( 14.1 )] and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment). The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study. Certain adverse reactions, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations. Within the IES study, discontinuations due to adverse reactions occurred in 6% and 5% of patients receiving exemestane and tamoxifen, respectively, and in 12% and 4.1% of patients receiving exemestane or placebo respectively within study 027. Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen. The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients. In the adjuvant treatment of early breast cancer, the most common adver …

7 DRUG INTERACTIONS Strong CYP 3A4 inducers: Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. Increase the exemestane dose to 50 mg ( 2.2 , 7 ). Drugs That Induce CYP 3A4 Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may significantly decrease exposure to exemestane. Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ].

Drug Interaction Studies Exemestane does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma C max and AUC 0–∞ of exemestane were decreased by 41% and 54%, respectively [see Dosage and Administration (2.2) and Drug Interactions (7) ]. In a clinical pharmacokinetic study, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Although no other formal drug-drug interaction studies with inhibitors have been conducted, significant effects on exemestane clearance by CYP isoenzyme inhibitors appear unlikely.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action , exemestane can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Limited human data from case reports are insufficient to inform a drug-associated risk. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions, embryo-fetal toxicity, and prolonged gestation with abnormal or difficult labor [see Data ] . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In animal reproduction studies in rats and rabbits, exemestane caused embryo-fetal toxicity, and was abortifacient. Radioactivity related to 14 C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m 2 basis). Increased resorptions, reduced number of live fetuses, decreased fetal weight, retarded ossification, prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day (approximately 7.5 times the recommended human daily dose on a mg/m 2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m 2 basis) and in the presence of maternal toxicity, abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. No malformations were noted when exemestane was administered to pregnant rats or rabbits during the organogenesis period at doses up to 810 and 270 mg/kg/day, respectively (approximately 320 and 210 times the recommended human dose on a mg/m 2 basis, respectively). 8.2 Lactation Risk Summary There is no information on the presence of exemestane in human milk, or on its effects on the breastfed infant or milk production. Exemestane is present in rat milk at concentrations similar to maternal plasma [see Data ] . Because of the potential for serious adverse reactions in breast-fed infants from exemestane, advise a woman not to breastfeed during treatment with exemestane tablets and for 1 month after the final dose. Data Radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14 C-exemestane. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating exemestane tablets. Contraception Females Exemestane 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 exemestane tablets and for 1 month after the final dose. Infertility Based on findings in animals, male and female fertility may be impaired by treatment with exemestane tablets [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.6 Hepatic Impairment …

12.1 Mechanism of Action Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

11 DESCRIPTION Exemestane tablets, USP for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane, USP is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C 20 H 24 O 2 and its structural formula is as follows: The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water. Each exemestane tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. FDA approved dissolution test specifications differs from USP. Chemical Structure

10 OVERDOSAGE Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. A male child (age unknown) accidentally ingested a 25 mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25,000/mm 3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given. In mice, mortality was observed after a single oral dose of exemestane of 3,200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m 2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5,000 mg/kg (about 2,000 times the recommended human dose on a mg/m 2 basis) and of 3,000 mg/kg (about 4,000 times the recommended human dose on a mg/m 2 basis), respectively. Convulsions were observed after single doses of exemestane of 400 mg/kg and 3,000 mg/kg in mice and dogs (approximately 80 and 4,000 times the recommended human dose on a mg/m 2 basis), respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING Exemestane tablets, USP are white to off white, round, biconvex film-coated tablet, debossed with "C316" on one-side and plain on other side. Exemestane tablets, USP are packaged in HDPE bottles with a child-resistant screw cap, supplied in packs of 30 tablets. 30-tablet HDPE bottle NDC 69097-316-02 Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].