Exemestane

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.

1 INDICATIONS AND USAGE Exemestane tablets are 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 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 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 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 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 tablets 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 tablets is 50 mg once daily after a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Reductions in Bone Mineral Density (BMD) [see Warnings and Precautions (5.1) ] Early breast cancer: Adverse reactions occurring in ≥10% of patients in any treatment group (exemestane tablets 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 tablets and tamoxifen (6% vs. 5%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane tablets 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane tablets 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 tablets and megestrol acetate, respectively ( 6 , 6.1 ). 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 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 tablets in 2325 postmenopausal women with early breast cancer. Exemestane tablets 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 tablets or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane tablets or placebo within the 027 study. Median duration of observation after randomization for exemestane tablets 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 tablets 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 adverse reactions occurring in ≥10% of patients in any treatment group (exemestane tablets 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 tablets and tamoxifen (6% vs. 5%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane tablets 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane tablets 0.4%, tamoxifen 0.3%. Treatment-emergent adverse reactions and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2. Table 2. Incidence (%) of Adverse Reactions of all Grades Graded according to Common Toxicity Criteria; and

7 DRUG INTERACTIONS Strong CYP 3A4 inducers: Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. Increase the exemestane tablets 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) ] .