EXEMESTANE

Exemestane Tablets, USP for oral administration contain 25 mg of exemestane, USP, 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 or almost white crystalline powder with a molecular weight of 296.41. Exemestane, USP is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water. Each Exemestane Tablet, USP contains the following inactive ingredients: mannitol, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, talc, polyethylene glycol 3350, titanium dioxide, and polyvinyl alcohol. Chemical Structure

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 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 is 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 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 is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy [see Clinical Studies (14.2) ].

Recommended Dose: One 25 mg tablet once daily after a meal ( 2.1 ). 2.1 Recommended Dose The recommended dose of exemestane 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 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 with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of exemestane is 50 mg once daily after a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3) ].

Exemestane is 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 ).

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 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 Florida Pharmaceutical Products, LLC at 1-800-315-0985 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 in 2325 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 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%. 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 Illnesses Occurring in (≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer % of patients Body system and Adverse Reaction by MedDRA dictionary Exemestane 25 mg daily (N=2252) Tamoxifen 20 mg daily 75 patients received tamoxifen 30 mg daily; (N=2280) Eye Visual disturbances Event actively sought. 5 3.8 Gastrointestinal Nausea 9 9 General Disorders Fatigue 16 15 Musculoskeletal Arthralgia 15 9 Pain in limb 9 6 Back pain 9 7 Osteoarthritis 6 4.5 Nervous System Headache 13 11 Dizziness 10 8 Psychiatric Insomnia 12 9 Depression 6 6 Skin & Subcutaneous Tissue Increased sweating 12 10 Vascular Hot flushes 21 20 Hypertension 10 8 In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis [0.3% vs. 0%] and stenosing tenosynovitis (trigger finger) [0.3% vs. 0%], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]). Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the exemestane group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history. Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%]. Common adverse reactions occurring in study 027 are described in Table 3. Table 3. Incidence of Selected Treatment-Emergent Adverse Reactions of all CTC Grades Most events were CTC grade 1–2. Occurring in ≥5% of Patients in Either Arm in Study 027 Adverse Reaction Exemestane N=73 (% incidence) Placebo N=73 (% incidence) Hot flushes 33 25 Arthralgia 29 29 Increased sweating 18 21 Alopecia 15 4.1 Hypertension 15 7 Insomnia 14 15 Nausea 12 16 Fatigue 11 19 Abdominal pain 11 14 Depression 10 7 Diarrhea 10 1.4 Dizziness 10 10 Dermatitis 8 1.4 Headache 7 4.1 Myalgia 6 4.1 Edema 6 7 Treatment of Advanced Breast Cancer A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. One death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, 3% of the patients discontinued treatment with exemestane because of adverse reactions, 2.7% of patients discontinued exemestane within the first 10 weeks of treatment. In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse reactions than those treated with megestrol acetate (2% vs. 5%). Adverse reactions that were considered drug related or of indeterminate cause included hot flashes (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. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). In the treatment of advanced breast cancer, the most common adverse reactions 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. Table 4 shows the adverse reactions of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or megestrol acetate. Table 4. Incidence (%) of Adverse Reactions of all Grades Graded according to Common Toxicity Criteria and Causes Occurring in 5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study Body system and Adverse Reaction by WHO ART dictionary Exemestane 25 mg once daily (N=358) Megestrol Acetate 40 mg QID (N=400) Autonomic Nervous Increased sweating 6 9 Body as a Whole Fatigue 22 29 Hot flashes 13 6 Pain 13 13 Influenza-like symptoms 6 5 Edema (includes edema, peripheral edema, leg edema) 7 6 Cardiovascular Hypertension 5 6 Nervous Depression 13 9 Insomnia 11 9 Anxiety 10 11 Dizziness 8 6 Headache 8 7 Gastrointestinal Nausea 18 12 Vomiting 7 4 Abdominal pain 6 11 Anorexia 6 5 Constipation 5 8 Diarrhea 4 5 Increased appetite 3 6 Respiratory Dyspnea 10 15 Coughing 6 7 Adverse reactions of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. Additional adverse reactions of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). Adverse reactions of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of exemestane. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders - hypersensitivity Hepatobiliary disorders - hepatitis including cholestatic hepatitis Nervous system disorders- paresthesia Musculoskeletal and connective tissue disorder -tendon disorders including tendon rupture, tendonitis, and tenosynovitis Skin and subcutaneous tissue disorders- acute generalized exanthematous pustulosis, urticaria, pruritus

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) ] .

Store at 25°C (77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].