Exemestane Drug Information

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.

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.

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.

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.

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 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. 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 ( %). 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 Illnesses Occurring in (≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer 8 In the IES study, as compared to tamoxifen, exemestane tablets were 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, osteochondrosis and trigger finger, paresthesia, carpal tunnel syndrome, and neuropathy ). Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). 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 tablets group compared to tamoxifen (0.7% vs. <0.1%).

The majority of patients on exemestane tablets 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, thromboembolism, endometrial hyperplasia, and uterine polyps. Common adverse reactions occurring in study 027 are described in Table 3.

Table 3. 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 tablets and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane tablets discontinued treatment because of adverse reactions than those treated with megestrol acetate (2% vs. 5%). The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane tablets (17% vs. 8%).

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 tablets 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 6 7 Adverse reactions of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane tablets 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema.

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.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of exemestane tablets. 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- tenosynovitis stenosans 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 tablets dose to 50 mg. 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.

Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, exemestane tablets can cause fetal harm when administered to a pregnant woman. 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.

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.

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.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.

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 25000/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 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m 2 basis).