AROMASIN (exemestane) Adverse Reactions

Adjuvant Treatment of Early Breast Cancer

Adverse Drug Reaction Overview:

AROMASIN (exemestane) Tablets tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the Intergroup Exemestane Study 031 (IES) (see CLINICAL STUDIES) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group, phase II study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids and coagulation factors over 2 years of treatment).

Certain adverse events, 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.

The median duration of adjuvant treatment was 30.0 months and 29.9 months for patients receiving AROMASIN or tamoxifen, respectively, within the IES study, and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization at the time of primary analysis, for AROMASIN was 40.4 months and for tamoxifen 39.1 months; and at the time of the updated analysis for AROMASIN was 53.6 months and for tamoxifen 51.6 months. Median duration of observation was 30 months for both groups in the 027 study.

AROMASIN was generally well tolerated, and adverse events were usually mild to moderate. Within the IES study discontinuations due to adverse events occurred in 7.4% and 6.2% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo within Study 027. Within the IES study, the most commonly reported adverse reactions were hot flushes (AROMASIN 22%; tamoxifen 20%), arthralgias (AROMASIN 18%; tamoxifen 11%), and fatigue (AROMASIN 16%; tamoxifen 15%). On-treatment deaths due to any cause were reported for 1.5% of the exemestane-treated patients, and 1.5% of the tamoxifen-treated patients within the IES study. There were 6 on-treatment deaths due to stroke and 3 due to cardiac failure in the AROMASIN-treated patients compared with 2 deaths due to stroke and 1 due to cardiac failure in the tamoxifen-treated patients. There were no deaths in Study 027.

Clinical Trial Adverse Drug Reactions:

Treatment-emergent adverse events 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.

In the IES study, more patients receiving exemestane were reported to have ischemic cardiac events (myocardial infarction, angina, and myocardial ischemia) compared to patients receiving tamoxifen (treatment-emergent cases: 2.0% versus 1.3%; all-cases [either on treatment or during follow up]: 5.8% versus 3.8%). No significant difference was noted for any individual treatment-emergent cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). The proportion of patients reporting hypercholesterolemia was 3.7% in the AROMASIN-treated group versus 2.1% in the tamoxifen-treated group.

In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in the musculoskeletal disorders and in the nervous system disorders, including the following events occurring with frequency lower than 5%: paraesthesia (2.8% vs. 1.0%), carpal tunnel syndrome (2.8% vs. 0.2%) and neuropathy (0.5% vs. <0.1%).

AROMASIN was associated with a significantly higher incidence of gastric ulcer events in comparison to tamoxifen (0.7% vs. <0.1%). In addition, diarrhea was also more frequent in the AROMASIN group (4.2% vs. 2.2%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Clinical fractures were reported in 101 patients receiving exemestane (4.5%) and 75 patients receiving tamoxifen (3.3%).

Tamoxifen was associated with a greater incidence of muscle cramps (3.2% vs. 1.4%), uterine polyps (1.8% vs. 0.4%), venous thromboembolic disease (1.8% vs. 0.7%), endometrial hyperplasia (0.9% vs. <0.1%) and uterine polypectomy (0.8% vs. 0.2%).

A lower incidence of other second (non-breast) primary cancers was observed in the AROMASIN-treated patients versus tamoxifen-treated patients (3.6% vs. 5.3%) in the IES study.

Based on reports of adverse events in 73 postmenopausal women in each treatment group in the 027 study, Table 3 shows treatment-emergent adverse events including all causalities and occurring with an incidence of > 5% in either treatment group.

Events were mostly grade 1 or 2 in severity for both AROMASIN and placebo treated patients.

Treatment of Advanced Breast Cancer after Failure on Tamoxifen:

Adverse Drug Reaction Overview:

A total of 1058 patients who had failed prior tamoxifen therapy were treated with AROMASIN (exemestane) Tablets 25 mg once daily in the clinical trials program. AROMASIN was generally well tolerated and adverse events were usually mild to moderate. Only one death was potentially related to treatment with AROMASIN; 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, only 2.8% of the patients discontinued treatment with AROMASIN because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations due to adverse events were uncommon (0.3%).

Clinical Trial Adverse Drug Reactions:

In the Phase III study, 358 patients were treated with AROMASIN and 400 patients were treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (1.7% versus 5%). Adverse events in the Phase III study that were considered drug related or of indeterminate cause included hot flashes (12.6%), nausea (9.2%), fatigue (7.5%), increased sweating (4.5%), and increased appetite (2.8%). The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17.1% versus 7.6%, p=0.001). The following table (Table 4) shows the adverse events of all National Cancer Institute (NCI) Common Toxicity grades regardless of causality reported in 5% or greater of patients in the Phase III study treated either with AROMASIN or megestrol acetate.

In the overall clinical trials program for advanced cancer (N = 1058), additional adverse events reported in 5% or greater of patients treated with AROMASIN 25 mg once daily included pain at tumor site (8%), peripheral edema (7.6%), asthenia (5.8%) and fever (5%). Less frequent but common adverse events (1% to 5%) reported in these patients were liver enzyme abnormalities (AST, ALT, alkaline phosphatase), elevated bilirubin, arthralgia, peripheral edema, back pain, dyspepsia, paresthesia, bronchitis, rash, chest pain, edema, hypertension, upper respiratory tract infection, pruritus, urinary tract infection, pathological fracture, alopecia, leg edema, sinusitis, skeletal pain, infection, pharyngitis, rhinitis, hypoesthesia, confusion, and lymphedema.

Post-Market Adverse Drug Reactions

Post-market adverse events/illnesses include case observed in other clinical trials (not described above) as well as reports from post-marketing surveillance. Because these events are not uniformly reported, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to AROMASIN exposure. The following events are listed according to MedDRA system organ class.

Vascular disorders: Cerebrovascular accident, pulmonary embolus and deep vein thrombosis were among the most frequently reported adverse events/illnesses in the post-market setting.

Cardiac disorders: Cardiac failure and myocardial infarction have been reported in association with AROMASIN.

Nervous System disorders: Carpal tunnel and paraesthesia has been reported frequently in the post-market setting.

Hepatobilliary disorders: Rare cases of hepatitis including cholestatic hepatitis have been observed in other clinical trials with additional reports identified through post-marketing surveillance.

Investigations: ALT, AST, blood bilirubin and blood alkaline phosphatase increases that have been reported as common events above have also been reported as very common events in other clinical trials. Additionally, in post-market surveillance elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been observed. Increase in liver enzymes was not necessarily due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed.

Skin and subcutaneous tissue disorders: Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis have been reported in association with AROMASIN. Urticaria and pruritus have also been reported in association with AROMASIN.

Immune System disorders: Hypersensitivity, including anaphylactic reactions, has occurred between 8 hours to 26 days of starting exemestane therapy.