AROMASIN Drug Interactions (exemestane)

AROMASIN (exemestane) Tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.

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.

Recommended Dose and Dosage Adjustment:

The recommended dose of AROMASIN (exemestane) Tablets in early and advanced breast cancer is 25 mg once daily after a meal.

In postmenopausal women with early breast cancer, treatment with AROMASIN should continue until completion of five years of adjuvant endocrine therapy, or until local or distant recurrence or new contralateral breast cancer.

In patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident. 

No dose adjustments are required for patients with hepatic or renal insufficiency.

Mechanism of Action:

Breast cancer cell growth is often estrogen-dependent and anti-tumour activity is expected following effective and continuous estrogen suppression in patients with hormone-sensitive breast cancer. Aromatase is the key 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 (mainly androstenedione) to estrogens (primarily estrone) by the aromatase enzyme in peripheral tissues. This occurs mainly in the adipose tissue, but also in the liver, muscle, hair follicles, and breast tissue. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for postmenopausal patients with hormone-dependent breast cancer.

AROMASIN (exemestane) is a potent aromatase inactivator, causing estrogen suppression and inhibition of peripheral aromatisation. It is a steroidal irreversible Type I aromatase inhibitor, structurally related to the natural substrate androstenedione. Exemestane is a specific competitive inactivator of human placental aromatase, which has been shown to be more potent than the irreversible aromatase inhibitor formestane or the reversible inhibitor aminoglutethimide in vitro.

In vivo studies of aromatase inactivation indicate that exemestane, by the oral route, is several times more potent than formestane. 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”. De novo aromatase enzyme synthesis is required for recovery of enzyme activity.  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.

Pharmacokinetics:

Absorption:

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (C_max) was observed within 2 hours of receiving exemestane. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast; however, no further effect on estrogen suppression was observed since maximum activity was already achieved under fasting conditions. Exemestane appears to be more rapidly absorbed in women with breast cancer than in healthy women.  After repeated doses, mean T_max was 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. Mean AUC values following repeated doses were approximately 2-fold higher in women with breast cancer (75.4 ng.h/mL) compared with healthy women (41.4 ng.h/mL).  However, there was considerable overlap between the range of pharmacokinetic parameters observed in these two populations. 

Distribution:

Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α₁-acid glycoprotein contribute equally to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion:

After reaching maximum plasma concentration, exemestane levels declined polyexponentially with a mean terminal half-life of about 24 hours.  Following administration of a single oral dose of radiolabeled exemestane, the elimination of drug-related products was essentially complete within 1 week. Approximately equal proportions of the dose were eliminated in urine and feces. The amount of drug excreted unchanged in urine was less than 1% of the dose, indicating that renal excretion is a limited elimination pathway. Exemestane was extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites.  Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or demonstrate minimal ability to inhibit aromatase compared with the parent drug. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Additional studies in humans demonstrated that exemestane does not affect the activity of CYP3A4 to any great extent. No significant inhibition of any of the CYP isoenzymes (including CYP3A4) involved in xenobiotic metabolism was observed in human liver preparations. This would suggest that possible drug-drug interactions involving inhibition of CYP by co-administration with exemestane are unlikely.

Special Populations and Conditions:

Geriatrics:

Although women ranging in age up to 99 years were enrolled in the clinical studies (see WARNINGS AND PRECAUTIONS), healthy postmenopausal women aged 43 to 68 years were enrolled in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender:

The pharmacokinetics of exemestane following administration of a single, 25 mg tablet to fasted healthy males (mean age 32 years; range 19 to 51 years) or to fasted healthy postmenopausal women (mean age 55 years; range 45 to 68 years) have been compared. Mean C_max and AUC values in healthy males (12.3 ± 5.8 ng/mL and 28.4 ± 17.3 ng.h/mL, respectively) were similar to those determined in healthy postmenopausal women (11.1 ± 4.4 ng/mL and 29.7 ± 7.8 ng.h/mL, respectively). Thus, the pharmacokinetics of exemestane does not appear to be influenced by gender.

Race:

The influence of race on exemestane pharmacokinetics has not been formally evaluated.

Hepatic Insufficiency:

The pharmacokinetics of exemestane have been investigated in subjects with moderate and severe hepatic insufficiency. Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25-mg daily dose (see WARNINGS AND PRECAUTIONS).

Renal Insufficiency:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m²) compared with the AUC in healthy volunteers.  However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see WARNINGS AND PRECAUTIONS).

Pediatrics:

The pharmacokinetics of exemestane have not been studied in pediatric patients.

Not applicable.