DailyMed Label: Aromasin

DailyMed Label: Aromasin

2010

DailyMed Prescription

Aromasin

exemestane

Physicians Total Care, Inc.

NDC: 54868-5261

NDC: 54868-5261

AROMASIN® Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane 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 to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water. Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol. image of Aromasin chemical structure

AROMASIN 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 AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy. AROMASIN is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

The recommended dose of AROMASIN in early and advanced breast cancer is one 25 mg tablet once daily after a meal. In postmenopausal women with early breast cancer who have been treated with 2–3 years of tamoxifen, treatment with AROMASIN should continue in the absence of recurrence or contralateral breast cancer until completion of five years of adjuvant endocrine therapy. For patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident. For patients receiving AROMASIN with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg once daily after a meal. The safety of chronic dosing in patients with moderate or severe hepatic or renal impairment has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment does not appear to be necessary (see CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS ).

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

General AROMASIN Tablets should not be administered to premenopausal women. AROMASIN should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action. Hepatic Insufficiency The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. The safety of chronic dosing in patients with moderate or severe hepatic impairment has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment does not appear to be necessary. Renal Insufficiency The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance less than 35 mL/min/1.73 m 2 ) compared with the AUC in healthy volunteers. The safety of chronic dosing in patients with moderate or severe renal impairment has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment does not appear to be necessary. Laboratory Tests In patients with early breast cancer the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade greater than or equal to 1 was lower in the exemestane treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer, experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of patients either recovered or improved to a lesser severity while on treatment. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevations of serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase less than greater than 5 times the upper value of the normal range (i.e., greater than or equal to  CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with AROMASIN and in 1.8% of patients treated with megestrol acetate. In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Treatment emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the IES, and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients on the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients on study 027. Creatinine elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients on study 027. Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 7 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, Vitamin D supplementation and Calcium was not allowed. Table 7: Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control* IES IES 027 027 BMD Exemestane N=29 Tamoxifen N=38 Exemestane N=59 Placebo N=65 Lumbar spine (%) -3.14 -0.18 -3.51 -2.35 Femoral neck (%) -4.15 -0.33 -4.57 -2.59 *   For patients who had 24-month data. Drug Interactions Exemestane is extensively metabolized by CYP 3A4, but coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely. 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 potent CYP 3A4 inducer (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY ). Drug/Laboratory Tests Interactions No clinically relevant changes in the results of clinical laboratory tests have been observed. Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study in mice at doses of 50, 150 and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUCs (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. A separate carcinogenicity study was conducted in rats at the doses of 30, 100 and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC (0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients, receiving the recommended clinical dose. Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro. In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with greater than or equal to 500 mg/kg/day exemestane (greater than or equal to 200 times the recommended human dose on a mg/m 2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at greater than or equal to 4 mg/kg/day greater than or equal to 1.5 times the human dose on a mg/m 2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m 2 basis), however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at greater than or equal to 20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts and a decrease in corpora lutea were observed with variable frequency in mice, rats and dogs at doses that ranged from 3–20 times the human dose on a mg/m 2 basis. Pregnancy Pregnancy Category D See WARNINGS . Nursing Mothers AROMASIN is only indicated in postmenopausal women. However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14 C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if a nursing woman is inadvertently exposed to AROMASIN (see WARNINGS ). Pediatric Use The safety and effectiveness of AROMASIN in pediatric patients have not been evaluated. Geriatric Use The use of AROMASIN in geriatric patients does not require special precautions.

AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (see

AROMASIN Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number "7663" in black. AROMASIN is packaged in HDPE bottles with a child-resistant screw cap, supplied in packs of 30 tablets. 30-tablet HDPE bottle          NDC 54868-5261-0 Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. Rx only Distributed by Pfizer       Pharmacia & Upjohn Company                  Division of Pfizer Inc., NY, NY    10017

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. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. 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. Pharmacokinetics Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean t max of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL). Absorption Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast. 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 α 1 -acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible. Metabolism and Excretion Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. Exemestane is 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 inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity (see Pharmacodynamics, Other Endocrine Effects ). Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Special Populations Geriatric Healthy postmenopausal women aged 43 to 68 years were studied 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) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years). Race The influence of race on exemestane pharmacokinetics has not been evaluated. Hepatic Insufficiency The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers (see PRECAUTIONS ). Renal Insufficiency The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance less than 35 mL/min/1.73 m 2 ) compared with the AUC in healthy volunteers (see PRECAUTIONS ). Pediatric The pharmacokinetics of exemestane have not been studied in pediatric patients. Drug-Drug Interactions Exemestane is metabolized by cytochrome P-450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. In a clinical pharmacokinetic study, ketoconazole showed no significant influence on the pharmacokinetics of exemestane. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isoenzymes inhibitors appear unlikely. In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma C max and AUC 0–∞ of exemestane were decreased by 41% and 54%, respectively (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Pharmacodynamics Effect on Estrogens Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days. Effect on Corticosteroids In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment. Other Endocrine Effects Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100-times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH)]. Coagulation and Lipid Effects In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT] and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo.

Adjuvant Treatment in Early Breast Cancer The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) versus tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive 3 to 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormonal therapy. The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to AROMASIN rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause. The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated. A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to AROMASIN (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 1. Prior breast cancer therapy is summarized in Table 2. Table 1. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane Tamoxifen Age (years): (N = 2352) (N = 2372) Median age (range)                            63.0 (38.0 - 96.0) 63.0 (31.0 - 90.0) Race, n (%): Caucasian 2315 (98.4) 2333 (98.4) Hispanic 13 (0.6) 13 (0.5) Asian 10 (0.4) 9 (0.4) Black 7 (0.3) 10 (0.4) Other/not reported 7 (0.3) 7 (0.3) Nodal status, n (%): Negative 1217 (51.7) 1228 (51.8) Positive 1051 (44.7) 1044 (44.0)    1-3 Positive nodes 721 (30.7) 708 (29.8)    4-9 Positive nodes 239 (10.2) 244 (10.3)    Greater than 9 Positive nodes 88 (3.7) 86 (3.6)    Not reported 3 (0.1) 6 (0.3) Unknown or missing 84 (3.6) 100 (4.2) Histologic type, n (%): Infiltrating ductal 1777 (75.6) 1830 (77.2) Infiltrating lobular 341 (14.5) 321 (13.5) Other 231 (9.8) 213 (9.0) Unknown or missing 3 (0.1) 8 (0.3) Receptor status (*), n (%): ER and PgR Positive 1331 (56.6) 1319 (55.6) ER Positive and PgR Negative/Unknown 677 (28.8) 692 (29.2) ER Unknown and PgR Positive (**)/Unknown 288 (12.2) 291 (12.3) ER Negative and PgR Positive 6 (0.3) 7 (0.3) ER Negative and PgR Negative/Unknown (none positive) 48 (2.0) 58 (2.4) Missing 2 (0.1) 5 (0.2) Tumor Size, n (%): Less than or equal to 0.5 cm 58 (2.5) 46 (1.9) Greater than 0.5 - 1.0 cm 315 (13.4) 302 (12.7) Greater than 1.0 - 2 cm 1031 (43.8) 1033 (43.5) Greater than 2.0 - 5.0 cm 833 (35.4) 883 (37.2) Greater than 5.0 cm 62 (2.6) 59 (2.5) Not reported 53 (2.3) 49 (2.1) Tumor Grade, n (%): G1 397 (16.9) 393 (16.6) G2 977 (41.5) 1007 (42.5) G3 454 (19.3) 428 (18.0) G4 Unknown/Not Assessed/Not reported 23 (1.0 501 (21.3) 19 (0.8) 525 (22.1) (*)    Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization. (**)  Only one subject in the exemestane group had unknown ER status and positive PgR status. Table 2. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane (N = 2352) Tamoxifen (N = 2372) Type of surgery, n (%): Mastectomy 1232 (52.4) 1242 (52.4) Breast-conserving 1116 (47.4) 1123 (47.3) Unknown or missing 4 (0.2) 7 (0.3) Radiotherapy to the breast, n (%): Yes 1524 (64.8) 1523 (64.2) No 824 (35.5) 843 (35.5) Not reported 4 (0.2) 6 (0.3) Prior therapy, n (%): Chemotherapy 774 (32.9) 769 (32.4) Hormone replacement therapy 567 (24.1) 561 (23.7) Bisphosphonates 43 (1.8) 34 (1.4) Duration of tamoxifen therapy at randomization months: Median (range) 28.5 (15.8 - 52.2) 28.4 (15.6 - 63.0) Tamoxifen dose, n (%): 20 mg 2270 (96.5) 2287 (96.4) 30 mg (*) 78 (3.3) 75 (3.2) Not reported 4 (0.2) 10 (0.4) (*)   The 30 mg dose was used only in Denmark, where this dose was the standard of care. After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the AROMASIN group and 307 in the tamoxifen group (Table 3). Table 3. Primary Endpoint Events (ITT Population) Event First Event N (%) Exemestane (N = 2352) Tamoxifen (N = 2372) Loco-regional recurrence 34 (1.4) 45 (1.90) Distant recurrence 126 (5.36) 183 (7.72) Second primary - contralateral breast cancer 7 (0.30) 25 (1.05) Death - breast cancer 1 (0.04 6 (0.25) Death - other reason 41 (1.74) 43 (1.81) Death - missing/unknown 3 (0.13) 5 (0.21) Ipsilateral breast cancer 1 (0.04) 0 Total number of events 213 (9.06) 307 (12.94) Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 4, Figure 1] in the AROMASIN arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the AROMASIN arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the AROMASIN group and 137 in the tamoxifen group. Table 4. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer Hazard Ratio p-value ITT Population (95% CI) (log-rank test) Disease free survival 0.69 (0.58 - 0.82) 0.00003 Time to contralateral breast cancer 0.32 (0.15 - 0.72) 0.00340 Distant recurrence free survival 0.74 (0.62 - 0.90) 0.00207 Overall survival 0.86 (0.67 - 1.10) 0.22962 ER and/or PgR positive Disease free survival 0.65 (0.53 - 0.79) 0.00001 Time to contralateral breast cancer 0.22 (0.08 - 0.57) 0.00069 Distant recurrence free survival 0.73 (0.59 - 0.90) 0.00367 Overall survival 0.88 (0.67 - 1.17) 0.37460 Figure 1. Disease Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) image of Figure 1.Disease Free Survival graph

AROMASIN Tablets image of 25 mg package label