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 (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 (14.2).

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

For patients receiving EXEMESTANE with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of EXEMESTANE 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 Use In Specific Populations (8.5 and 8.6)].

4.1 Hypersensitivity

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

4.2 Pregnancy

EXEMESTANE can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action EXEMESTANE is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, EXEMESTANE was embryotoxic, fetotoxic, and abortifacient.

EXEMESTANE is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

EXEMESTANE tablets should not be administered to premenopausal women [see Use in Specific Populations (8.1)].

5.1 Administration with Estrogen-Containing Agents

EXEMESTANE should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

5.2 Laboratory Tests

In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥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 > 5 times the upper value of the normal range (i.e., ≥ 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 EXEMESTANE 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 Intergroup EXEMESTANE Study (IES), and in 6.9% of EXEMESTANE treated patients vs. 0% of placebo treated patients in 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 in 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 in study 027.

5.3 Reductions in Bone Mineral Density (BMD)

Reductions in bone mineral density (BMD) over time are seen with EXEMESTANE use. Table 1 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.

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 nd may not reflect the rates observed in clinical practice.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of EXEMESTANE. Because 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.

Cases of hepatitis including cholestatic hepatitis have been observed in clinical trials and reported through post-marketing surveillance.

7.1 Drugs That Induce CYP 3A4

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 Cmax and AUC 0–∞ of EXEMESTANE were decreased by 41% and 54%, respectively.

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 (2.2)].

7.2 Drugs That Inhibit CYP 3A4

In a clinical pharmacokinetic study, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on EXEMESTANE pharmacokinetics. Although no other formal drug-drug interaction studies have been conducted, significant effects on EXEMESTANE clearance by CYP isoenzyme inhibitors appear unlikely.

8.1 Pregnancy

8.3 Nursing Mothers

EXEMESTANE 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 14C-EXEMESTANE. It is not known whether EXEMESTANE is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reaction in nursing infants from EXEMESTANE, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

The use of EXEMESTANE in geriatric patients does not require special precautions.

8.6 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.

8.7 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 <35 mL/min/1.73 m2) 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.

12.1 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.

12.2 Pharmacodynamics

12.3 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 -tmax 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).

13.1 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 AUC (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 ≥500 mg/kg/day EXEMESTANE (≥200 times the recommended human dose on a mg/m2 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 ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 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/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥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/m2 basis.

14.1 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) vs. 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 an additional 3 or 2 years of EXEMESTANE 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 EXEMESTANE 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 EXEMESTANE (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 5. Prior breast cancer therapy is summarized in Table 6.

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 EXEMESTANE group and 307 in the tamoxifen group (Table 7).

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 8, Figure 1] in the EXEMESTANE 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 EXEMESTANE 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 EXEMESTANE group and 137 in the tamoxifen group.

Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

14.2 Treatment of Advanced Breast Cancer

EXEMESTANE 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive EXEMESTANE tablets 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.

The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that EXEMESTANE was not different from megestrol acetate. Response rates for EXEMESTANE from the two single-arm trials were 23.4% and 28.1%.

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

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

17.1 Premenopausal Women

Patients should be advised that EXEMESTANE is not for use in premenopausal women.

17.2 Other Estrogen-Containing Agents

Patients should be informed that they should not take estrogen-containing agents while they are taking EXEMESTANE as these could interfere with its pharmacologic action.

17.3 Bone Effects

Patients should be informed that EXEMESTANE lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of osteoporosis and fracture.