Exemestane

Roxane Laboratories, Inc
Roxane Laboratories, Inc

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Exemestane Tablets safely and effectively. See full prescribing information for Exemestane Tablets. Exemestane Tablets, oralInitial U.S. Approval: 1999RECENT MAJOR CHANGESWarnings and Precautions, Vitamin D Assessment (5.4) 02/2013 INDICATIONS AND USAGEExemestane Tablets are an aromatase inhibitor 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). •treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (14.2). DOSAGE AND ADMINISTRATIONOne 25 mg tablet once daily after a meal (2.1). DOSAGE FORMS AND STRENGTHSTablets: 25 mg CONTRAINDICATIONS •Patients with a known hypersensitivity to the drug or to any of the excipients (4.1). •Women of premenopausal endocrine status, including pregnant women (4.2). WARNINGS AND PRECAUTIONS •Reductions in bone mineral density (BMD) over time are seen with exemestane use (5.3). •Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed (5.4).   Side Effects •Early breast cancer: Adverse events occurring in ≥10% of patients in any treatment group (exemestane vs. tamoxifen) were hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane and tamoxifen (6.3% vs. 5.1%). Incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane 0.4%, tamoxifen 0.3% (6, 6.1). •Advanced breast cancer: Most common adverse events were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively (6, 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS •CYP 3A4 inducers: Caution, may significantly decrease exposure to exemestane (2.2, 7.1). •CYP 3A4 inhibitors: Significant pharmacokinetic interactions appear unlikely (7.2). USE IN SPECIFIC POPULATIONS •Hepatic impairment: No dose adjustment required. The safety of chronic dosing in patients with moderate or severe hepatic impairment has not been studied (8.6). •Renal impairment: No dose adjustment required. The safety of chronic dosing in patients with moderate or severe renal impairment has not been studied (8.7).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 EXEMESTANE INDICATIONS AND USAGE
  • 1.1 Adjuvant Treatment of Postmenopausal Women
  • 1.2 Advanced Breast Cancer in Postmenopausal Women
• 2 EXEMESTANE DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dose
  • 2.2 Dose Modifications
• 3 DOSAGE FORMS AND STRENGTHS
• 4 EXEMESTANE CONTRAINDICATIONS
  • 4.1 Hypersensitivity
  • 4.2 Pregnancy
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Administration with Estrogen-Containing Agents
  • 5.2 Laboratory Tests
  • 5.3 Reductions in Bone Mineral Density (BMD)
• 6 EXEMESTANE ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
  • Adjuvant Therapy
  • Treatment of Advanced Breast Cancer
  • 6.2 Post-Marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Drugs That Induce CYP 3A4
  • 7.2 Drugs That Inhibit CYP 3A4
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Insufficiency
  • 8.7 Renal Insufficiency
• 10 OVERDOSAGE
• 11 EXEMESTANE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Adjuvant Treatment in Early Breast Cancer
  • 14.2 Treatment of Advanced Breast Cancer
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Premenopausal Women
  • 17.2 Other Estrogen-Containing Agents
  • 17.3 Bone Effects
• PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 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 [see Clinical Studies (14.1)].

1.2 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 [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 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 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 tablets with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of exemestane tablets 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 Population s (8.6 and 8.7)].

3 DOSAGE FORMS AND STRENGTHS

Exemestane Tablets are round, white film coated, biconvex tablets, debossed with product identification "54 571" on one side and plain on the other side. Each tablet contains 25 mg of exemestane.

4 CONTRAINDICATIONS

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 Tablets may 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 Tablets are 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 WARNINGS AND PRECAUTIONS

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% 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.

Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D.

6 ADVERSE REACTIONS

Exemestane was generally well tolerated and adverse events were usually mild to moderate.

In the adjuvant treatment of early breast cancer, adverse events occurring in ≥10% of patients in any treatment group (exemestane vs. tamoxifen) were hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane and tamoxifen (6.3% vs. 5.1%). Incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane 0.4%, tamoxifen 0.3%.

In the treatment of advanced breast cancer, the most common adverse events were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively.

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 practice.

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 and may not reflect the rates observed in clinical practice.

Adjuvant Therapy

The data described below reflect exposure to exemestane in 2325 postmenopausal women with early breast cancer. Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) 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 or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane 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 events, 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.

Exemestane was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving exemestane and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027.

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.

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.

Table 2. Incidence (%) of Adverse Events of all GradesGraded 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

	% of patients
Body system and Adverse Event by MedDRA dictionary	Exemestane 25 mg daily (N=2252)	Tamoxifen 20 mg daily 75 patients received tamoxifen 30 mg daily; (N=2280)
Eye
5	3.8
Gastrointestinal
8.5	8.7
General Disorders
16.1	14.7
Musculoskeletal
14.6	8.6
9.0	6.4
8.6	7.2
5.9	4.5
Nervous System
13.1	10.8
9.7	8.4
Psychiatric
12.4	8.9
6.2	5.6
Skin & Subcutaneous Tissue
11.8	10.4
Vascular
21.2	19.9
9.8	8.4

In the IES study, as compared to tamoxifen, exemestane was 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 [4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs. 0 for both events], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]. Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). 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 group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on exemestane 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 [3.1% vs. 1.5%], thromboembolism [2% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%].

Common adverse events occurring in study 027 are described in Table 3.

Table 3. Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm in Study 027

* Most events were CTC grade 1 to 2

Treatment of Advanced Breast Cancer

A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Only 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, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%).

In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or megestrol acetate.

Table 4. Incidence (%) of Adverse Events of all Grades* and Causes Occurring in ≥5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study

Less frequent adverse events 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.

Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). Adverse events 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.

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.

Cases of hypersensitivity, urticaria, and pruritus have been reported.

7 DRUG INTERACTIONS

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 C_max 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X.

See “Contraindications” section.

Exemestane can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Exemestane tablets are contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of exemestane in pregnant women.

In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to ¹⁴C-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. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m² basis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m² 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/m² basis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m² basis).

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.

8.3 Nursing Mothers

Exemestane Tablets are 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.

10 OVERDOSAGE

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/mm³ 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/m² basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m² basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m² basis), respectively.

Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m² basis), respectively.

11 DESCRIPTION

Exemestane 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 C₂₀H₂₄O₂ and its structural formula is as follows: