Label: AROMASIN- exemestane tablet
- NDC Code(s): 0009-7663-04
- Packager: Pharmacia and Upjohn Company
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
If you are a consumer or patient please visit this version.
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AROMASIN safely and effectively. See full prescribing information for AROMASIN.
AROMASIN® (exemestane) tablets, oral
Initial U.S. Approval: 1999
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
AROMASIN is 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 AROMASIN 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 ADMINISTRATION
One 25 mg tablet once daily after a meal (2.1).
DOSAGE FORMS AND STRENGTHS
Tablets: 25 mg (3)
WARNINGS AND PRECAUTIONS
- Early breast cancer: Adverse events occurring in ≥10% of patients in any treatment group (AROMASIN 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 AROMASIN and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 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 AROMASIN and megestrol acetate, respectively (6, 6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
1.1 Adjuvant Treatment of Postmenopausal Women
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 [see Clinical Studies (14.1)].
1.2 Advanced Breast Cancer in Postmenopausal Women
AROMASIN is 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 AROMASIN 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 AROMASIN 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.
- 3 DOSAGE FORMS AND STRENGTHS
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.Close
- 4 CONTRAINDICATIONS
AROMASIN Tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients.
AROMASIN may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action AROMASIN is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient.
AROMASIN 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.
AROMASIN 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
AROMASIN 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 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 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)
Table 1. Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control1 IES 027 BMD Exemestane
Lumbar spine (%) -3.14 -0.18 -3.51 -2.35 Femoral neck (%) -4.15 -0.33 -4.57 -2.59
5.4 Vitamin D Assessment
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
AROMASIN 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 (AROMASIN 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 AROMASIN and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 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 AROMASIN and megestrol acetate, respectively.
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.
The data described below reflect exposure to AROMASIN in 2325 postmenopausal women with early breast cancer. AROMASIN 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 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 for AROMASIN 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.
AROMASIN 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 AROMASIN 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 Grades* 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 AROMASIN
25 mg daily
20 mg daily†
Eye Visual disturbances‡ 5.0 3.8 Gastrointestinal Nausea‡ 8.5 8.7 General Disorders Fatigue‡ 16.1 14.7 Musculoskeletal Arthralgia 14.6 8.6 Pain in limb 9.0 6.4 Back pain 8.6 7.2 Osteoarthritis 5.9 4.5 Nervous System Headache‡ 13.1 10.8 Dizziness‡ 9.7 8.4 Psychiatric Insomnia‡ 12.4 8.9 Depression 6.2 5.6 Skin & Subcutaneous Tissue Increased sweating‡ 11.8 10.4 Vascular Hot flushes‡ 21.2 19.9 Hypertension 9.8 8.4
In the IES study, as compared to tamoxifen, AROMASIN 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 AROMASIN group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on AROMASIN 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 [2.0% 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 Adverse Event Exemestane
- Most events were CTC grade 1–2
Hot flushes 32.9 24.7 Arthralgia 28.8 28.8 Increased sweating 17.8 20.6 Alopecia 15.1 4.1 Hypertension 15.1 6.9 Insomnia 13.7 15.1 Nausea 12.3 16.4 Fatigue 11.0 19.2 Abdominal pain 11.0 13.7 Depression 9.6 6.9 Diarrhea 9.6 1.4 Dizziness 9.6 9.6 Dermatitis 8.2 1.4 Headache 6.9 4.1 Myalgia 5.5 4.1 Edema 5.5 6.9 Anxiety 4.1 5.5
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 AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving AROMASIN 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 AROMASIN 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 AROMASIN (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 AROMASIN 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 Body system and Adverse Event by WHO ART dictionary AROMASIN
40 mg QID (N=400)
- Graded according to Common Toxicity Criteria
Autonomic Nervous Increased sweating 6 9 Body as a Whole Fatigue 22 29 Hot flashes 13 6 Pain 13 13 Influenza-like symptoms 6 5 Edema (includes edema, peripheral edema, leg edema) 7 6 Cardiovascular Hypertension 5 6 Nervous Depression 13 9 Insomnia 11 9 Anxiety 10 11 Dizziness 8 6 Headache 8 7 Gastrointestinal Nausea 18 12 Vomiting 7 4 Abdominal pain 6 11 Anorexia 6 5 Constipation 5 8 Diarrhea 4 5 Increased appetite 3 6 Respiratory Dyspnea 10 15 Coughing 6 7
Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving AROMASIN 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 AROMASIN. 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.
Immune system disorders- hypersensitivity
Hepatobiliary disorders- hepatitis including cholestatic hepatitis
Nervous system disorders- paresthesia
Skin and subcutaneous tissue disorders- acute generalized exanthematous pustulosis, urticaria, pruritus
- 7 DRUG INTERACTIONS
Drugs That Induce CYP 3A4
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 strong CYP 3A4 inducer [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
- 8 USE IN SPECIFIC POPULATIONS
Pregnancy Category X. See "Contraindications" section.
AROMASIN can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. AROMASIN is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of AROMASIN 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
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 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 AROMASIN, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
8.6 Hepatic Impairment
The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C) [see Clinical Pharmacology (12.3)]. However, 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 Impairment
The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. However, 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.Close
- 11 DESCRIPTION
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 C20H24O2 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.Close
- 13 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
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 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 5. Prior breast cancer therapy is summarized in Table 6.
Table 5. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane
(N = 2352)
(N = 2372)
Age (years): 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) >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 (%): ≤ 0.5 cm 58 (2.5) 46 (1.9) > 0.5 – 1.0 cm 315 (13.4) 302 (12.7) > 1.0 – 2 cm 1031 (43.8) 1033 (43.5) > 2.0 – 5.0 cm 833 (35.4) 883 (37.2) > 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 23 (1.0) 19 (0.8) Unknown/Not Assessed/Not reported 501 (21.3) 525 (22.1) Table 6. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane
(N = 2352)
(N = 2372)
- The 30 mg dose was used only in Denmark, where this dose was the standard of care.
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)
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 7).
Table 7. Primary Endpoint Events (ITT Population) Event First Events
(N = 2352)
(N = 2372)
Loco-regional recurrence 34 (1.45) 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 8, 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 8. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer ITT Population Hazard Ratio
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)
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 AROMASIN (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.
Table 9. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy Parameter AROMASIN
(N = 366)
(N = 403)
Median Age (range) 65 (35–89) 65 (30–91) ECOG Performance Status 0 167 (46%) 187 (46%) 1 162 (44%) 172 (43%) 2 34 (9%) 42 (10%) Receptor Status ER and/or PgR + 246 (67%) 274 (68%) ER and PgR unknown 116 (32%) 128 (32%) Responders to prior tamoxifen 68 (19%) 85 (21%) NE for response to prior tamoxifen 46 (13%) 41 (10%) Site of Metastasis Visceral ± other sites 207 (57%) 239 (59%) Bone only 61 (17%) 73 (18%) Soft tissue only 54 (15%) 51 (13%) Bone & soft tissue 43 (12%) 38 (9%) Measurable Disease 287 (78%) 314 (78%) Prior Tamoxifen Therapy Adjuvant or Neoadjuvant 145 (40%) 152 (38%) Advanced Disease, Outcome CR, PR, or SD ≥ 6 months 179 (49%) 210 (52%) SD < 6 months, PD or NE 42 (12%) 41 (10%) Prior Chemotherapy For advanced disease ± adjuvant 58 (16%) 67 (17%) Adjuvant only 104 (28%) 108 (27%) No chemotherapy 203 (56%) 226 (56%)
The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that AROMASIN was not different from megestrol acetate. Response rates for AROMASIN from the two single-arm trials were 23.4% and 28.1%.
Table 10. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy Response Characteristics AROMASIN
Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = time to tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN Objective Response Rate = CR + PR (%) 15.0 12.4 Difference in Response Rate (AR-MA)
95% C.I. 7.5, -2.3 CR (%) 2.2 1.2 PR (%) 12.8 11.2 SD ≥ 24 Weeks (%) 21.3 21.1 Median Duration of Response (weeks) 76.1 71.0 Median TTP (weeks) 20.3 16.6 Hazard Ratio (AR-MA) 0.84
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.
Figure 2. Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy
- 16 HOW SUPPLIED/STORAGE AND HANDLING
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 0009-7663-04
Store at 25°C (77ºF); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].
- 17 PATIENT COUNSELING INFORMATION
17.1 Premenopausal Women
Patients should be advised that AROMASIN 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 AROMASIN as these could interfere with its pharmacologic action.
17.3 Bone Effects
Patients should be informed that AROMASIN 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.
Pharmacia & Upjohn Company
Division of Pfizer Inc, NY, NY 10017
- PATIENT PACKAGE INSERT
AROMASIN® (ah ROME ah sin)
Read the patient information leaflet that comes with AROMASIN before you start taking it. Read the leaflet each time you get a refill. There may be new information. This leaflet does not replace talking with your doctor about your condition or treatment. If you have any questions about AROMASIN, ask your nurse, doctor, or pharmacist.
What is AROMASIN?
AROMASIN is used in women who are past menopause. It is used in:
- Early breast cancer (cancer that has not spread outside the breast). AROMASIN lowers the risk the cancer will come back. It is for women who:
- Have cancer that needs the female hormone estrogen to grow and
- Had surgery for breast cancer, and possibly other treatments for breast cancer including radiation or chemotherapy and
- Have taken tamoxifen for 2 to 3 years and
- Are switching to AROMASIN to finish 5 years in a row of hormonal therapy.
- Advanced breast cancer (cancer that has spread), to treat cancer that came back after treatment with tamoxifen.
Certain breast cancers need the female hormone estrogen to grow (estrogen receptor-positive cancer).
While you are taking AROMASIN, your body stops making estrogen. AROMASIN may slow or stop the growth of the cancer.
AROMASIN is hormone therapy. It is not chemotherapy. It is not hormone replacement therapy (HRT).
Who should not take AROMASIN?
Do not take AROMASIN if:
- You are allergic to AROMASIN or anything in it. The active ingredient is exemestane. There is a list of what is in AROMASIN at the end of this leaflet.
What should I tell my doctor before taking AROMASIN?
Tell your doctor about all your medical conditions. Be sure to tell your doctor if you:
- Are still having menstrual periods (are not past menopause). AROMASIN is only for women who are past menopause.
- Are pregnant or could be pregnant. Taking AROMASIN during pregnancy may cause birth defects or miscarriage.
- Are breast-feeding. Do not breast-feed while you are being treated with AROMASIN.
- Have liver or kidney problems.
Tell your doctor about all the medicines you take. Include prescription and nonprescription medicines, herbal remedies, and vitamins. AROMASIN and other medicines may affect how each other work.
Be sure to tell your doctor if you take:
- Medicines with estrogen, such as Premarin®, other hormone replacement therapy, or birth control pills or patches. AROMASIN should not be taken with these medicines as they could affect how well AROMASIN works.
- Rifadin® (rifampin)
- Dilantin® (phenytoin), Tegretol® (carbamazepine), or Luminal® (phenobarbital)
- St. John's wort
Know what medicines you take. Keep a list of them with you. Show it to your doctor or pharmacist each time you get a new prescription.
What are the possible side effects of AROMASIN?
Serious Side Effects
- Bone loss. AROMASIN may reduce your bone mineral density (BMD) over time. This may raise your risk for bone fractures.
- Chest pain, heart failure, or stroke. A small number of women had chest pain, heart failure, or a stroke while taking AROMASIN.
Common Side Effects
- hot flashes
- difficulty in breathing
- feeling tired
- trouble sleeping
- feeling anxious
- joint pain
- increased sweating
- upset stomach
Your doctor may do blood tests to check your liver and kidney function during treatment.
These are not all the side effects with AROMASIN. Ask your cancer nurse or doctor for a more complete list.
How should I take AROMASIN?
- Take your dose of AROMASIN once a day, every day, after a meal. AROMASIN comes in 25mg tablets you take by mouth. Your doctor will tell you how many AROMASIN tablets to take for your dose.
- Try to take your treatment at the same time each day.
- Take your medicine for as long as your doctor tells you.
- Tell your doctor if you do not feel well after starting AROMASIN.
- If you miss a dose of AROMASIN, take it as soon as you remember. If it is close to your next dose, just take your next dose at your regular time.
- Don't take more than one dose of AROMASIN at a time.
- Make a note of when your prescription will run out. That way, you can get it refilled on time.
How should I store AROMASIN?
- Keep AROMASIN and all medicines out of the reach of children.
- Store AROMASIN at room temperature, 77°F (25°C), in its original container.
General information about AROMASIN
Doctors can prescribe medicines for conditions that are not in the patient information leaflet. Use AROMASIN only for what your doctor prescribed. Do not give it to other people, even if they have the same conditions you have. It may harm them.
This leaflet gives the most important information about AROMASIN. For more information about AROMASIN, talk with your doctor, nurse, or pharmacist. You can visit our Web site at www.AROMASIN.com, or call 1-888-AROMASIN (1-888-276-6274).
What is in AROMASIN?
Active ingredient: exemestane
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.
Pharmacia & Upjohn Company
Division of Pfizer Inc, NY, NY 10017
- Early breast cancer (cancer that has not spread outside the breast). AROMASIN lowers the risk the cancer will come back. It is for women who:
- PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label
- INGREDIENTS AND APPEARANCE
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0009-7663 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EXEMESTANE (UNII: NY22HMQ4BX) (EXEMESTANE - UNII:NY22HMQ4BX) EXEMESTANE 25 mg Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) CROSPOVIDONE (UNII: 68401960MK) POLYSORBATE 80 (UNII: 6OZP39ZG8H) HYPROMELLOSES (UNII: 3NXW29V3WO) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) SUCROSE (UNII: C151H8M554) MAGNESIUM CARBONATE (UNII: 0E53J927NA) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) METHYLPARABEN (UNII: A2I8C7HI9T) POLYVINYL ALCOHOL (UNII: 532B59J990) Product Characteristics Color WHITE (off-white to slighly gray) Score no score Shape ROUND Size 6mm Flavor Imprint Code 7663 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0009-7663-04 30 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020753 10/21/1999 Labeler - Pharmacia and Upjohn Company (829076566) Registrant - Pfizer Inc (113480771) Establishment Name Address ID/FEI Business Operations Pfizer Italia S.r.l. 431227388 ANALYSIS(0009-7663) , MANUFACTURE(0009-7663) Establishment Name Address ID/FEI Business Operations Olon, SpA 433371143 API MANUFACTURE(0009-7663) Establishment Name Address ID/FEI Business Operations Microchem S.r.l. 445019862 API MANUFACTURE(0009-7663)