Aromasin (exemestane 25 mg) Dailymed

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 5.

Table 5. 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)	Megestrol Acetate(N = 403)
Median Age (range)	65 (35-89)	65 (30-91)
ECOG Performance Status  0  1  2	167 (46%)162 (44%)34 (9%)	187 (46%)172 (43%)42 (10%)
Receptor Status  ER and/or PgR +  ER and PgR unknown    Responders to prior tamoxifen    NE for response to prior tamoxifen	246 (67%)116 (32%)68 (19%)46 (13%)	274 (68%)128 (32%)85 (21%)41 (10%)
Site of Metastasis  Visceral + other sites  Bone only  Soft tissue only  Bone & soft tissue	207 (57%)61 (17%)54 (15%)43 (12%)	239 (59%)73 (18%)51 (13%)38 (9%)
Measureable Disease	287 (78%)	314 (78%)
Prior Tamoxifen Therapy  Adjuvant or Neoadjuvant  Advanced Disease, Outcome    CR, PR or SD greater than or equal to 6 months    SD less than months, PD or NE	145 (40%) 179 (49%)42 (12%)	152 (38%) 210 (52%)41 (10%)
Prior Chemotherapy  For advanced disease + adjuvant  Adjuvant only  No chemotherapy	58 (16%)104 (28%)203 (56%)	67 (17%)108 (27%)226 (56%)

The efficacy results from the comparative study are shown in Table 6. 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 6. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy

Response Characteristics	AROMASIN(N =366)		Megestrol Acetate(N=403)
Objective Response Rate = CR + PR (%)	15.0		12.4
          Difference in Response Rate (AR-MA)          95% C.I.		2.67.5, -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)          Hazard Ratio (AR-MA)	20.3	0.84	16.6

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
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

Indications And Usage

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.

Contraindications

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

Warnings

AROMASIN Tablets may cause fetal harm when administered to a pregnant woman. 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).

There are no studies in pregnant women using AROMASIN. AROMASIN is indicated for postmenopausal women. If there is exposure to AROMASIN during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.

Precautions

Adverse Reactions

Adjuvant Treatment of Early Breast Cancer
AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (see CLINICAL STUDIES) 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).

Certain adverse events, expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checkul. 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 checkul without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations.

The median duration of adjuvant treatment was 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.

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 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 8.

Table 8. 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 Eventby MedDRA dictionary	AROMASIN25 mg daily(N=2252)		Tamoxifen20 mg daily† (N=2280)
Eye   Visual disturbances‡	5.0		3.8
Gastrointestinal   Nausea‡	8.5		8.7
General Disorders   Fatigue‡	16.1		14.7
Musculoskeletal   Arthralgia  Pain in limb  Back pain  Osteoarthritis	14.69.08.65.9		8.66.47.24.5
Nervous System   Headache‡  Dizziness‡	13.19.7		10.88.4
Psychiatric   Insomnia‡  Depression	12.46.2		8.95.6
Skin & Subcutaneous Tissue   Increased sweating‡	11.8		10.4
Vascular   Hot flushes‡  Hypertension	21.29.8		19.98.4

*   Graded according to Common Toxicity Creiteria;†   75 patients received tamoxifen 30 mg daily;‡   Event actively sought.
In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in the musculoskeletal disorders and in the nervous system disorders, including the following events occurring with frequency lower than 5% (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% versus less than 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 on study 027 are described in Table 9.

Table 9: Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm on Study 027

Adverse Event	ExemestaneN=73(% incidence)	PlaceboN=73(% incidence)
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

*    Most events were CTC grade 1-2 Treatment of Advanced Breast Cancer
A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Exemestane was generally well tolerated, and adverse events were usually mild to moderate. 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%). The proportion of patients experiencing an excessive weight gain (greater than 10% of their baseline weight) was significantly higher with megestrol acetate than with AROMASIN (17% vs. 8%). Table 10 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 10. 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 ARTdictionary	AROMASIN25 mgonce daily(N=358)	Megestrol Acetate40 mg QID(N=400)
Autonomic Nervous  Increased sweating	6	9
Body as a Whole  Fatigue  Hot flashes  Pain  Influenza-like symptoms  Edema (includes edema, peripheral edema, leg edema)	22131367	2961356
Cardiovascular  Hypertension	5	6
Nervous  Depression  Insomnia  Anxiety  Dizziness  Headache	13111088	991167
Gastrointestinal  Nausea  Vomiting  Abdominal pain  Anorexia  Constipation  Diarrhea  Increased appetit	18766543	124115856
Respiratory  Dyspnea  Coughing	106	157

*    Graded according to Common Toxicity Criteria
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.
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.

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

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.

Dosage And Administration

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).

How Supplied

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].

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