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AROMASIN (exemestane)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

tablet 25 mg

Not applicable.

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

AROMASIN (exemestane) is indicated for the sequential adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer who have received 2-3 years of initial adjuvant tamoxifen therapy.

Approval is based on improved disease-free survival for sequential AROMASIN in comparison to continuous tamoxifen.  However, overall survival was not significantly different between the two treatments (see PART II, CLINICAL TRIALS). 

AROMASIN (exemestane) is also indicated for hormonal treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status whose disease has progressed following antiestrogen therapy. 

Contraindications

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

Warnings And Precautions

Serious Warnings and Precautions

Aromasin should be administered under the supervision of a qualified physician experienced in the use of anti-cancer agents.

  • Not recommended for use in pre-menopausal women (see General section below)
  • Osteoporosis (see Musculoskeletal section below).

General:

AROMASIN should not be administered to women with premenopausal endocrine status as safety and efficacy have not been established in these patients. AROMASIN should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

Drug Interactions
In patients receiving tamoxifen and warfarin concurrently, re-titration of the warfarin dose may be required following the switch from tamoxifen to exemestane. Possible interaction between tamoxifen and warfarin that required dose adjustments have been described. As a result, patients on warfarin treatment were excluded from the IES trial because the risk of experiencing a coagulation problem in switching from previous tamoxifen to exemestane could not be excluded. Although a potential interaction between warfarin and exemestane has not been studied clinically, in vitro studies have demonstrated that exemestane does not inhibit the activity of CYP2C9 (enzyme responsible for the metabolism of s-warfarin) and exemestane is not anticipated to alter the pharmacokinetics of warfarin. Therefore, the dosage of warfarin should be controlled by periodic determinations of prothrombin times (PT) ratio/International Normalized Ratio (INR) or other suitable coagulation tests at the time of switch from tamoxifen to exemestane as per recommendations in the warfarin Product Monograph

Effects on Coagulation
To date, there is no indication that exemestane affects antithrombin III. Some steroidal compounds are known to affect antithrombin III, increasing the risk of thromboembolic events. Preclinical data evaluating exemestane’s potential to affect antithrombin III is not available; however, studies in humans are ongoing. In a study in postmenopausal women with early breast cancer at low risk treated with exemestane (n=73) or placebo (n=73) (Study 027), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT] and fibrinogen.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In a carcinogenicity study conducted in rats, exemestane was administered by gavage at doses of 30, 100 and 315 mg/kg/day for 92 weeks in males and 104 weeks in females. No evidence of carcinogenic activity was observed in female rats. The male rat study was inconclusive since it was terminated prematurely at Week 92.

In a 2-year carcinogenicity study in mice, exemestane, dosed at 50, 150 and 450 mg/kg/day, induced an increased incidence of hepatocellular adenomas and carcinomas at the high dose in both sexes. An increased incidence of renal tubular adenomas was also observed in male mice at the high dose. Plasma levels in male and female mice at the high dose were approximately 34 and 75-fold higher than the AUC in postmenopausal patients at the therapeutic dose. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. (see Toxicology: Carcinogenicity).

Cardiovascular disease

The use of aromatase inhibitors, including AROMASIN, may increase the risk of ischemic cardiovascular diseases. During the Intergroup Exemestane Study (IES), more patients receiving exemestane were reported to have ischemic cardiac events (myocardial infarction, angina, and myocardial ischemia) compared to patients receiving tamoxifen (treatment-emergent cases: 2.0% versus 1.3%; all-cases [either on treatment or during follow up]: 5.8% versus 3.8%). In addition, a larger number of events were reported for exemestane in comparison to tamoxifen for some individual treatment-emergent cardiovascular events including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). Women with significant cardiac disorders were excluded from the clinical studies of exemestane in early breast cancer.

Endocrine and Metabolism

The use of aromatase inhibitors, including AROMASIN, may increase the occurrence of hypercholesterolemia. During the IES study, more patients receiving exemestane were reported to have treatment-emergent hypercholesterolemia compared to patients receiving tamoxifen (3.7% vs. 2.1%, respectively).

In a study in postmenopausal women with early breast cancer at low risk treated with exemestane (n=73) or placebo (n=73) (Study 027) plasma HDL cholesterol was decreased 6-9% in exemestane-treated patients; total cholesterol, LDL-cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was observed in exemestane-treated patients compared with a 12% increase seen with placebo. Exemestane induced a significant increase in both bone formation and bone resorption markers [bone-specific alkaline phosphatase (BAP), serum procollagen type I N propeptide (PINP) and serum osteocalcin; serum and urinary C-terminal cross-linked telopeptide of type 1 collagen (CTX-I), and urinary N-terminal cross-linked telopeptide of type I collagen (NTX-I)].

Gastrointestinal

The use of AROMASIN may increase the risk of gastric ulcer. In the early breast cancer IES trial, gastric ulcer was observed at a slightly higher frequency in the exemestane arm compared to tamoxifen (0.7% versus <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.

Hematologic

In patients with early breast cancer (IES Study) 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 AROMASIN in clinical studies in advanced breast cancer, particularly those with pre-existing lymphocytopenia, experienced a moderate transient decrease in lymphocytes. However, mean lymphocyte values in these patients did not change significantly over time. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed.

Hepatic/Biliary/Pancreatic

In patients with early breast cancer, elevations in bilirubin and alkaline phosphatase were more common in those receiving exemestane than either tamoxifen or placebo. Treatment emergent bilirubin elevations occurred in 5.9% of exemestane-treated patients compared to 0.9% of tamoxifen-treated patients on the IES, and in 6.9% of exemestane-treated patients versus 0% of placebo-treated patients on the 027 study; CTC grade 3-4 increases in bilirubin occurred in 0.9% of exemestane-treated patients compared to 0.1% of tamoxifen-treated patients on the IES. Alkaline phosphatase elevations occurred in 15.9% of exemestane-treated patients compared to 3.1% of tamoxifen-treated patients on the IES, and in 13.7% of exemestane-treated patients compared to 6.9% of placebo-treated patients on Study 027.

In patients treated for advanced breast cancer, elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been reported rarely. These changes were mostly attributable to the underlying presence of liver and/or bone metastases. However, in the Phase III study in advanced breast cancer patients, elevation of the 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. Additionally, in post-market surveillance elevations of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range were not necessarily due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed.

Rare cases of hepatitis including cholestatic hepatitis have been observed in other clinical trials with additional reports identified through post-marketing surveillance.

Musculoskeletal

The use of estrogen lowering agents, including AROMASIN, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of fracture. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines. Women with clinical evidence of severe osteoporosis or a history of osteoporotic fracture were excluded from the clinical studies of exemestane in early breast cancer.

Reductions in BMD over time were seen with exemestane use in these clinical trials; Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027).

Table 1: Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control
 

IES

027

BMD

Exemestane

Tamoxifen

Exemestane

N=59

Placebo

N=65

Lumbar spine (%)

-3.68 (N=82)

-0.19 (N=94)

-3.51

-2.39

Femoral neck (%)

-3.96 (N=77)

-0.69 (N=87)

-4.57

-2.59

The use of aromatase inhibitors, including AROMASIN, may cause arthralgias and/or myalgias, which may impact on treatment compliance and quality of life.  In the IES study, 17.6% of patients in exemestane arm reported arthralgia as an adverse event versus 10.8% of patients in tamoxifen arm.  Arthralgia-related disorders such as arthralgia, back pain, and pain in limb led to study drug discontinuation more often in AROMASIN-treated patients than tamoxifen-treated patients (1.3% versus 0.3% of total patients treated, respectively).

Renal

In patients with early breast cancer, elevations in creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Creatinine elevations occurred in 6.4% of exemestane-treated patients versus 5.0% of tamoxifen-treated patients on the IES and in 5.5% of exemestane-treated patients versus 0% of placebo-treated patients on Study 027.

Skin

Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis (AGEP) have been reported in association with AROMASIN. The latency of AGEP was 2 weeks after starting exemestane treatment, which is consistent with the temporal pattern of drug-related AGEP. Patients that experience severe cutaneous reactions should permanently discontinue AROMASIN.

Special population

Pregnant Women:

AROMASIN (exemestane) should not be used in women who are or may become pregnant because it may cause harm to the fetus. Exemestane caused placental enlargement, dystocia, and prolonged gestation when given to pregnant rats at doses greater than 4 mg/kg/day (24 mg/m2/day), approximately 1.5 times the recommended human daily dose (16.0 mg/m2/day) on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using exemestane. 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 or the potential risk for loss of the pregnancy.

Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. The administration of exemestane to pregnant rats at doses of 50 mg/kg/day during the organogenesis period caused an increase in fetal resorption, but there was no evidence of teratogenicity up to the dose of 810 mg/kg/day (4860 mg/m2/day).

Daily doses of exemestane 270 mg/kg/day (4320 mg/m2/day), which is greater than 200 times the recommended human daily dose, given to rabbits during organogenesis caused abortions, an increase in resorptions, and a reduction in fetal body weight; there was no increase in the incidence of malformations (see TOXICOLOGY: Reproduction and Teratology).

Hepatic Impairment:

Following a single 25-mg oral dose, the AUC of exemestane in patients with hepatic dysfunction (moderate hepatic impairment, Child Pugh B; severe hepatic impairment, Child Pugh C) was approximately 3 times higher than that observed in healthy volunteers. However, no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25 mg daily dose (see ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m2) compared with the AUC in healthy volunteers. However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see ACTION AND CLINICAL PHARMACOLOGY).

Nursing Women:

Although it is not known whether exemestane is excreted in human milk, the drug was shown to be excreted in the milk of lactating rats. Because there is a potential for serious adverse reactions in nursing infants, nursing should be discontinued when receiving therapy with AROMASIN.

Pediatrics:

The safety and effectiveness of AROMASIN in pediatric patients have not been established.

Geriatrics:

Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range (see ACTION AND CLINICAL PHARMACOLOGY).

Monitoring and Laboratory Tests:

Women should have their cholesterol levels and osteoporosis risks assessed and managed according to current clinical practice and guidelines.

Adverse Reactions

Adjuvant Treatment of Early Breast Cancer

Adverse Drug Reaction Overview:

AROMASIN (exemestane) Tablets tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the Intergroup Exemestane Study 031 (IES) (see CLINICAL STUDIES) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group, phase II 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 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.

The median duration of adjuvant treatment was 30.0 months and 29.9 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 at the time of primary analysis, for AROMASIN was 40.4 months and for tamoxifen 39.1 months; and at the time of the updated analysis for AROMASIN was 53.6 months and for tamoxifen 51.6 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 7.4% and 6.2% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo within Study 027. Within the IES study, the most commonly reported adverse reactions were hot flushes (AROMASIN 22%; tamoxifen 20%), arthralgias (AROMASIN 18%; tamoxifen 11%), and fatigue (AROMASIN 16%; tamoxifen 15%). On-treatment deaths due to any cause were reported for 1.5% of the exemestane-treated patients, and 1.5% of the tamoxifen-treated patients within the IES study. There were 6 on-treatment deaths due to stroke and 3 due to cardiac failure in the AROMASIN-treated patients compared with 2 deaths due to stroke and 1 due to cardiac failure in the tamoxifen-treated patients. There were no deaths in Study 027.

Clinical Trial Adverse Drug Reactions:

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 Grades1 and Illnesses Occurring in ≥ 5% of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer
1
Graded according to Common Toxicity Criteria;
2
75 patients received tamoxifen 30 mg daily;
3
Event actively sought

% of patients

Body system and Adverse Event by MedDRA dictionary

AROMASIN

25 mg daily
(N=2249)

Tamoxifen

20 mg daily2
(N=2279)

Gastrointestinal disorders

Nausea3

8.9

9.1

General disorders and administration site conditions

Fatigue3

16.3

15.1

Investigations

Weight increased

5.7

6.1

Musculoskeletal and connective tissue disorders

Arthralgia

17.6

10.8

Pain in limb

6.4

4.7

Back pain

9.3

7.7

Osteoarthritis

6.1

4.7

Osteoporosis

5.2

2.9

Nervous system disorders

Headache3

13.6

11.2

Dizziness3

10.0

8.8

Psychiatric disorders

Insomnia3

12.9

9.0

Depression

6.2

5.6

Reproductive system and breast disorders

Vaginal hemorrhage

4.0

5.3

Skin and subcutaneous tissue disorders

Increased sweating3

12.0

10.6

Vascular

Hot flushes3

21.8

20.1

Hypertension3

9.9

8.4

In the IES study, more patients receiving exemestane were reported to have ischemic cardiac events (myocardial infarction, angina, and myocardial ischemia) compared to patients receiving tamoxifen (treatment-emergent cases: 2.0% versus 1.3%; all-cases [either on treatment or during follow up]: 5.8% versus 3.8%). No significant difference was noted for any individual treatment-emergent cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%). The proportion of patients reporting hypercholesterolemia was 3.7% in the AROMASIN-treated group versus 2.1% in the tamoxifen-treated group.

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%: paraesthesia (2.8% vs. 1.0%), carpal tunnel syndrome (2.8% vs. 0.2%) and neuropathy (0.5% vs. <0.1%).

AROMASIN was associated with a significantly higher incidence of gastric ulcer events in comparison to tamoxifen (0.7% vs. <0.1%). In addition, diarrhea was also more frequent in the AROMASIN group (4.2% vs. 2.2%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Clinical fractures were reported in 101 patients receiving exemestane (4.5%) and 75 patients receiving tamoxifen (3.3%).

Tamoxifen was associated with a greater incidence of muscle cramps (3.2% vs. 1.4%), uterine polyps (1.8% vs. 0.4%), venous thromboembolic disease (1.8% vs. 0.7%), endometrial hyperplasia (0.9% vs. <0.1%) and uterine polypectomy (0.8% vs. 0.2%).

A lower incidence of other second (non-breast) primary cancers was observed in the AROMASIN-treated patients versus tamoxifen-treated patients (3.6% vs. 5.3%) in the IES study.

Based on reports of adverse events in 73 postmenopausal women in each treatment group in the 027 study, Table 3 shows treatment-emergent adverse events including all causalities and occurring with an incidence of > 5% in either treatment group.

Table 3: Incidence (%) of Adverse Events of all Grades1 Occurring in ≥ 5% of Patients in either Treatment Group in Study 027
1
Graded according to Common Toxicity Criteria
 

% of patients

Body system and Adverse Event by MedDRA dictionary

AROMASIN

25 mg daily

(N=73)

Placebo

(N=73)

Gastrointestinal disorders

   

Nausea

12.3

16.4

Abdominal pain

11.0

13.7

Diarrhea

9.6

1.4

General disorders and administration site conditions

   

Fatigue

11.0

19.2

Musculoskeletal and connective tissue disorders

   

Arthralgia

28.8

28.8

Pain in limb

8.2

6.9

Myalgia

5.5

4.1

Tendonitis

5.5

5.5

Nervous system disorders

   

Dizziness

9.6

9.6

Headache

6.9

4.1

Psychiatric disorders

   

Insomnia

13.7

15.1

Depression

9.6

6.9

Anxiety

4.1

5.5

Infections and infestations

   

Urinary tract infection

8.2

8.2

Skin and subcutaneous tissue disorders

   

Increased sweating

17.8

20.6

Alopecia

15.1

4.1

Dermatitis

6.9

1.4

Vascular disorders

   

Hot flushes

32.9

24.7

Hypertension

15.1

6.9

Events were mostly grade 1 or 2 in severity for both AROMASIN and placebo treated patients.

Treatment of Advanced Breast Cancer after Failure on Tamoxifen:

Adverse Drug Reaction Overview:

A total of 1058 patients who had failed prior tamoxifen therapy were treated with AROMASIN (exemestane) Tablets 25 mg once daily in the clinical trials program. AROMASIN was generally well tolerated and adverse events were usually mild to moderate. Only one death was potentially related to treatment with AROMASIN; 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 2.8% of the patients discontinued treatment with AROMASIN because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations due to adverse events were uncommon (0.3%).

Clinical Trial Adverse Drug Reactions:

In the Phase III study, 358 patients were treated with AROMASIN and 400 patients were treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (1.7% versus 5%). Adverse events in the Phase III study that were considered drug related or of indeterminate cause included hot flashes (12.6%), nausea (9.2%), fatigue (7.5%), increased sweating (4.5%), and increased appetite (2.8%). The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17.1% versus 7.6%, p=0.001). The following table (Table 4) shows the adverse events of all National Cancer Institute (NCI) Common Toxicity grades regardless of causality reported in 5% or greater of patients in the Phase III study treated either with AROMASIN or megestrol acetate.

Table 4: Incidence (%) of Adverse Events of all NCI* Common Toxicity
Grades and Causes Occurring in >5% of Patients in the Phase III Study
*
NCI = National Cancer Institute

Event

AROMASIN

25 mg

once daily

(N=358)

Megestrol Acetate

40 mg QID (N=400)

Any Adverse Event

79.3

80

Skin and subcutaneous tissue disorders

   

Increased sweating

6.1

9.0

General Disorders and Administration Site Conditions

   

Fatigue

21.8

29.3

Pain

13.1

12.5

Influenza-like symptoms

5.9

5.3

Vascular disorders

   

Hypertension

Hot flushes

4.7

13.4

5.8

5.5

Psychiatric Disorders

   

Depression

12.8

8.8

Insomnia

10.9

9.0

Anxiety

10.1

10.8

Dizziness

8.1

5.8

Headache

8.1

6.5

Gastrointestinal disorders

   

Nausea

18.4

11.5

Vomiting

7.3

3.8

Abdominal pain

6.1

10.5

Anorexia

6.1

4.8

Constipation

4.7

8.0

Diarrhea

3.6

5.0

Metabolism and nutrition disorders

Increased appetite

2.8

5.8

Respiratory, thoracic and mediastinal disorders

   

Dyspnea

9.8

15.0

Coughing

5.9

7.0

In the overall clinical trials program for advanced cancer (N = 1058), additional adverse events reported in 5% or greater of patients treated with AROMASIN 25 mg once daily included pain at tumor site (8%), peripheral edema (7.6%), asthenia (5.8%) and fever (5%). Less frequent but common adverse events (1% to 5%) reported in these patients were liver enzyme abnormalities (AST, ALT, alkaline phosphatase), elevated bilirubin, arthralgia, peripheral edema, back pain, dyspepsia, paresthesia, bronchitis, rash, chest pain, edema, hypertension, upper respiratory tract infection, pruritus, urinary tract infection, pathological fracture, alopecia, leg edema, sinusitis, skeletal pain, infection, pharyngitis, rhinitis, hypoesthesia, confusion, and lymphedema.

Post-Market Adverse Drug Reactions

Post-market adverse events/illnesses include case observed in other clinical trials (not described above) as well as reports from post-marketing surveillance. Because these events are not uniformly reported, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to AROMASIN exposure. The following events are listed according to MedDRA system organ class.

Vascular disorders: Cerebrovascular accident, pulmonary embolus and deep vein thrombosis were among the most frequently reported adverse events/illnesses in the post-market setting.

Cardiac disorders: Cardiac failure and myocardial infarction have been reported in association with AROMASIN.

Nervous System disorders: Carpal tunnel and paraesthesia has been reported frequently in the post-market setting.

Hepatobilliary disorders: Rare cases of hepatitis including cholestatic hepatitis have been observed in other clinical trials with additional reports identified through post-marketing surveillance.

Investigations: ALT, AST, blood bilirubin and blood alkaline phosphatase increases that have been reported as common events above have also been reported as very common events in other clinical trials. Additionally, in post-market surveillance elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been observed. Increase in liver enzymes was not necessarily due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed.

Skin and subcutaneous tissue disorders: Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis have been reported in association with AROMASIN. Urticaria and pruritus have also been reported in association with AROMASIN.

Immune System disorders: Hypersensitivity, including anaphylactic reactions, has occurred between 8 hours to 26 days of starting exemestane therapy.

Drug Interactions

Drug-Drug Interactions:

In vitro evidence showed that AROMASIN (exemestane) is metabolized by cytochrome P450 (CYP) 3A4 and aldoketoreductases, and does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A.  In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 by ketoconazole administration showed no significant influence on the pharmacokinetics of exemestane.  Although pharmacokinetic effects were observed in a pharmacokinetic interaction study with rifampin, a potent CYP3A4 inducer, the suppression of plasma estrogen concentrations (estrone sulfate) produced by exemestane was not affected and a dosage adjustment is not required.

In patients receiving tamoxifen and warfarin concurrently, re-titration of the warfarin dose may be required following the switch from tamoxifen to exemestane.  Possible interaction between tamoxifen and warfarin that required dose adjustments have been described.  As a result, patients on warfarin treatment were excluded from the IES trial because the risk of experiencing a coagulation problem in switching from previous tamoxifen to exemestane could not be excluded.  Although a potential interaction between warfarin and exemestane has not been studied clinically, in vitro studies have demonstrated that exemestane does not inhibit the activity of CYP2C9 (enzyme responsible for the metabolism of s-warfarin) and exemestane is not anticipated to alter the pharmacokinetics of warfarin.  Therefore, the dosage of warfarin should be controlled by periodic determinations of prothrombin times (PT) ratio/International Normalized Ratio (INR) or other suitable coagulation tests at the time of switch from tamoxifen to exemestane as per recommendations in the warfarin Product Monograph.

Drug-Laboratory Interactions:

No clinically relevant changes in the results of clinical laboratory tests have been observed.

Dosage And Administration

Recommended Dose and Dosage Adjustment:

The recommended dose of AROMASIN (exemestane) Tablets in early and advanced breast cancer is 25 mg once daily after a meal.

In postmenopausal women with early breast cancer, treatment with AROMASIN should continue until completion of five years of adjuvant endocrine therapy, or until local or distant recurrence or new contralateral breast cancer.

In patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident. 

No dose adjustments are required for patients with hepatic or renal insufficiency.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Clinical trials have been conducted with AROMASIN (exemestane) Tablets given up to 800 mg as a single dose to healthy female volunteers and up to 600 mg daily for 12 weeks to postmenopausal women with advanced breast cancer. 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 rats and dogs, mortality was observed after single oral doses 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.

Action And Clinical Pharmacology

Mechanism of Action:

Breast cancer cell growth is often estrogen-dependent and anti-tumour activity is expected following effective and continuous estrogen suppression in patients with hormone-sensitive breast cancer. Aromatase is the key 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 (mainly androstenedione) to estrogens (primarily estrone) by the aromatase enzyme in peripheral tissues. This occurs mainly in the adipose tissue, but also in the liver, muscle, hair follicles, and breast tissue. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for postmenopausal patients with hormone-dependent breast cancer.

AROMASIN (exemestane) is a potent aromatase inactivator, causing estrogen suppression and inhibition of peripheral aromatisation. It is a steroidal irreversible Type I aromatase inhibitor, structurally related to the natural substrate androstenedione. Exemestane is a specific competitive inactivator of human placental aromatase, which has been shown to be more potent than the irreversible aromatase inhibitor formestane or the reversible inhibitor aminoglutethimide in vitro.

In vivo studies of aromatase inactivation indicate that exemestane, by the oral route, is several times more potent than formestane. 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”. De novo aromatase enzyme synthesis is required for recovery of enzyme activity.  Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Pharmacokinetics:

Absorption:

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (Cmax) was observed within 2 hours of receiving exemestane. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast; however, no further effect on estrogen suppression was observed since maximum activity was already achieved under fasting conditions. Exemestane appears to be more rapidly absorbed in women with breast cancer than in healthy women.  After repeated doses, mean Tmax was 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. Mean AUC values following repeated doses were approximately 2-fold higher in women with breast cancer (75.4 ng.h/mL) compared with healthy women (41.4 ng.h/mL).  However, there was considerable overlap between the range of pharmacokinetic parameters observed in these two populations. 

Distribution:

Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α1-acid glycoprotein contribute equally to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion:

After reaching maximum plasma concentration, exemestane levels declined polyexponentially with a mean terminal half-life of about 24 hours.  Following administration of a single oral dose of radiolabeled exemestane, the elimination of drug-related products was essentially complete within 1 week. Approximately equal proportions of the dose were eliminated in urine and feces. The amount of drug excreted unchanged in urine was less than 1% of the dose, indicating that renal excretion is a limited elimination pathway. Exemestane was extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites.  Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or demonstrate minimal ability to inhibit aromatase compared with the parent drug. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Additional studies in humans demonstrated that exemestane does not affect the activity of CYP3A4 to any great extent. No significant inhibition of any of the CYP isoenzymes (including CYP3A4) involved in xenobiotic metabolism was observed in human liver preparations. This would suggest that possible drug-drug interactions involving inhibition of CYP by co-administration with exemestane are unlikely.

Special Populations and Conditions:

Geriatrics:

Although women ranging in age up to 99 years were enrolled in the clinical studies (see WARNINGS AND PRECAUTIONS), healthy postmenopausal women aged 43 to 68 years were enrolled in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender:

The pharmacokinetics of exemestane following administration of a single, 25 mg tablet to fasted healthy males (mean age 32 years; range 19 to 51 years) or to fasted healthy postmenopausal women (mean age 55 years; range 45 to 68 years) have been compared. Mean Cmax and AUC values in healthy males (12.3 ± 5.8 ng/mL and 28.4 ± 17.3 ng.h/mL, respectively) were similar to those determined in healthy postmenopausal women (11.1 ± 4.4 ng/mL and 29.7 ± 7.8 ng.h/mL, respectively). Thus, the pharmacokinetics of exemestane does not appear to be influenced by gender.

Race:

The influence of race on exemestane pharmacokinetics has not been formally evaluated.

Hepatic Insufficiency:

The pharmacokinetics of exemestane have been investigated in subjects with moderate and severe hepatic insufficiency. Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25-mg daily dose (see WARNINGS AND PRECAUTIONS).

Renal Insufficiency:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m2) compared with the AUC in healthy volunteers.  However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see WARNINGS AND PRECAUTIONS).

Pediatrics:

The pharmacokinetics of exemestane have not been studied in pediatric patients.

Storage And Stability

Store between 15° to 30° C.

Special Handling Instructions

Not applicable.

Dosage Forms, Composition And Packaging

AROMASIN (exemestane) 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 supplied as follows:

HDPE bottles of 30 tablets with a child-resistant screw cap: 25 mg.
Aluminium-PVDC/PVC-PVDC opaque white blisters of 30 tablets: 25 mg.
Aluminium-PVDC/PVC-PVDC opaque white blisters of 15 tablets: 25 mg.

Composition:

AROMASIN Tablets for oral administration contain 25 mg of exemestane. Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hydroxypropyl methylcellulose, silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethyleneglycol 6000, sucrose, magnesium carbonate, titanium dioxide, methyl-p-hydroxybenzoate, polyvinyl alcohol, cetyl esters wax, talc, carnauba wax, shellac and iron oxides.

 

Control #: 204398
March 6, 2018

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