Aromasin 25 mg

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.

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

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.

A total of 1058 patients 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%).

Among the most frequently reported serious post-market adverse events/illnesses in clinical trial and non-clinical trial cases were cerebrovascular accident, pulmonary embolus, cardiac failure, deep vein thrombosis, and myocardial infarction. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a casual relationship to AROMASIN exposure. Carpal tunnel syndrome has also been frequently reported as a post-marketing adverse drug reaction. Rare cases of hepatitis including cholestatic hepatitis have been observed in clinical trials and reported through post-marketing surveillance. Also, 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. Increase in liver enzymes was not due to liver or bone metastases and normalization of liver enzyme values post discontinuation of drug has been observed. Severe cutaneous reactions erythema multiforme and acute generalized exanthematus pustulosis have also been reported in association with AROMASIN.

In the overall clinical trials program (N=1058), adverse events reported in 5% or greater of patients treated with AROMASIN 25 mg once daily included pain at tumor site (8%), asthenia 5.8%) and fever (5%). Less frequent adverse events (2% to 5%) reported in all patients receiving AROMASIN 25 mg once daily were 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.

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

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 Action and Clinical Pharmacology). AROMASIN should be used with caution in patients with hepatic impairment (see Adverse Reactions, Post-Market Adverse Drug Reactions).

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.

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).

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.

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

AROMASIN (exemestane) Tablets might cause fetal harm when administered to a pregnant woman. 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 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.

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).

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.

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).

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). Physicians should continue their routine practice of checking lipid levels on a regular basis.

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.

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. 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)].

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.

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 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. 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.

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. 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.

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.

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.

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.

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).

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.

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.

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (C_max) 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 T_max 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.

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.

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

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.

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).

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 C_max 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.

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