AROMASIN (exemestane) Warnings And Precautions

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).

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.