PRODUCT MONOGRAPH PrAROMASIN* exemestane Tablets, 25 mg Professed Standard Aromatase Inactivator; Anti-Tumour Agent Pfizer Canada Inc. Date of Revision: 17,300 Trans-Canada Highway March 6, 2018 Kirkland, Quebec H9J 2M5 Submission Control No: 204398 * TM Pfizer Enterprises SARL Pfizer Canada Inc., Licensee ©Pfizer Canada Inc 2018 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................3 WARNINGS AND PRECAUTIONS ..................................................................................4 ADVERSE REACTIONS ....................................................................................................8 DRUG INTERACTIONS ..................................................................................................15 DOSAGE AND ADMINISTRATION ..............................................................................15 OVERDOSAGE ................................................................................................................16 ACTION AND CLINICAL PHARMACOLOGY ............................................................16 STORAGE AND STABILITY ..........................................................................................18 SPECIAL HANDLING INSTRUCTIONS .......................................................................19 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................19 PART II: SCIENTIFIC INFORMATION ...............................................................................20 PHARMACEUTICAL INFORMATION ..........................................................................20 CLINICAL TRIALS ..........................................................................................................21 DETAILED PHARMACOLOGY .....................................................................................33 TOXICOLOGY .................................................................................................................36 REFERENCES ..................................................................................................................40 PART III: CONSUMER INFORMATION...............................................................................44 AROMASIN (exemestane) Product Monograph Page 2 of 46 AROMASIN exemestane PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form / Clinically Relevant Nonmedicinal Administration Strength 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. AROMASIN (exemestane) Product Monograph Page 3 of 46 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 AROMASIN (exemestane) Product Monograph Page 4 of 46 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.