MAR-ANASTROZOLE

2 Recommended Dose and Dosage Adjustment MAR-Anastrozole should be administered 1 mg orally, once a day. In the adjuvant setting, it is currently recommended that treatment be given for 5 years. Serious Warnings and Precautions • Not recommended for use in pre-menopausal women as safety and efficacy have not been established in these patients (see 10 CLINICAL PHARMACOLOGY).

3 Pharmacokinetics). • Potential risk/benefit should be carefully assessed in patients with osteoporosis or risk factors for osteoporosis (see Musculoskeletal).

MAR-Anastrozole (Anastrozole Tablets) Page 5 of 54 Pediatrics (< 18 years of age):

Health Canada has not authorized an indication for pediatric use for anastrozole.

Geriatrics (> 65 years of age):

No changes in dose are necessary for elderly patients (see 1 INDICATIONS).

Dose modification for Patients with Hepatic Impairment:

Although the apparent oral clearance of anastrozole was decreased in subjects with cirrhosis due to alcohol abuse, plasma anastrozole concentrations remained within the range seen across all clinical trials in subjects without liver disease.

Therefore, no changes in dose are recommended for patients with mild-to- moderate hepatic impairment, although patients should be monitored for side effects. Anastrozole has not been studied in patients with severe hepatic impairment.

3 Pharmacokinetics).

Dose modification for Patients with Renal Impairment:

No changes in dose are necessary for patients with renal impairment. 3 Pharmacokinetics). 4 Administration Patients should swallow MAR-Anastrozole with fluids. Patients should try to take MAR-Anastrozole at the same time each day. 5 Missed Dose A missed dose should be taken as soon as possible, as long as it is taken at least 12 hours before the next dose is due.

A missed dose should not be taken within 12 hours of the next dose.

1 Adverse Reaction Overview Adverse events have usually been mild to moderate with few withdrawals from treatment due to undesirable events. The pharmacological action of anastrozole may give rise to certain expected effects. Arthritis/arthralgia, joint pain/stiffness and hot flushes were reported very commonly (≥10%).

Common adverse reactions (≥1% - <10%) are: asthenia, bone pain, myalgia, carpal tunnel syndrome, sensory disturbances (including paraesthesia, taste loss and taste perversion), vaginal dryness, hair thinning (alopecia), rash, nausea, diarrhea, headache and increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase.

In the ATAC trial, ischemic cardiovascular events were reported more frequently in patients treated with anastrozole compared to those treated with tamoxifen, although the difference was not statistically significant. A retrospective evaluation has shown that this numerical difference was associated with a sub-group of patients with pre-existing ischemic heart disease.

A statistical analysis could not be performed on this subgroup evaluation. 9% vs. 7%, respectively). Events of carpal tunnel syndrome have been reported in patients receiving anastrozole treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen.

The majority of these events occurred in patients with identifiable risk factors for the development of the condition. In the ATAC adjuvant trial, 83 events of carpal tunnel syndrome occurred in 78 patients in the anastrozole monotherapy arm, and 22 events occurred in 22 patients in the tamoxifen arm.

Vaginal bleeding has been reported infrequently, mainly in patients during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. General Anastrozole has not been investigated in patients with any degree of brain or leptomeningeal involvement or with pulmonary lymphangitic disseminated disease. Cardiovascular In the ATAC trial, ischemic cardiovascular events were reported more frequently in patients treated with anastrozole compared to those treated with tamoxifen, although the difference was not statistically significant.

A retrospective evaluation has shown that this numerical difference was associated with a sub-group of patients with pre-existing ischemic heart disease. A statistical analysis could not be performed on this subgroup evaluation. 9% vs.

7%, respectively). Driving and Operating Machinery MAR-Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

Monitoring and Laboratory Tests Anastrozole has not been observed to interfere with routine clinical laboratory test results.

Bone assessment:

Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines. MAR-Anastrozole (Anastrozole Tablets) Page 7 of 54 Musculoskeletal Arthralgia/Arthritis: The use of Aromatase Inhibitors, including anastrozole, may cause arthralgia/arthritis, which may impact on treatment compliance and quality of life.

4% of patients on the tamoxifen arm. 4% of patients on the tamoxifen arm.

Bone Mineral Density:

The use of estrogen lowering agents, including anastrozole, may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. In the SABRE study, postmenopausal women with hormone receptor positive early breast cancer with existing moderate or high risk of fragility fracture, bone mineral density (BMD) loss could be inhibited by using anastrozole together with a bisphosphonate (risedronate) (see Assessment of Bone).

• Patients who are hypersensitive to MAR-Anastrozole or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

• Pregnant or lactating women.