PRODUCT MONOGRAPH PrPremplus® conjugated estrogens tablets CSD 0.625 mg and medroxyprogesterone acetate tablets USP 2.5 mg, 5.0 mg (Continuous therapy) PrPremplus Cycle® conjugated estrogens tablets CSD 0.625 mg and medroxyprogesterone acetate tablets USP 10.0 mg (Cyclic therapy) Estrogenic Hormones/Progestin Date of Revision: ® Wyeth LLC December 8, 2010 Pfizer Canada Inc., Licensee 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control No: 141329 Premplus ® and Premplus Cycle® Page 1 of 49 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3 SUMMARY PRODUCT INFORMATION...........................................................................3 INDICATIONS AND CLINICAL USE ................................................................................3 CONTRAINDICATIONS......................................................................................................4 WARNINGS AND PRECAUTIONS ....................................................................................4 ADVERSE REACTIONS....................................................................................................14 DRUG INTERACTIONS ..................................................................................................22 DOSAGE AND ADMINISTRATION ................................................................................23 OVERDOSAGE...................................................................................................................24 ACTION AND CLINICAL PHARMACOLOGY...............................................................25 STORAGE AND STABILITY ............................................................................................30 SPECIAL HANDLING INSTRUCTIONS..........................................................................30 DOSAGE FORMS, COMPOSITION AND PACKAGING................................................30 PART II: SCIENTIFIC INFORMATION ...............................................................................32 PHARMACEUTICAL INFORMATION............................................................................32 CLINICAL TRIALS ............................................................................................................33 DETAILED PHARMACOLOGY .......................................................................................38 TOXICOLOGY....................................................................................................................38 REFERENCES.....................................................................................................................41 PART III: CONSUMER INFORMATION..............................................................................44 Premplus ® and Premplus Cycle® Page 2 of 49 Premplus® Continuous therapy of conjugated estrogens tablets CSD and medroxyprogesterone acetate tablets USP Premplus Cycle® Cyclic therapy of conjugated estrogens tablets CSD and medroxyprogesterone acetate tablets USP PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form / Clinically Relevant Nonmedicinal Administration Strength Ingredients ® Premplus conjugated estrogens lactose oral tablets 0.625 mg and For a complete listing see Dosage Forms, medroxyprogesterone Composition and Packaging section. acetate tablets 2.5 mg, 5.0 mg ® Premplus Cycle conjugated estrogens lactose oral tablets 0.625 mg and medroxyprogesterone For a complete listing see Dosage Forms, acetate tablets USP Composition and Packaging section 10.0 mg INDICATIONS AND CLINICAL USE Premplus® and Premplus Cycle® therapy is indicated in women with intact uteri for the following: • relief of moderate to severe vasomotor symptoms associated with menopause,9 occurring in naturally or surgically induced estrogen deficiency states; • prevention of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy with Premplus® and Premplus Cycle® should be considered in light of other available therapies (please see the Serious Warnings and Precautions box), and should only be considered in women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Adequate diet, calcium and vitamin D intake, cessation of smoking, as well as regular physical weight-bearing exercise are required in addition to the administration of Premplus® and Premplus Cycle®. Premplus ® and Premplus Cycle® Page 3 of 49 • treatment of vulvar and vaginal atrophy associated with menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Premplus® and Premplus Cycle® therapy is recommended for the above indications only in women with intact uteri since the regimen includes a progestin whose role is to prevent endometrial hyperplasia. Geriatrics (> 65 years of age): See above indications. Pediatrics: Clinical studies have not been conducted in the pediatric population. Premplus® and Premplus Cycle® are not indicated for use in children. CONTRAINDICATIONS • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. • Liver dysfunction or disease as long as liver function tests have failed to return to normal. • Known or suspected estrogen-dependent or progestin-dependent malignant neoplasia (e.g. endometrial cancer). • Endometrial hyperplasia • Known, suspected, or past history of breast cancer. • Undiagnosed abnormal genital bleeding. • Known or suspected pregnancy. • Active or past history of confirmed venous thromboembolism (such as deep venous thrombosis or pulmonary embolism) or active thrombophlebitis. • Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease). • Partial or complete loss of vision due to ophthalmic vascular disease. • Known thrombophilic disorders (e.g., protein C, protein S, antithrombin deficiency, or anti- cardiolipin antibodies). • Migraine with aura WARNINGS AND PRECAUTIONS Serious Warnings and Precautions The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.19,24,32 Premplus ® and Premplus Cycle® Page 4 of 49 The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for 19 5.2 years compared to those receiving placebo. The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE-alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.32 Therefore, the following should be given serious consideration at the time of prescribing: • Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases. • Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication. • Estrogens with or without progestins should be prescribed for the shortest period possible for the approved indication. • The use of Premplus® or Premplus Cycle® for the prevention of osteoporosis should be considered in light of other available therapies. General Combined Estrogen and Progestin Therapy The benefits and risks of HRT must always be carefully weighed, including consideration of the emergence of risks as therapy continues. There are additional and/or increased risks that may be associated with the use of combination estrogen-plus-progestin therapy compared with using estrogen-alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer. Carcinogenesis and Mutagenesis Breast cancer Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer. The use of estrogen and progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. Premplus ® and Premplus Cycle® Page 5 of 49 In the estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were: • 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).19 The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at year one and persisted in each year thereafter.24 In the estrogen-alone