ACTIVELLE LD

1 Dosing Considerations Activelle® LD is a low-dose continuous combined Hormone Replacement Therapy (HRT) product intended for use in women with intact uteri. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.

In women with amenorrhea and not taking HRT or women in transition from another continuous combined HRT product, treatment with Activelle® LD may be started on any convenient day. In women in transition from sequential HRT regimens, treatment should start right after their withdrawal bleeding has ended.

1 mg) should be taken orally once a day without interruption, preferably at the same time every day. Patients should be re-evaluated within 3-6 months after initiation of treatment, to assess response to treatment. 5 Missed Dose If the patient has forgotten to take a tablet, the tablet should be taken as soon as possible Activelle® LD Product Monograph Page 7 of 39 within the next 12 hours.

After 12 hours the tablet should be discarded and next dose taken at the normal time. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

1 Adverse Reaction Overview See 7 WARNINGS AND PRECAUTIONS regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives. g. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug. Adverse events reported by investigators in the Activelle® LD pivotal trial at a frequency of 1% are shown in Table 1 below.

The regimens evaluated Activelle® LD over a 6-month treatment period.

Table 1:

Treatment-Emergent Adverse Events with Possible or Probable Relationship Reported at a Frequency of  1% with Activelle® LD Activelle® LD Placebo (n=194) (n=200) Gastrointestinal disorder Nausea Dyspepsia Abdominal distension 3% 2% 1% 2% -1 -1 Abdominal pain 1% 2% Diarrhea 1% -1 Musculoskeletal and connective tissue Back pain 1% -1 Nervous System Headache Dizziness Vascular disorder Vaginal hemorrhage Hot flush 11% 1% 25% 2% 8% -1 12% 3% Urogenital/Reproductive System Endometrial thickening 9% 4% Uterine leiomyoma Ovarian cyst Vaginal discharge Breast pain Vulvovaginal mycotic infection Uterine polyp 3% 2% 1% 1% 1% 1% 2% -1 -1 -1 -1 -1 1.

No adverse events reported The most frequently reported adverse events in the clinical trials with Activelle® LD tablets were vaginal hemorrhage (any release of blood from uterus), endometrial thickening (double layer measured at ≥ 5 mm) and headache.

The majority of AEs occurred with similar frequency in the treatment groups and were classified as mild or moderate in severity. As Activelle® LD Product Monograph Page 17 of 39 expected, the incidence of vaginal bleeding was higher in the continuous combined treatment groups Activelle® LD (25%) than in the placebo group (12%).

General For the treatment of postmenopausal symptoms, Hormone Replacement Therapy (HRT) should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

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. 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.

2 It is recommended that estrogens with or without progestins not be given to women with existing breast cancer or those with a previous history of the disease (see 2 CONTRAINDICATIONS). There is a need for caution in prescribing estrogens with or without progestins for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).

Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated. It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

Taking estrogens with progestins may increase the density of breast tissue, potentially adversely affecting the capability of mammography to detect breast cancer. The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients.

• Patients with known hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.

g. g. stroke, myocardial infarction, coronary heart disease) • Active or past history of confirmed venous thromboembolism (such as deep vein thrombosis or pulmonary embolism) or active thrombophlebitis • Partial or complete loss of vision due to ophthalmic vascular disease • Porphyria • Classical migraine • Breastfeeding Activelle® LD Product Monograph Page 6 of 39