Estradiol and Norethindrone Acetate Tablets Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................ 2

TABLE OF CONTENTS ......................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ............................................................. 4

• 1 INDICATIONS ............................................................................................................. 4

  • 1.1 Pediatrics ..................................................................................................... 4

2 CONTRAINDICATIONS .............................................................................................. 4

• 3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................... 5

• 4 DOSAGE AND ADMINISTRATION ............................................................................. 5

  • 4.1 Dosing Considerations ................................................................................. 5
  • 4.2 Recommended Dose and Dosage Adjustment ............................................. 5

4.5 Missed Dose ................................................................................................ 5

5 OVERDOSAGE ........................................................................................................... 6

• 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ..................... 6

• 7 WARNINGS AND PRECAUTIONS ............................................................................. 6

  • 7.1 Special Populations ................................................................................... 13
  • 7.1.1 Pregnant Women ....................................................................................... 13
  • 7.1.2 Breast-feeding ............................................................................................ 13
  • 7.1.3 Pediatrics ................................................................................................... 13
  • 7.1.4 Geriatrics ................................................................................................... 13

8 ADVERSE REACTIONS ........................................................................................... 13

• 8.1 Adverse Reaction Overview ....................................................................... 13
• 8.2 Clinical Trial Adverse Reactions ................................................................. 14
• 8.3 Less Common Clinical Trial Adverse Reactions ......................................... 17
• 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ....................................................................................... 17
• 8.5 Post-Market Adverse Reactions ................................................................. 17

9 DRUG INTERACTIONS ............................................................................................ 18

• 9.2 Drug Interactions Overview ........................................................................ 18
• 9.3 Drug-Behavioural Interactions .................................................................... 18
• 9.4 Drug-Drug Interactions ............................................................................... 18
• 9.5 Drug-Food Interactions .............................................................................. 19
• 9.6 Drug-Herb Interactions ............................................................................... 19
• 9.7 Drug-Laboratory Test Interactions .............................................................. 19

10 CLINICAL PHARMACOLOGY .................................................................................. 20

• 10.1 Mechanism of Action ................................................................................. 20
• 10.2 Pharmacodynamics ................................................................................... 21
• 10.3 Pharmacokinetics ...................................................................................... 22

11 STORAGE, STABILITY AND DISPOSAL ................................................................. 23

PART II: SCIENTIFIC INFORMATION ................................................................................. 24

• 13 PHARMACEUTICAL INFORMATION ....................................................................... 24

• 14 CLINICAL TRIALS .................................................................................................... 25

  14.1 Clinical Trials by Indication ......................................................................... 25

  Effects on Menopausal Symptoms ............................................................. 25

  Effects on Endometrium............................................................................. 27

  Effects on bleeding .................................................................................... 29

  Lipid Effects ............................................................................................... 30

  Hemostatic Changes ................................................................................. 31

  Glucose Metabolism .................................................................................. 32

  14.2 Comparative Bioavailability Studies .............................................................. 32

15 MICROBIOLOGY ...................................................................................................... 34

• 16 NON-CLINICAL TOXICOLOGY ................................................................................ 34
• 17 SUPPORTING PRODUCT MONOGRAPHS ............................................................. 34

PATIENT MEDICATION INFORMATION ............................................................................. 35

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Estradiol and Norethindrone Acetate Tablets is indicated for:

• Treatment of moderate to severe vasomotor symptoms occurring in naturally or surgically induced estrogen deficiency states.
• Treatment of vulvar or vaginal atrophy associated with menopause.

Estradiol and Norethindrone Acetate Tablets is recommended only in women with intact uteri since the regimen includes a progestin to prevent endometrial hyperplasia.

1.1 Pediatrics

Pediatrics (< 18 years of age): Estradiol and Norethindrone Acetate Tablets is not indicated for use in a pediatric population. Safety and effectiveness in pediatric patients have not been established.

2 CONTRAINDICATIONS

• Patients with known hypersensitivity to this drug or any ingredient in the formulation or components of the container. For complete listing, see the 6 DOSAGE FORMS, STRENGTHS, 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, suspected, or past history of 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 arterial thromboembolic disease (e.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 from ophthalmic vascular disease
• Porphyria
• Classical migraine
• Breastfeeding

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

4 DOSAGE AND ADMINISTRATION

• 4.1 Dosing Considerations

Estradiol and Norethindrone Acetate Tablets is a continuous combined Hormone Replacement Therapy (HRT) 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 Estradiol and Norethindrone Acetate Tablets 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.

4.2 Recommended Dose and Dosage Adjustment

One tablet of Estradiol and Norethindrone Acetate Tablets 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.

4.5 Missed Dose

If the patient has forgotten to take a tablet, the tablet should be taken as soon as possible within the next 12 hours. After 12 hours the tablet should be discarded and next dose taken at the

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^1-3.

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 5.2 years compared to those receiving placebo¹.

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 placebo².

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.

normal time. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

5 OVERDOSAGE

Symptoms of overdose

Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral contraceptives by young children have not revealed acute serious ill effects. Overdosage with estrogen may cause nausea, vomiting, breast discomfort, fluid retention, bloating or vaginal bleeding in women. Progestin (e.g. norethindrone acetate) overdosage has been characterized by depressed mood, tiredness, acne and hirsutism.

Treatment of overdose

Symptomatic treatment should be given.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Estradiol and Norethindrone Acetate Tablets are yellow, round, biconvex tablets, debossed “J2” on one side and plain on another side. Estradiol and Norethindrone Acetate Tablets is supplied as 28 active tablets in 1 or 3 blister cards per carton. Each blister card of 28 tablets is placed in a dispenser. Each tablet contains estradiol 1 mg and norethindrone acetate 0.5 mg.

7 WARNINGS AND PRECAUTIONS

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.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada's toll-free number, 1-844 POISON-X (1-844-764-7669).

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.

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).¹

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.³

In the estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo. 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. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.

Instructions for regular self-examination of the breasts should be included in this counseling.

Endometrial Hyperplasia & Endometrial Carcinoma

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods to women with intact uteri. The role of a progestin, when combined with estrogen, is to prevent endometrial hyperplasia/carcinoma in women with intact uteri. The addition of progestin for at least 12 days per cycle in non-hysterectomised women reduces this risk.

In the WHI study, endometrial cancer rates were low and were not increased by 5 years of estrogen plus progestin exposure (hazard ratio 0.83 [adjusted 95% CI 0.29-2.32]) ¹. Because endometrial cancer has a relatively low incidence rate, the incidence of endometrial hyperplasia is used as a surrogate endpoint in clinical studies.

In a 12 months prospective, double-blind, randomized, multicentre clinical trial of 1,176 postmenopausal women (age range 44 to 82), who were randomized to one of four arms: 1 mg estradiol unopposed (n=296), 1 mg E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA (n=291), and estradiol and norethindrone acetate tablets (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects and the incidence of endometrial hyperplasia with estradiol and norethindrone acetate tablets was 0.4% (one simple hyperplasia without atypia) compared with 14.6% with 1 mg unopposed estradiol.

All women taking estrogen/progestin combination should undergo clinical surveillance for endometrial abnormalities. Adequate diagnostic measures, including endometrial sampling, should be performed in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

Ovarian Cancer

Some recent epidemiologic studies have found that the use of hormone replacement therapy (estrogen-alone and estrogen plus progestin therapies), in particular for 5 or more years, has been associated with an increased risk of ovarian cancer.

Cardiovascular

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women’s Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.^1,4,5, The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women. ^1,2

WHI Trial Findings

In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one- year period, there were:

• 8 more cases of stroke (29 on combined HRT versus 21 on placebo)
• 7 more cases of CHD (37 on combined HRT versus 30 on placebo).

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one-year period, there were/was:

• 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)
• No statistically significant difference in the rate of CHD.²

HERS and HERS II Findings

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n=2763, average age 66.7 years), a randomized placebo- controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow- up of 4.1 years, treatment with CEE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the hormone-treated group than in the placebo group in year 1, but not during the subsequent years.⁴

From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.⁵

Blood Pressure

Women using hormone replacement therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT may have to be discontinued.

Ear/Nose/Throat

Otosclerosis

Estrogens should be used with caution in patients with otosclerosis.

Endocrine and Metabolism

Calcium and Phosphorus Metabolism

Because the prolonged use of estrogens with or without progestins influences the metabolism of calcium and phosphorus, estrogens with or without progestins should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.

Glucose and Lipid Metabolism

A worsening of glucose tolerance and lipid metabolism have been observed in a significant percentage of peri- and postmenopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.

In 38 randomized postmenopausal women (age range 53 to 70) with type 2 diabetes included in a 6-month randomised, parallel, double-blind, single-center trial randomized to one of two arms: 1 mg E2 (n=19) and 1 mg E2 + 0.5 mg NETA (n=19) showed no change over time in glycemic control as measured by fasting glucose, serum free insulin, HBA1c or fructosamine. In postmenopausal women with type 2 diabetes after 6 months of treatment, diabetic women receiving estradiol and norethindrone acetate tablets had a significant decrease over time in total cholesterol, LDL-cholesterol and lipoprotein (a), without modifying triglycerides or HDL-cholesterol levels.

Women with familial hyperlipidemias need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started. Women with pre-existing

hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Hypothyroidism

Patients who require thyroid hormone replacement therapy and who are also taking estrogen should have their thyroid function monitored regularly to assure that thyroid hormone levels remain in an acceptable range (see 9.7 Drug-Laboratory Test Interactions).

Other Conditions

Estradiol and Norethindrone Acetate Tablets contains lactose. In patient with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the severity of the condition should be taken into careful consideration before prescribing Estradiol and Norethindrone Acetate Tablets. The patients should be closely monitored.

Genitourinary

Endometriosis

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

Uterine Leiomyomata

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

Vaginal Bleeding

Breakthrough bleeding and spotting may occur during the first months of treatment. Abnormal vaginal bleeding, such as breakthrough bleeding or spotting due to its prolongation, irregularity or heaviness, occurring during therapy or continuing after treatment has been discontinued should prompt appropriate diagnostic measures, which may include endometrial biopsy to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Hematologic

Venous Thromboembolism

Available epidemiological data indicate that use of estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined HRT over a one-year period, there were 18 more cases of VTE, including 8 more cases of pulmonary embolism.¹

In the estrogen-alone arm of the WHI trial, among 10,000 women on estrogen therapy over a one-year period, there were 7 more cases of VTE, although there was no statistically significant difference in the rate of pulmonary embolism.²

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index > 30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, estrogens with or without progestins should be discontinued at least 4-6 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Hepatic/Biliary/Pancreatic

Gallbladder Disease

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

Hepatic Hemangioma

Particular caution is indicated in women with hepatic hemangiomas as estrogen may cause an exacerbation of this condition.

Jaundice

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.

Liver Function Tests

Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see Monitoring and Laboratory Tests.

Liver Disorders

Patients who have or have previously had liver disorder such as liver adenoma should be closely supervised as this condition may recur or be aggravated during treatment with Estradiol and Norethindrone Acetate Tablets.

Immune

Angioedema

Estrogen may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Systemic Lupus Erythematosus

Particular caution is indicated in women with systemic lupus erythematosus, as HRT may cause an exacerbation of this condition.

Monitoring and Laboratory Tests

Before Estradiol and Norethindrone Acetate Tablets is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

The importance of regular self-examination of the breasts should be discussed with the patient.

Neurologic

Cerebrovascular Insufficiency

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.

Dementia

Available epidemiological data indicate that the use of combined estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

The Women’s Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.^6,7

In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:

• 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).⁶

In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:

• 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.⁷

When data from the estrogen plus progestin arm of the WHIMS and the estrogen-alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10,000 women over a one- year period, there were:

• 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone

versus 23 on placebo). ⁷

Epilepsy

Particular caution is indicated in women with epilepsy, as estrogens with or without progestins may cause an exacerbation of this condition.

Ophthalmologic

See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS – Neurologic.

Renal

Fluid Retention

Estrogens with or without progestins may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be re-assessed based on the individual case.

Reproductive Health

See 7.1 Special Populations.

7.1 Special Populations

• 7.1.1 Pregnant Women

Estradiol and Norethindrone Acetate Tablets is contraindicated during pregnancy.

If pregnancy occurs during medication with Estradiol and Norethindrone Acetate Tablets treatment should be withdrawn immediately.

Data on a limited number of exposed pregnancies indicate adverse effects of norethindrone on the fetus. At doses higher than normally used in Oral Contraceptives (OC) and HRT formulations masculinisation of female fetuses was observed.

The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of estrogens and progestins indicate no teratogenic or fetotoxic effect.

7.1.2 Breast-feeding

Estradiol and Norethindrone Acetate Tablets is contraindicated when breastfeeding.

7.1.3 Pediatrics

Estradiol and Norethindrone Acetate Tablets is not indicated for use in a pediatric population. Safety and effectiveness in pediatric patients have not been established.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): Experience in treating women older than 65 years is limited.

8 ADVERSE REACTIONS

• 8.1 Adverse Reaction Overview

See 7 WARNINGS AND PRECAUTIONS regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.

The following adverse reactions have been reported with other estrogen/progestin combinations in general:

Blood and Lymphatic System Disorders

Altered coagulation tests (see 7 WARNINGS AND PRECAUTIONS, 9.7 Drug-Laboratory Test Interactions)

Cardiac Disorders

Palpitations; increase in blood pressure (see 7 WARNINGS AND PRECAUTIONS); coronary thrombosis

Endocrine Disorders

Increased blood sugar levels; decreased glucose tolerance

Eye Disorders

Neuro-ocular lesions (e.g. retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses

Gastrointestinal Disorders

Nausea; vomiting; abdominal discomfort (cramps, pressure, pain, bloating)

General Disorders and Administration Site Conditions

Fatigue; changes in appetite; changes in body weight; change in libido

Hepatobiliary Disorders

Gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur

Nervous System Disorders

Aggravation of migraine episodes; headaches; dizziness; neuritis

Psychiatric Disorders

Mental depression; nervousness; irritability

Renal and Urinary Disorders

Cystitis; dysuria; sodium retention; edema

Reproductive System and Breast Disorders

Breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness

Skin and Subcutaneous Tissue Disorders

Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism and acne

Vascular Disorders

Isolated cases of: thrombophlebitis; thromboembolic disorders

8.2 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 estradiol and norethindrone acetate tablets Phase 3 studies regardless of causality assessment are shown in Table 1 below.

Table 1 - All Treatment-Emergent Adverse Events Regardless of Relationship Reported at a Frequency of ≥ 1% with estradiol and norethindrone acetate tablets

^1.No adverse events reported

The most frequently reported adverse events in the clinical trials regardless of relationship to estradiol and norethindrone acetate tablets were breast pain / tenderness (22.9%), upper respiratory tract infection (17.0%) and headache (15.6%).

There were no significant changes in mean body weight from baseline to the end of the trial (3 months or 12 months) in any estradiol and norethindrone acetate tablets study.

• 8.3 Less Common Clinical Trial Adverse Reactions

Gastrointestinal: Abdominal distension

Immune System: Hypersensitivity

Metabolism and Nutrition: Fluid retention

Musculoskeletal, Connective Tissue and Bone: Leg cramps

Nervous System Disorders: Migraine

Skin and Subcutaneous Tissue Disorders: Alopecia

Vascular Disorders: Thrombophlebitis superficial/deep; pulmonary embolism

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

None of the observed changes with regard to hematology and clinical chemistry in clinical studies of estradiol and norethindrone acetate tablets were clinically relevant.

• 8.5 Post-Market Adverse Reactions

Cardiac Disorders: Myocardial infarction

Eye Disorders: Visual disturbances

Gastrointestinal Disorders: Dyspepsia, vomiting

Hepatobiliary Disorders: Gallbladder disease, gallstones, cholelithiasis, cholelithiasis aggravated, cholelithiasis recurrence

Immune System Disorders: Generalized hypersensitivity reactions (e.g. anaphylactic reaction/shock)

Musculoskeletal and Connective Tissue Disorders: Leg cramps

Neoplasm Benign and Malignant: Endometrial cancer, uterine fibroid

Nervous System Disorders: Dizziness, stroke

Other: Weight decreased, blood pressure increased

Psychiatric Disorders: Insomnia, anxiety, libido decreased, libido increased

Reproductive System and Breast Disorders: Endometrial hyperplasia, vulvovaginal pruritus

Skin and Subcutaneous Tissue Disorders: Seborrhea, rash, angioneurotic edema, vascular purpura

Vascular Disorders: Hypertension aggravated

If adverse symptoms persist, the prescription of HRT should be re-considered.

9 DRUG INTERACTIONS

• 9.2 Drug Interactions Overview

Estrogens are partially metabolized by cytochrome P450 3A4 (CYP3A4) as shown in vitro and in vivo studies. Therefore, estrogen drug metabolism may be affected by inducers or inhibitors of CYP3A4.

9.3 Drug-Behavioural Interactions

None identified.

9.4 Drug-Drug Interactions

Table 2 - Established or Potential Drug-Drug Interactions

• 9.5 Drug-Food Interactions

A single dose-study in 24 healthy postmenopausal women was conducted to investigate any potential impact of administration of estradiol and norethindrone acetate tablets with and without food.

Administration of estradiol and norethindrone acetate tablets with food did not modify the bioavailability of E₂, although food increased AUC_0-72 for NET by 19% and decreased C_max for NET by 36%.

Grapefruit juice may increase plasma concentrations of estrogen.

9.6 Drug-Herb Interactions

It was found that some herbal products (e.g. St. John’s Wort) which are available as over-the- counter (OTC) products might interfere with steroid metabolism, and therefore alter the efficacy and safety of estrogen/progestin products.

Physicians and other health care providers should be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread health stores.

9.7 Drug-Laboratory Test Interactions

The results of certain endocrine and liver function tests may be affected by estrogen-containing products:

• increased sulfobromophthalein retention;
• increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephtrine-induced platelet aggregability; decreased antithrombin III;
• increased thyroxin-binding globulin (TBG), leading to increased circulating total thyroid hormone (T₄) as measured by column or radioimmunoassay; free T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ concentration is unaltered;
• other binding proteins may be elevated in serum (eg, corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged;
• impaired glucose tolerance;
• increased serum triglycerides and phospholipids concentration

The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for two to four weeks.

The pathologist should be informed that the patient is receiving hormone replacement therapy when relevant specimens are submitted.

10 CLINICAL PHARMACOLOGY

• 10.1 Mechanism of Action

Estradiol: The active ingredient, synthetic estradiol, is chemically and biologically identical to endogenous human estradiol.

Estradiol, E2, is the major estrogenic hormone secreted by the human ovary. Among numerous effects, E2 is responsible for the development and maintenance of the female reproductive system and of secondary sexual characteristics. It promotes growth and development of the vagina, uterus, fallopian tubes and breasts. E2 contributes to the shaping of the skeleton, to the maintenance of tone and elasticity of urogenital structures, to changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, to the growth of auxiliary and pubic hair, and to the pigmentation of the nipples and genitals. It also affects the release of pituitary gonadotropins.

After menopause, when the ovaries have ceased to function, only small amounts of E2 are still produced. E2 is produced in the body by the aromatisation of androstenedione to estrone, E1, and to a lesser extent, testosterone to estradiol. Estrone is transformed to estradiol by the enzyme 17ß-hydroxysteroid-dehydrogenase. Both enzymes prevail in fat, liver and muscle tissue.

Loss of ovarian E2 production after menopause can result in instability of thermoregulation causing hot flushes associated with sleep disturbance and excessive sweating; accelerated loss of bone matrix and mineral, resulting in osteoporosis; alterations in lipid metabolism and urogenital atrophy, causing dyspareunia and urinary incontinence.

Norethindrone acetate: Because estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestin may reduce the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Norethindrone acetate, NETA, is a potent progestin that essentially mimics the biological effects of progesterone. Tissue effects of NETA are dependent on prior estrogen stimulation, and progesterone receptors have been identified in all tissues containing estrogen receptors.

NETA induces protein synthesis and also reduces the number of estrogen and progesterone receptors, thereby limiting excessive growth stimulation of target tissues by estrogen. 17- hydroxysteroid-dehydrogenase, which locally oxidizes E2 to its weaker estrogenic metabolite estrone, is also produced by NETA.

One of the major targets of NETA is the uterus, where it induces secretory transformation of the estrogen-primed endometrium. Once transformation of the endometrium is completed, the estrogen-primed endometrium is shed resulting in a regular cyclical bleeding.

Continuous addition of NETA in addition to estradiol will result in maintenance of the endometrium in an atrophic state in most of the women. This regimen avoids monthly withdrawal bleeding.

10.2 Pharmacodynamics

Estrogen pharmacology

Estradiol, E₂, is chemically and biologically identical to the endogenous human hormone. It is the major estrogenic hormone secreted by the human ovary which is also produced in small quantities (<20 pg/mL) in the postmenopausal woman. Among numerous effects, E₂, is responsible for the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, it causes growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, it causes enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat.

E2 is intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy and affect the release of pituitary gonadotropins. It also contributes to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bone that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals.

Estrogen replacement therapy acts through a negative feedback pathway to reduce elevated circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) observed in postmenopausal women.

Progestin pharmacology

Norethindrone Acetate, NETA, is a progestin that essentially mimics the biological effects of progesterone. NETA enhances cellular differentiation and generally opposes the actions of estrogen, by decreasing estrogen receptor levels, increasing local metabolism of estrogen to less active metabolites, or by inducing gene products that blunt cellular responses to estrogen.

NETA exerts its effect in target cells by binding to specific progesterone receptors which interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus and central nervous system. NETA produces similar endometrial changes to those of the naturally occurring hormone progesterone.

Unopposed estrogen therapy in women with intact uteri is associated with an increased risk of endometrial hyperplasia and endometrial carcinoma. The concomitant use of an appropriate dose of a progestin for an adequate time period reduces the incidence of endometrial hyperplasia and carcinoma in women with intact uteri who are receiving estrogen replacement therapy.

10.3 Pharmacokinetics

Table 3 - Pharmacokinetic Parameters of estradiol and norethindrone acetate tablets after Single Dose

¹baseline adjusted

Absorption

E2 is well absorbed through the gastrointestinal tract. When given orally, E2 is extensively metabolized (first pass effect) to estrone sulfate. E2 circulates bound to sex-hormone-binding globulin (SHBG) (37%) and to albumin (61%), while only approximately 1-2% is unbound. The half-life of E2 is about 12-14 hours following single administration. See Table 3.

Distribution

After oral administration NETA (norethindrone acetate) is rapidly absorbed and transformed to norethindrone (NET). The terminal half-life of NET is about 8-11 hours. NET binds to SHBG (36%) and albumin (61%).

Metabolism

Metabolism of E2, occurs mainly in the liver and gut but also in target organs. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between E₁ and E₂ and between esterified and nonesterified forms.

Elimination

A significant proportion of the circulating estrogen exists as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo thorough conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

Following oral administration of estradiol and norethindrone acetate tablets, a peak plasma concentration is reached within 5-8 hours. The most important metabolites of norethindrone are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

NETA undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5-1.5 hours.

The pharmacokinetics of estradiol are not influenced by NET.

Special Populations and Conditions

• Pediatrics: Estradiol and Norethindrone Acetate Tablets is not indicated for use in pediatric populations. Safety and effectiveness in pediatric patients have not been established.
• Geriatrics: Experience in treating women older than 65 years is limited. The pharmacokinetics in the elderly has not been studied.
• Sex: Estradiol and Norethindrone Acetate Tablets is not indicated for use in male population.
• Genetic Polymorphism: No specific information available.
• Ethnic Origin: No specific information available.
• Hepatic Insufficiency: No specific information available.
• Renal Insufficiency: No specific information available.

11 STORAGE, STABILITY AND DISPOSAL

Keep out of reach of children. Store in a dry place, protected from light. Store between 15º-30ºC. Do not refrigerate.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance: 17ß-estradiol

Non-proprietary name of the drug product: Estradiol (hemihydrate) USP/Ph.Eur.

Chemical name: 1. 17ß-estradiol ½ H₂O

1. 2. Estra-1, 3, 5 (10)-triene, 3, 17ß-diol hemihydrate

Molecular formula and molecular mass: C18H24O2

281.4

Structural formula:

Physicochemical properties:

Description: White or almost white crystalline powder

Solubility: Practically insoluble in water. 5.0 x 10^-3 g/L

Melting point: 173 - 179°C

pKa: 10.71

n-octanol/water partition coefficient: log POW =3.30

Drug Substance: Norethindrone acetate

Non-proprietary name of the drug product: Norethindrone acetate USP/Ph. Eur.

Chemical name: 1. 19-Norpregn-4-en-20-yn-3-one, 17- (acetyloxy)-, (17α)

1. 2. 17-Hydroxy-19-nor-17α-pregn-4-en- 20-yn-3-one acetate

Molecular formula and molecular mass: C22H28O3

340.5

Structural formula:

Physicochemical properties:

Description: White to yellowish-white crystalline powder

Solubility: Practically insoluble (USP definition) in water

Melting point: 161 - 162°C

pKa: The highest pKa value of NETA protonated at the conjugated ketone group in position 3 was calculated as -5, and the lowest pKa value of the neutral molecule was calculated as 19.

n-octanol/water partition coefficient: log POW = 3.67.

14 CLINICAL TRIALS

• 14.1 Clinical Trials by Indication

Effects on Menopausal Symptoms

Study demographics and trial design

A 12 week clinical trial, KLIM/PD/9/USA, was conducted to evaluate the efficacy of estradiol and norethindrone acetate tablets in relief of moderate to severe vasomotor symptoms. The effects of both E₂ (N =29) alone and estradiol and norethindrone acetate tablets (N = 29) when compared to placebo (N = 34) were apparent after the initial weeks of therapy. A significantly (p<0.05) larger reduction in the number and severity of hot flushes was observed for estradiol and norethindrone acetate tablets compared to 1 mg E₂ after 4 weeks of treatment and throughout the remaining trial period (Figure 1). Thus, the addition of 0.5 mg NETA enhanced the reduction of vasomotor symptoms associated with 1 mg E₂.

Figure 1: Effect of estradiol and norethindrone acetate tablets on vasomotor symptoms as measured by a composite score of # and severity of hot flushes

Efficacy was assessed in terms of the weekly hot flush weighted score, weekly frequency of moderate and severe hot flushes, the occurrence of other menopausal symptoms, and menopausal symptoms recorded using the Greene Climacteric Scale.

In this trial, estradiol and norethindrone acetate tablets was able to provide an adequate response in 89% of the women after 12 weeks of treatment (Figure 2). The number of women obtaining adequate relief with estradiol and norethindrone acetate tablets was higher than that observed with 1 mg E₂.

Figure 2: Percentage of women achieving at least a 90% reduction in vasomotor symptoms as measured by a composite score of # and severity of hot flushes

Throughout the clinical trials, estradiol and norethindrone acetate tablets was associated with a high degree of adherence to treatment, as 95% of the women remained on treatment in placebo-controlled trials of 3 to 12 months duration. In the placebo-controlled trials, the rate of discontinuation due to adverse events was similar in the estradiol and norethindrone acetate tablets group (2%) and the placebo group (4%).

Study KLIM/PD/9/USA evaluated estradiol 1 mg alone or in combination with NETA 0.5 mg in 92 menopausal women. This was 3 months prospective randomized, placebo-controlled, double-blind, multi-center, parallel-group trial to evaluate the efficacy and safety of treatment with 1 mg E2 and 1 mg E2 + 0.5 mg NETA for the relief of vasomotor hot flushes, as assessed by patients, when compared to placebo treatment. Patients were randomly assigned to a single daily dose of one of the three treatment groups and returned every 4 weeks for evaluation. The subjects were generally healthy menopausal women 40 to 60 years of age, with an intact uterus.

Study KLIM/PD1/N was a multi-centre, double-blind, randomized controlled efficacy trial of 12 weeks duration preceded by a 2 week run-in period and including 119 patients. Subjects were healthy, menopausal women 45 to 65 years of age, with amenorrhea for ≥ 3 months, who spontaneously complained of sweating and hot flushes. Subjects were randomized to one of the two arms of the trial 1 mg E2 + 0.25 mg NETA or 1 mg E2 + 0.5 mg NETA. This trial compared climacteric symptoms of the two combination doses of E2 and NETA respectively and with placebo.

Study results

Effects on Menopausal Symptoms

The results of clinical studies indicate that the estrogen component of estradiol and norethindrone acetate tablets substitutes for the loss of estrogen production in menopausal and postmenopausal women occurring in naturally or surgically induced estrogen deficiency states, and thus alleviates vasomotor symptoms. A dose finding study evaluated E₂ alone for symptom relief and it was concluded that both 1 and 2 mg of E₂ are effective while 1 mg of E₂ is the optimum dose.

During the trial, KLIM/PD/1/N, a statistical decrease in the number of severe, moderate and mild hot flushes were reported in the active treatment groups. Efficacy in reducing vasomotor symptoms was demonstrated at 4 weeks of treatment, reaching and almost complete reduction in the score by week 8. Menopausal symptoms were improved as shown with the decrease in Kupperman Menopausal Index, and by the Visual Analog Scales. No statistically significant differences were seen between active treatment groups in any of the bleeding parameters.

Better bleeding control was observed with estradiol and norethindrone acetate tablets than with 1 mg E₂ + 0.25 mg NETA.

Effects on Endometrium

A pivotal study, KLIM/PD/7/USA, was designed to identify the lowest effective dose of NETA (0.1 or 0.25 mg) to be used in combination with 1 mg E2 that will substantially reduce the incidence of endometrial hyperplasia when compared with 1 mg E2 treatment alone. The uterine bleeding profile and the endometrium histology were assessed in this trial as well. This was a 12 month double-blind, randomized, parallel group, multicenter, dose finding study of 1,176 postmenopausal women. Subjects underwent a 4 week screening period followed by 12 months active treatment. Therapy consisted of a single daily dose of either 1 mg E2 with no norethindrone acetate or a combination of 1 mg of E2 and 0.1 mg, 0.25mg or 0.5 mg of NETA. The subjects’ mean age range was 44 to 82 years of age.

The progestin component of estradiol and norethindrone acetate tablets, norethindrone acetate (NETA), protects against the estrogen-induced proliferative changes in the endometrium. Long-term studies with estradiol and norethindrone acetate tablets have documented that NETA when given concomitantly with E₂ reduces the incidence of endometrial hyperplasia associated with unopposed estrogen therapy.

Figure 3: Completion Rates in Clinical Trials. Effects on the Endometrium

The following table summarizes the incidence of endometrial hyperplasia after long term treatment with 1 mg E₂ unopposed versus estradiol and norethindrone acetate tablets treatment in clinical trials of postmenopausal women. The incidence of endometrial hyperplasia associated with unopposed E₂ (1 mg) was decreased significantly in patients treated with estradiol and norethindrone acetate tablets.

Table 4 - Incidence of Endometrial Hyperplasia in a 12 Month Study

¹ simple hyperplasia without atypia

Effects on bleeding

Use of a continuous combined Hormone Replacement Therapy (HRT) such as estradiol and norethindrone acetate tablets avoids monthly withdrawal bleeding associated with sequential HRT regimens. Figures 4 and 5 summarize the percentage of women bleeding over time. Fifty percent of the women exposed to estradiol and norethindrone acetate tablets for up to one year did not experience any bleeding or spotting.

Figure 4: Incidence of bleeding or spotting over the 12 months treatment period.

Figure 5: Incidence of bleeding (without spotting)

The incidence of bleeding with estradiol and norethindrone acetate tablets is low, even during the initial months of treatment. Approximately 90% of the women were amenorrheic after 12 months of treatment. Of the remaining 10%, only 3% experienced bleeding and the remaining 7% spotting.

During the initial 3 months of therapy in a comparator trial, the frequency of women bleeding/spotting with estradiol and norethindrone acetate tablets was significantly lower compared to that in those receiving continuous combined conjugated equine estrogens (CEE) 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg. For women 1-3 years since last menses, the frequency of bleeding/spotting with estradiol and norethindrone acetate tablets was significantly lower during 6 months of therapy than with CEE 0.625 mg and MPA 2.5 mg.

TSM = Time Since Menopause

Figure 6: Frequency of Women Bleeding/Spotting in Months 1-3 and Months 4-6

Lipid Effects

The effect of estradiol and norethindrone acetate tablets on lipid and lipoprotein parameters in healthy postmenopausal women has been evaluated in double-blind, randomized, placebo-controlled trials of 3 to 24 months duration. A summary of the lipid and lipoprotein changes is displayed in Table 5.

Estradiol and norethindrone acetate tablets significantly decreases total cholesterol and LDL-cholesterol compared to placebo. estradiol and norethindrone acetate tablets do not increase triglycerides or VLDL-cholesterol. The decrease in total cholesterol observed with E2 alone is not attenuated but rather enhanced by the addition of NETA. In addition, NETA blunts or reverses the estradiol-induced raise of triglycerides.

HDL-cholesterol either does not change with estradiol and norethindrone acetate tablets, or decreases significantly when compared to baseline. However, the LDL/HDL ratio remains unchanged while it deteriorates significantly in the placebo group. Lipoprotein (a) has been found to decrease significantly after 12 months of treatment with estradiol and norethindrone acetate tablets.

Treatment for 12 months with estradiol and norethindrone acetate tablets did not modify apolipoprotein-A. A significant decrease in Apolipoprotein B has been reported after 6 and 12 months respectively of treatment with estradiol and norethindrone acetate tablets.

Table 5 - Percent Change from Baseline in Lipid/Lipoprotein Parameters with estradiol and norethindrone acetate tablets and Placebo

1. 1. significantly (p<0.05) different from baseline

Hemostatic Changes

The effect of estradiol and norethindrone acetate tablets in healthy postmenopausal women was evaluated in two placebo-controlled trials of 6 and 12 months duration.

Estradiol and norethindrone acetate tablets significantly decreases factor VII activity compared to placebo and unopposed estradiol. Combined E₂ and NETA appears to decrease factor VII activity. Fibrinogen is not modified during treatment with estradiol and norethindrone acetate tablets; this is in contrast with the significant increase in fibrinogen observed with placebo.

Antithrombin III activity is significantly reduced following treatment with estradiol and norethindrone acetate tablets. With regards to fibrinolytic parameters, plasminogen activator inhibitor-1 (PAI-1) is decreased after 12 months of treatment with estradiol and norethindrone acetate tablets. No other changes have been reported in the hemostatic parameters assessed during estradiol and norethindrone acetate tablets treatment.

A summary of the changes in hemostatic parameters assessed after 12 months of treatment with estradiol and norethindrone acetate tablets is displayed in Table 6.

Table 6 - Percent Change from Baseline in estradiol and norethindrone acetate tablets Compared to Placebo

1. 1. significantly (p<0.05) different from baseline

Glucose Metabolism

The effect of estradiol and norethindrone acetate tablets on carbohydrate metabolism in healthy postmenopausal women was evaluated in 4 double-blind, randomized, placebo-controlled trials of 3, 6, 12 and 24 months duration.

Fasting glucose, insulin and c-peptide levels do not change following 6 or 12 months of treatment with estradiol and norethindrone acetate tablets. There is no worsening of glucose tolerance with estradiol and norethindrone acetate tablets as glucose and insulin responses to an oral glucose tolerance test, do not change during treatment. Insulin sensitivity was assessed in a 3-month placebo-controlled trial in which estradiol and norethindrone acetate tablets did not change compared to placebo. Finally, glycemic control measured by HBA1c, was found to improve with estradiol and norethindrone acetate tablets compared to placebo.

14.2 Comparative Bioavailability Studies

A randomized, two-treatment, two-sequence, two-period, cross-over, single oral dose bioequivalence study of Estradiol and Norethindrone Acetate Tablets and ^PrActivelle^® was conducted in healthy, post-menopausal female subjects under fasting condition. Comparative bioavailability data from 45 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

FOR NORETHINDRONE

¹ Estradiol and Norethindrone Acetate Tablets (Novast Laboratories Ltd.)

^{2 Pr}Activelle^® (Novo Nordisk Canada Inc.)

³ Expressed as the median (range) only.

⁴ Expressed as the arithmetic mean (CV%) only.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

FOR BASELINE CORRECTED TOTAL ESTRONE

¹ Estradiol and Norethindrone Acetate Tablets (Novast Laboratories Ltd.)

^{2 Pr}Activelle^® (Novo Nordisk Canada Inc.)

³ Expressed as the median (range) only.

⁴ Expressed as the arithmetic mean (CV%) only.

15 MICROBIOLOGY

Not applicable.

16 NON-CLINICAL TOXICOLOGY

Due to physiological, pharmacokinetic and pharmacodynamic interspecies differences, quantitative extrapolation from animals to humans must be carried out with great caution. There is an extensive clinical experience with the use of E₂ and NETA in humans and no effects can be predicted from animal toxicology findings other than those documented with human use.

17 SUPPORTING PRODUCT MONOGRAPH

1. 1. ^PrActivelle^® (1 mg Estradiol and 0.5 mg Norethindrone acetate), control 289098, Product Monograph, Novo Nordisk Canada Inc. (2025-02-17)