Premarin (Pfizer Canada, Tablet) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Premarin® (conjugated estrogens tablets, C.S.D.) is indicated for the following:

1. 1. the relief of menopausal and postmenopausal symptoms occurring in naturally or surgically induced estrogen deficiency states including vulvar and vaginal atrophy.
2. 2. the prevention of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy with Premarin should be considered in light of other available therapies (see Boxed Warning) and should only be considered for women at significant risk of osteoporosis. Non-estrogen medications should be carefully considered. For older women who are not experiencing any more acute symptoms of menopause, use in combination with a progestin should only be considered for women who failed on, or were intolerant of, non-estrogen medication. 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 Premarin. Postmenopausal women require an average of 1000 mg to 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
3. 3. hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
4. 4. atrophic vaginitis
5. 5. vulvar atrophy (with or without pruritis). When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

In patients with an intact uterus, Premarin® should be prescribed with an appropriate dosage of a progestin for women with intact uteri, in order to prevent endometrial hyperplasia/carcinoma.

Geriatrics (> 65 years of age): See above indications.

Pediatrics (< 16 years of age): Clinical studies have not been conducted in the pediatric population. Premarin^® is not indicated for use in children.

CONTRAINDICATIONS

Premarin® (conjugated estrogens tablets, C.S.D.) should not be administered to patients with any of the following conditions:

• 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 malignant neoplasia (e.g. endometrial cancer).
• Endometrial hyperplasia.
• Known, suspected, or past history of breast cancer.
• Undiagnosed abnormal genital bleeding.

• Known or suspected pregnancy (see WARNINGS AND PRECAUTIONS, Special

  Populations Pregnant Women)

• 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, or antithrombin deficiency).
• Migraine with or without 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.^{15, 21, 22}

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 placebo.²²

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.²¹

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 Premarin® for the prevention of osteoporosis should be considered in light of other available therapies.

General

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms/conditions that are consistent with the indications (see INDICATIONS AND CLINICAL USE). 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 risks.”

Combined Estrogen and Progestin Therapy:

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.

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).

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.

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.

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see CONTRAINDICATIONS).

There is a need for caution in prescribing estrogens 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.

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 counselling.

Endometrial hyperplasia & endometrial carcinoma

Estrogen-only HRT increases the risk of endometrial hyperplasia/carcinoma if taken by women with intact uteri. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold or greater than in non-users and appears to be dependent on duration of treatment and on estrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five years or more, and this risk has been shown to persist for at least 8 to15 years after ERT is discontinued.

Clinical surveillance of all women taking combined estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Ovarian cancer

In some epidemiologic studies, the use of estrogen therapy has been associated with an increased risk of ovarian cancer over multiple years of use. Other epidemiologic studies have not found these associations.

Cardiovascular

Cardiovascular risk

ERT has been reported to increase the risk of stroke and deep venous thrombosis (DVT).

Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately.

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. 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.

Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.

Should a stroke occur or be suspected, Premarin^® should be discontinued immediately.

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.

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.

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.²⁹

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.

Endocrine and Metabolism

Glucose and lipid metabolism

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

A worsening of glucose tolerance and lipid metabolism has been observed in a significant percentage of peri- and post-menopausal 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.

Caution should be exercised in patients with pre-existing hypertriglyceridemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population.

Heme metabolism

Women with porphyria need special surveillance.

Estrogens should be used with caution in individuals with pre-existing severe hypocalcemia.

Calcium and phosphorus metabolism

Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients who require thyroid hormone replacement therapy and who are also taking estrogen may required increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels remain in an acceptable range (see Drug-Laboratory Test Interactions).

Other conditions

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

Genitourinary

Endometriosis

Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

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

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures 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 venous thromboembolism, including 8 more cases of pulmonary embolism.

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 venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.

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, Premarin^® should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, Premarin^® should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Hepatic/Biliary/Pancreatic

Liver disorders

Patients who have previously had liver disorders such as liver adenoma should be closely supervised as this condition may recur or be aggravated during treatment with Premarin®.

Gallbladder diseases

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

Hepatic hemangiomas

Particular caution is indicated in women with hepatic hemangiomas, as HRT 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. Estrogens may be poorly metabolized in patients with impaired liver function.

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.

Immune

Systemic lupus erythematosus

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

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

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.

Ophthalmologic

If visual abnormalities develop: Discontinue Premarin^® pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, Premarin^® should be withdrawn. Retinal vascular thrombosis has been reported in patients receiving estrogens with or without progestins.

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.

It is unknown whether these findings apply to younger postmenopausal women (see Special Populations, Geriatrics).

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).

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.

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).

Epilepsy

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

Ear/Nose/Throat

Otosclerosis

Estrogens should be used with cautions in patients with otosclerosis.

Psychiatric

Depression

Patients who are taking progestogens and have a history of depression should be observed. If the depression occurs to a serious degree, the drug should be discontinued.

Renal

Fluid retention

Estrogens may cause fluid retention.

Therefore, particular caution is indicated in cardiac, 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 reassessed based on the individual case.

Special Populations

Pregnant Women: Premarin^® should not be used during pregnancy (see CONTRAINDICATIONS).

Nursing Women: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the drug. Where an assessment of the risk to benefit ratio suggests the use of this product in nursing women is unfavourable, formula feeding should be substituted for breast feeding.

Pediatrics (< 16 years of age): Premarin^® is not indicated for use in children. Safety and effectiveness in pediatric patients have not been established.

Geriatrics (> 65 years of age): There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Premarin^® to determine whether those over 65 years of age differ from younger subjects in their response to Premarin^®.

The Women’s Health Initiative Study

In the Women’s Health Initiative (WHI) estrogen-alone substudy (daily [0.625 mg] versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.

Monitoring and Laboratory Tests

Before Premarin^® is administered, the patient should have a complete physical examination including 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. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with ERT/HRT therapy. The first follow-up examination should be done within three to six months of initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

Mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.

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

ADVERSE REACTIONS

Adverse Drug Reaction Overview

See Warnings/Precautions regarding potential induction of malignant neoplasia and other adverse effects similar to those observed with oral contraceptives.

The following additional adverse reactions have been reported with estrogen replacement therapy or are undesirable effects associated with hormone replacement therapy:

Blood and lymphatic system disorders

Altered coagulation tests (see WARNINGS AND PRECAUTIONS, Drug-Laboratory Tests Interactions).

Cardiac disorders

Palpitations; increase in blood pressure (see WARNINGS AND PRECAUTIONS); coronary thrombosis, myocardial infarction.

Endocrine disorders

Increased blood sugar levels; decreased glucose tolerance, carbohydrate tolerance

Eye disorders

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

Gastrointestinal disorders

Nausea; vomiting; abdominal discomfort (cramps, pressure, pain), bloating, pancreatitis, gallbladder disorder; ischemic colitis.

General disorders and administration site conditions

Fatigue; changes in appetite; changes in body weight; changes in libido. exacerbation of porphyria, hypocalcemia (in patients with disease that can predispose to severe hypocalcemia), exacerbation of asthma, angioedema, hypersensitivity; anaphylactic/anaphlactoid reactions, increased triglycerides.

Hepatobiliary disorders

Gallbladder disorder; 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, arthralgias, leg cramps. [Sponsor Comment: Editorial Change]

Neoplasms, benign

Fibrocystic breast changes; enlargement of hepatic hemangiomas.

Nervous system disorders

Aggravation of migraine episodes; headaches; dizziness; cerebrovascular accident/stroke, exacerbation of epilepsy, stroke, exacerbation of chorea, somnolence, insomnia.

Psychiatric disorders

Mental depression; nervousness; irritability, anxiety, mood disturbances, dementia, fatigue.

Renal and urinary disorders

Cystitis; dysuria; sodium retention; edema.

Reproductive system and breast disorders

Breakthrough bleeding; spotting; change in menstrual flow and abnormal withdrawal bleeding or flow, dysmenorrheal/pelvic pain; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; vaginal candidiasis, amenorrhea, vaginitis, increase in size of uterine leiomyomata, breast swelling and tenderness, breast pain, enlargement, galactorrhea, breast discharge; growth potentiation of benign meningioma; leukorrhea.

Skin and subcutaneous tissue disorders

Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne, urticaria, pruritus, generalized rash, rash (allergic) with without pruritus, alopecia.

Vascular disorders

Isolated cases of: thrombophlebitis; thromboembolic disorders, venous thrombosis.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

A phase III double-blind, randomized study was conducted to compare the efficacy and safety of various regimens of Premarin® (conjugated estrogens) and medroxyprogesterone acetate (MPA). Efficacy was determined by the incidence of endometrial hyperplasia at the twelve month evaluation. A total of 1,724 generally healthy postmenopausal women (mean age, 54.0 years ± SD 4.6) participated in the study. The patients were considered as having completed the study if they participated in all 13 cycles (28 days/cycle). The five arms in the study were: 2 for Premplus®, 2 for Premplus Cycle®, and 1 for Premarin® alone.

Prior to treatment, the following were performed: physical examinations, vital signs, papanicolaou smear, laboratory safety screen, mammography, follicle stimulating hormone (FSH), and endometrial biopsy. During the patient visit for Cycle 6, all but the mammography and FSH were performed. At the end of the study, Cycle 13, all but the FSH were performed.

No dose-dependent incidence of adverse experiences was seen in the multicenter efficacy and safety study. Significantly (p< 0.05) fewer (12%) Premarin® treated patients reported breast pain than in the Premarin®/MPA groups. Headache was the most common drug-related study event in the Premarin® alone group, reported by 69 (20%) patients. Table 1 summarizes the treatment-emergent drug-related study events reported by 2% or more of the patients.

Table 1: Treatment-Emergent Drug-Related Study Events With an Incidence of ≥2%

Table 1: Treatment-Emergent Drug-Related Study Events With an Incidence of ≥2%

Table 1: Treatment-Emergent Drug-Related Study Events With an Incidence of ≥2%

Study Event

Premarin^® 0.625 mg CE

(n=347)

No. (%) of Patients ⁺

+ Patients were counted only once for a particular study event.

* Breast pain also includes breast discomfort, breast soreness, breast tenderness, mastodynia, nipple soreness and nipple tenderness.

** Cervix disorder includes cervical dysplasia, cervical erosion, cervical hypersecretion. † Pap smear abnormal refers to positive Pap smear class III through V.

*** Vaginal bleeding includes menorrhagia, metrorrhagia, uterine hemorrhage, and vaginal hemorrhage. a, b, d, = Significant difference ( p < 0.05) from treatment group Premplus® (0.625/2.5 mg), Premplus®

(0.625/5.0 mg), Premplus Cycle® (0.625/10.0 mg) and Premarin® (0.625 mg) respectively.

The above Table 1 summarizes the treatment-emergent drug-related study events reported by greater than 2% of the patients. The number of patients with any study event is not necessarily the sum of the individual events since a patient might have reported two or more different study events. The addition of progestin to estrogen replacement therapy may contribute to breast pain. This is reflected by the greater percentage of patients with breast pain on combination therapy than on Premarin alone.

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

Post Marketing Adverse Drug Reactions

The following adverse reactions have been reported with PREMARIN tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Genitourinary System

Abnormal uterine bleeding, dysmenorrhea/pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leucorrhea.

Breasts

Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.

Cardiovascular

Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

Gastrointestinal

Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.

Skin

Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central Nervous System

Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

Miscellaneous

Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps , changes in libido, urticaria, angioedema, anaphylactoid/anaphylactic reactions, exacerbation of asthma, increased triglycerides, hypersensitivity. [Sponsor Comment: Editorial Change]

Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

DRUG INTERACTIONS

Overview

In vitro and in vivo studies have shown that 17 ß-estradiol, one of the components of conjugated estrogens, is metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, strong CYP3A4 inducers, such as St. John’s Wort (Hypericum performatum) preparations, phenobarbitol, phenytoin, carbamazepine, rifampicin and dexamethasome may reduce plasma concentrations of 17 ß-estradiol. This may lead to a decreased effect and/or changes in the uterine bleeding profile. CYP3A4 inhibitors such as cimetidine, erythromycin, ketoconazole, clarithromycin, itraconazole, ritonavir may increase plasma concentrations of 17 ß-estradiol and may result in side effects. [Sponsor Comment: Editorial Change]

Data from a drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs are not altered when the drugs are co-administered. Other clinical drug-drug interaction studies have not been conducted with conjugated estrogens.

Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.

Drug-Drug Interactions

The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the public literature. The clinical significance of these drugs is unknown; additionally, it is unknown whether such interactions occur with drug products containing other types of estrogens. Monitoring of patient response to therapy is recommended.

Hepatic metabolism

Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (eg., rifampin, barbiturates, phenytoin, carbamazepine, troglitazone).

Gastrointestinal wall

Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal (GI) wall. Therefore, drugs which act as competitive inhibitors for sulfation in the GI wall may increase ethinyl estradiol bioavailability (eg., ascorbic acid, acetaminophen).

Interference in the metabolism of other drugs

Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (eg., oral contraceptives containing ethinyl estradiol). In addition, products containing ethinyl estradiol may induce the conjugation of other compounds.

Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl estradiol-containing drug products (eg., oral contraceptives containing ethinyl estradiol).

Other interactions with ethinyl estradiol

Coadministration of atorvastatin and certain ethinyl estradiol-containing drug products (eg., oral contraceptives) increase AUC values for ethinyl estradiol by 20 percent.

Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Drug-Food Interactions

CYP3A4 inhibitors such as grapefruit juice may increase plasma concentrations of 17 ß-estradiol and may result in side effects.

A single dose study in healthy, postmenopausal women was conducted to investigate any potential drug interaction when 2 x 0.625 mg Premarin (conjugated estrogens) and 2.5 mg medroxyprogesterone acetate (MPA) tablets were administered immediately following a high-fat breakfast. Administration with food slowed the absorption of the conjugated estrogens, thereby reducing the C_max of the various estrogens by 25% to 30%, and increasing MPA C_max by 89% and AUC_0-∞ by 28%. Thus, food slightly lowered the C_max, but did not affect the AUC, of the estrogens from a 0.625 mg Premarin tablet; food significantly increased the C_max and AUC of MPA from a 2.5-mg tablet.

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. Hot flashes and vaginal bleeding have been reported in patients taking estrogen replacement therapy (ERT) and combined estrogen plus progestin therapy (HRT) and St. John’s Wort (Hypericum perforatum) preparations. St. John’s Wort may induce hepatic microsomal enzymes, which theoretically may result in reduced efficacy of ERT and HRT.

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

Drug-Laboratory Test Interactions

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

• increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity, increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III;
• increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone (T4), as measured by column or radioimmunoassay;T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered;
• impaired glucose tolerance;
• increased serum triglycerides and phospholipids concentration;
• other binding proteins may be elevated in serum i.e., 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.

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 (HRT) when relevant specimens are submitted.

Drug-lifestyle interactions

Acute alcohol ingestion during HRT may lead to elevations in circulating estradiol levels.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The benefits and risks of HRT must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Use of estrogens alone or in combination with progestins therapy should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary (see boxed Serious Warnings and Precautions). For women who have intact uteri, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. In the absence of comparable data, the risks of HRT should be assumed to be similar for all estrogens and estrogen/progestin combinations.

Hormone replacement therapy (HRT) involving either estrogen alone or estrogen plus progestin combined therapy should only be continued as the benefits outweigh the risks for the individual.

Recommended Dose and Dosage Adjustment

Premarin therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug) as is medically appropriate on an individualized basis.

Continuous, non-cyclic therapy may be indicated in hysterectomized women or in cases where the signs and symptoms of estrogen deficiency become problematic during the treatment-free interval. In women with an intact uterus, a progestin should be coadministered for a minimum of 10, but preferably at least 12 to 14 days per cycle to avoid overstimulation of the endometrium. In addition, progestin should be administered to minimize the occurrence of endometrial hyperplasia. Unexpected or abnormal vaginal bleeding in such patients requires institution of prompt diagnostic measures, such as endometrial biopsy or curettage to rule out the possibility of uterine malignancy. Since progestins are administered to reduce the risk of hyperplastic changes of the endometrium, patients without a uterus do not require a progestin for this purpose.

For maintenance therapy one should always use the lowest dose that still proves effective. The requirement for hormone replacement therapy for menopausal symptoms should be reassessed periodically.

Usual Dosage Range

Menopausal symptoms

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Premarin daily, cyclically or continuously as is medically required. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level providing effective control.

Osteoporosis (loss of bone mass)

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Premarin daily. Subsequent dosage adjustments may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider.

Hypoestrogenism due to

1. 1. Female hypogonadism: 0.3 mg to 0.625 mg daily, administered cyclically (e.g., 3 weeks on and 1 week off) or continuously as required. Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.
2. 2. Female castration or primary ovarian failure: 1.25 mg daily, cyclically or continuously as required. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.

Atrophic Vaginitis

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Premarin daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.

Vulvar Atrophy

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg Premarin daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.

Administration

Oral

Premarin® should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma. Progestin therapy is not required as part of hormone replacement therapy in women who have had a previous hysterectomy.

Missed Dose

If a patient misses a dose, advise them to take the dose as soon as possible. If it is almost time for the patient’s next dose, advise the patient to skip the missed dose and go back to their normal schedule. Patients should not take 2 doses at the same time.

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, breast discomfort, fluid retention, bloating or vaginal bleeding in women.

Treatment of overdose

There is no specific antidote and further treatment if necessary should be symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.

Pharmacodynamics

Conjugated estrogens used in therapy are soluble in water and are well absorbed through the skin, mucous membranes, and gastrointestinal tract after release from the drug formulation.

For management of a suspected drug overdose, contact your regional Poison Control Centre. Effects on vasomotor symptoms associated with estrogen deficiency

Hot flushes, feelings of intense heat over the upper trunk and face, with flushing of the skin and sweating occur in approximately 80% of women as a result of the decrease in ovarian hormones. These vasomotor symptoms are seen in women whether menopause is surgically induced or spontaneous. However, hot flushes may be more severe in women who undergo surgical menopause. Hot flushes can begin before the cessation of menses.

Effects on Osteoporosis associated with estrogen deficiency

For several years following natural or induced menopause, the rate of bone mass decline is accelerated. Conjugated estrogens reduce bone resorption and retard postmenopausal bone loss. Case-control studies have shown a reduction of up to 60% in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause.³⁷ Studies also suggest that estrogen reduces the rate of vertebral fractures. One clinical study³⁸ demonstrated that even when estrogen was started as late as fifteen years after menopause, further loss of bone mass was prevented, but was not restored to premenopausal levels. The effect on bone mass conservation is sustained only as long as conjugated estrogens therapy is continued.

Effects on female hypogonadism

In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12-month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.

Effects on the Endometrium

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma.^{39, 40} The results of clinical studies indicate that the addition of a progestin to an estrogen replacement regimen for more than 10 days per cycle reduces the incidence of endometrial hyperplasia and the attendant risk of adenocarcinoma in women with intact uteri. The addition of a progestin into an estrogen replacement regimen has not been shown to interfere with the efficacy of estrogen replacement therapy for its approved indications.

Effect on bleeding patterns

With a continuous therapy, several bleeding patterns may occur. These may range from absence of bleeding to irregular bleeding. If bleeding occurs, it is frequently light spotting or moderate bleeding.

Pharmacokinetics

Absorption

Conjugated estrogens are soluble in water and are well absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation. However, PREMARIN contains a modified-release formulation of conjugated estrogens that slowly releases estrogens over several hours. Maximum plasma concentrations of the various conjugated and unconjugated estrogens are attained within 4 to 10 hours after dose administration.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and non-esterified forms.

Estrogen drug products administered by non-oral routes, while not subject to true “first-pass” metabolism, do undergo significant hepatic uptake, metabolism, and enterohepatic recycling. Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are re-absorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favour excretion through the kidneys since tubular re-absorption is minimal.

When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency.

Excretion

During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through 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).

Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

Special Populations and Conditions

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

STORAGE AND STABILITY

Store at 15◦C - 30◦C.

Keep out of reach of children.

Special Handling Instructions

None required.

DOSAGE FORMS, COMPOSITION AND PACKAGING

^PrPremarin7 Tablets are available as:

0.3 mg (green) tablets in bottles of 100, 500;

0.625 mg (maroon) tablets in bottles of 100, 1000;

and

1.25 mg (yellow) tablets in bottles of 100.

Non-Medicinal Ingredients: Each Premarin tablet contains:

Calcium Sulphate Anhydrous

Carnauba Wax

Glyceryl Monooleate

Lactose

Magnesium Stearate

Methylcellulose

Microcrystalline Cellulose

Pharmaceutical Glaze

Polyethylene Glycol

Stearic Acid

Sucrose

Titanium Dioxide

Edible Ink

In addition, the following ingredients are contained in specific strengths as indicated:

Erythrosine Aluminum Lake (0.625 mg) Methyl Parahydroxybenzoate (0.3mg) Povidone (0.3mg, 0.625 mg)

Propyl parahydroxybenzoate (0.3mg) Sodium Benzoate (0.3 mg, 0.625 mg) FD&C Blue No. 2 (0.3 mg, 0.625 mg) FD&C Yellow No. 6 (0.625 mg, 1.25 mg) Iron Oxide Yellow (0.3 mg)

Quinoline Yellow Lake (1.25 mg) PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Conjugated estrogens, C.S.D.

Chemical name: Not applicable

Molecular formula and molecular mass: Not applicable

Structural formula: Not applicable

Description: Conjugated estrogens C.S.D. contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of at least the following estrogens: estrone, equilin, 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, *8,9-dehydroestrone, 17β-estradiol, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin and as salts of their sulfate esters.

CLINICAL TRIALS

Published Studies

Vasomotor Symptoms

The Postmenopausal Estrogen Progestin Interventions (PEPI) Trial was a randomized clinical trial (RCT) in 875 postmenopausal women ages 45 to 64 years of age. Vasomotor symptoms were evaluated using a self-reported checklist at baseline, at 1 year, and at 3 years. The five treatment groups received either conjugated equine estrogens (CEE) 0.625 mg/day, CEE 0.625 mg/day plus cyclical (12 days per cycle) medroxyprogesterone acetate (MPA) 10 mg, CEE 0.625 mg/day plus MPA 2.5 mg/day, CEE 0.625 mg/day plus cyclical (12 days per cycle) micronized progesterone (MP) 200 mg, or placebo.

Key observations demonstrated that therapy with CEE alone and CEE with MPA and CEE with MP decreased levels of vasomotor symptoms in subjects over 36 months. On average there were no significant differences in symptom levels between each group.

At year 1, the adjusted odds of having higher vasomotor symptoms for continuous CEE with MPA vs. placebo were 0.17 (0.09, 0.32). At year 3, the adjusted odds for continuous CEE with MPA vs. placebo were 0.39 (0.22, 0.69). These reported results are the odds ratios with 95% confidence intervals from generalized Wald tests in parentheses.

Vasomotor Symptoms and Vaginal Atrophy

The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) Study was an RCT to evaluate the safety and efficacy of lower doses of CEE and MPA in postmenopausal women. The design included a one year basic study to evaluate the efficacy of lower doses of CEE with and without MPA in relieving vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA). A total of 2,673 healthy, postmenopausal women 40 to 65 years of age with an intact uterus (mean age of 53.3 years), including a vasomotor symptom efficacy-evaluable population (n=241 at baseline) participated.

Efficacy measures were frequency and severity of daily hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy.

There were a total of eight treatment arms consisting of the following:

CEE 0.625 mg/day; CEE 0.625 mg/MPA 2.5 mg/day; CEE 0.45 mg/day; CEE 0.45 mg/MPA 2.5 mg/day; CEE 0.45 mg/MPA 1.5 mg/day; CEE 0.3 mg/day; CEE 0.3 mg/MPA 1.5 mg/day; or placebo.

Key observations for VMS: All active treatment groups significantly reduced mean number of hot flushes from baseline by week 1 or 2 (P<0.01) and all active treatment groups significantly reduced mean number of hot flushes compared with placebo by week 2 or 3 (P<0.001).

Numbers of hot flushes

• For the placebo group, the mean daily number of hot flushes dropped from approximately 10 at week 1, to approximately 5 at week 12, and continuing at approximately 5 to cycle 13.
• For the 0.625 mg CEE/2.5 mg MPA treatment group, the mean daily number of hot flushes decreased from approximately 10 at week 1, to approximately 1 at week 12, dropping to approximately 0.5 at cycle 13. The difference from placebo was significant (P<0.5) beginning from week 2 to the end of cycle 13.

Severity of hot flushes

A mild hot flush was rated a 1, a moderate hot flush a 2, and a severe hot flush a 3.

• For the placebo group, the mean daily severity of hot flushes decreased from approximately 2.1 at week 1, to approximately 1.7 at week 12, and continuing at approximately 1.7 to cycle 13.

• The mean daily severity of hot flushes was significantly lower at all cycles in the

  CEE 0.625 group, compared with the CEE 0.45 group (P< 05). By cycle 2, mean severity in the CEE 0.625 group was significantly lower than in the CEE 0.3 group, and this difference continued through cycle 13 (P<.05).

Key observations for VVA: All active treatment groups significantly increased the percentage of superficial cells from baseline at cycles 6 and 13 (P<0.001) and all active treatment groups significantly increased the percentage of superficial cells compared with placebo at cycles 6 and 13 (P<0.001).

Osteoporosis – Bone Mineral Density

The PEPI Trial⁷ was a RCT in 875 postmenopausal women ages 45 to 64 years of age. This study was designed to assess the effects of CEE alone in comparison with CEE and MPA or MP on bone mineral density (BMD) at the spine and the hip as measured by dual-energy x-ray absorptometry (DXA) technology. Its primary measures were BMD scores at baseline, 12 months and 36 months. Five treatment groups received either CEE 0.625 mg/day, CEE 0.625 mg/day plus cyclical (12 days per cycle) MPA 10 mg, CEE 0.625 mg/day plus MPA 2.5 mg/day, CEE 0.625 mg/day plus cyclical (12 days per cycle) MP 200 mg, or placebo.

Key observations: Women in the placebo group lost significant amounts of BMD at both the spine and the hip compared with active treatments by month 12. All active treatment groups produced significant BMD gains at the spine and hip from baseline by month 12 continuing until month 36 compared with losses in the placebo group. At 36 months, the placebo group had lost an average of 1.8% of spine BMD, and 1.7% of hip BMD, while the active treatment groups gained from 3.5% to 5.0% mean total increases in spinal BMD and a mean total increase of 1.7% hip BMD.

The Women’s HOPE Study³² evaluated 822 healthy, postmenopausal women (mean age of 51.6 years) with a modified intent-to-treat population (n=695 at baseline) in a 2 year, randomized, double-blind, placebo controlled osteoporosis substudy.

The efficacy measures were changes in BMD of the lumbar spine (L2 to L4) and total hip, BMC of the total body as measured by DXA, and the two biochemical markers of bone turnover, osteocalcin and N-telopeptides of type I collagen.

There were a total of 8 treatment arms consisting of the following: CEE 0.625 mg/day; CEE 0.625 mg/MPA 2.5 mg/day; CEE 0.45 mg/day; CEE 0.45 mg/MPA 2.5 mg/day; CEE 0.45 mg/MPA 1.5 mg/day; CEE 0.3 mg/day; CEE 0.3 mg/MPA 1.5 mg/day; or placebo.

Key observations: Women in the placebo group experienced significant losses (P<0.001) in BMD at the spine compared with baseline at the 24 month visit. All dose formulations of CEE and CEE/MPA were effective in preventing bone loss at the spine and hip from baseline (P<0.001) and all were effective in reducing bone turnover from baseline (P<0.001).

The secondary analysis of the Women’s HOPE study³³ defined bone response to treatment. Response was defined as loss of >2%, <2% loss, or greater than or equal to 0% gain of spine or hip BMD from baseline at months 12 and 24.

The key findings were as follows:

• At 24 months, less than 15.5% of women failed to respond to active treatment (losing

  >2% in spine BMD) compared with 55.2% in the placebo group.

• At 24 months, less than 15% of women failed to respond to active treatment (losing >2% in hip BMD) compared with 36.5% in the placebo group
• Women who responded to treatment had a significantly greater reduction in markers of bone turnover (osteocalcin & N-telopeptides) at 12 months (P<0.0001 & P=0.0018, respectively) and at 24 months for both markers (P<0.0001) than women who did not respond to treatment.

Efficacy and Safety Studies

Study demographics and trial design

A phase III double-blind, randomized study was conducted to compare the efficacy and safety of various regimens of Premarin® and medroxyprogesterone acetate (MPA). Efficacy was determined by the incidence of endometrial hyperplasia at the twelve month evaluation. Patients in all five treatment groups took 0.625 mg of Premarin® every day of a 28-day cycle; in four groups, they also took MPA (see Table 2 below).³⁴

A total of 1,724 generally healthy postmenopausal women between the ages of 43 and 66 years were admitted to the study. They were eligible to participate in the study if they had their last natural menstrual cycle at least 12 months before entering the study (baseline screening). The serum screening follicle-stimulating hormone (FSH) concentrations had to be higher than the lower limit for postmenopausal women for the given laboratory. The women were relatively healthy and had intact reproductive organs.³⁴

The study was comprised of five arms: 4 Premarin® and MPA and 1 for Premarin alone, as indicated below. Each patient was to participate for 13 cycles (28 days/cycle). A total of 1,361 patients completed the study.

Table 2: Pivotal Trial Treatment Groups

Strengths (mg)

Treatment Group Premarin MPA Days of Use/Cycle

A 0.625 2.5 1-28 B 0.625 5.0 1-28 C* 0.625

0.625 Placebo

5.0

1-14 15-28 D* 0.625

0.625 Placebo

10.0

1-14 15-28 E 0.625 Placebo 1-28 * results from these two non-commercialized product presentations

have not been included in the “Study results” section.

Study results

Effects on the Endometrium

Table 3 summarizes the incidence of endometrial hyperplasia after one year of treatment³⁴ with the continuous (28 days/cycle of both the CE and MPA tablets) therapy.

Table 3: Incidence of Endometrial Hyperplasia after One Year of Treatment

.................Dose Groups.......................

Patient

Premarin^®/MPA

0.625 mg/2.5 mg

Premarin^®/MPA 0.625 mg/5.0 mg

Premarin^®

0.625 mg Total number of patients

No. (%) of patients with abnormal biopsies

• all focal and non-focal hyperplasia

  279

  2(<1)*

  274

  0(0)*

  283 57(20) *Significant (p<0.001) in comparison with Premarin alone (0.625 mg).

Premarin 0.625 mg tablets contain 0.625 mg CE per tablet.

Table 4 summarizes the incidence of endometrial hyperplasia after one year of treatment³⁴ with conjugated estrogen/medroxyprogesterone acetate, cyclic therapy (MPA tablets taken concomitantly with Premarin tablets only on days 15 to 28).

Table 4: Incidence of Endometrial Hyperplasia after One Year of Treatment

...............Dose Groups...............

Patient

Premarin^®/MPA

0.625 mg/10 mg

Premarin^®

0.625 mg Total number of patients

No. (%) of patients with abnormal biopsies

• all focal and non-focal hyperplasia

  272

  0(0)*

  283 57(20) *Significant (p<0.001) in comparison with Premarin alone (0.625 mg).

Women treated with Premarin and MPA had a significantly (p < 0.001) lower incidence of endometrial hyperplasia than women treated with Premarin alone.

Effect on bleeding patterns

Table 5 presents the incidence of amenorrhea for cycles 7 through 13, of the patient group who completed the study with a continuous regimen of Premarin 0.625 mg alone.

Table 5: Incidence of Amenorrhea for Cycles 7 through 13

Withdrawals from the clinical study

Safety-related events were the most common primary reasons for withdrawal from the clinical study except in the group treated with Premarin 0.625 mg CE/10 mg MPA, in which patient request predominated. The reasons for patient withdrawal and the number of patients withdrawn for each of these reasons are shown in Table 6 below.

Table 6: Summary of reasons for withdrawals from clinical study

---------------------------Number of Patients (%)---------------------------- Study Drug #

patients

Safety-

Related

Reasons

Failed

to

Return

Other Medical Event

Other

Non-

medical

Event

Patient Request

Prestudy Screen or Protocol Violation

Lack Of

Efficacy^a

0.625 mg for 28 days

in each group:

2.5 mg MPA/28 days 340 20 (6) 6 (2) 5 (1) 5 (1) 12 (4) 10 (3) 1 (<1) 5.0 mg MPA/28 days 338 19 (6) 8 (2) 8 (2) 4 (1) 10 (3) 10 (3) 2 (<1) 10 mg MPA/14 days 348 24 (7) 6 (2) 8 (2) 7 (2) 27(8) 6 (2) 1 (<1) No MPA 347 42 (12) 6 (2) 14 (4) 1 (<1) 15 (4) 14 (4) 0 a: Interpreted by the investigator as lack of symptom control

DETAILED PHARMACOLOGY

See “Action and Clinical Pharmacology” section under the Health Professional Information Section.

TOXICOLOGY

Acute toxicity studies have been conducted with conjugated estrogens (Premarin^®).

Acute Toxicity

Premarin^®

In studies conducted by Wyeth, Premarin (125 mg/kg) was administered orally. The LD₅₀ value for Premarin administered orally or intraperitoneally to male and female CD-1 mice and CD rats was greater than 125 mg/kg.

REFERENCES

SELECTED BIBLIOGRAPHY

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