PRODUCT MONOGRAPH

Prpms-CONJUGATED ESTROGENS CSD (Conjugated Estrogens) Tablets, CSD 0.3, 0.625, 0.9 and 1.25 mg

Estrogenic Hormones

PHARMASCIENCE INC.

Date of Preparation:

6111 Royalmount Avenue, Suite 100 February 12, 1999 Montreal, Quebec H4P 2T4

Control #: 084722

Date of Revision: February 19, 2004

PRODUCT MONOGRAPH

Prpms-CONJUGATED ESTROGENS C.S.D. (Conjugated Estrogens) Tablets, CSD 0.3, 0.625, 0.9 and 1.25 mg

PHARMACOLOGIC CLASSIFICATION

Estrogenic Hormones

Warning

As the Women's Health Initiative (WHI) study results indicated increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli and deep venous thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens and medroxyprogesterone acetate compared to those receiving placebo tablets, the following should be highly considered:

• 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.

• In the prevention and/or treatment of osteoporosis, pms-CONJUGATED ESTROGENS should be considered in light of other available therapies.

• Estrogens with or without progestins should be prescribed for the shortest period possible for the recognized indication.

ACTION AND CLINICAL PHARMACOLOGY

Estrogen drug products act by regulating the transcription of a limited number of genes. They may act directly at the cell's surface via non "estrogen receptor" mechanism or directly with the estrogen receptor inside the cell. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in the wall of blood vessels, in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals. Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone -- especially in its sulfate ester form -- is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.

Clinical Pharmacology of Estrogen

In postmenopausal women already diagnosed with osteoporosis and vertebral fractures, treatment with pms-CONJUGATED ESTROGENS may prevent further loss of bone mass. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. The estrogens in pms-CONJUGATED ESTROGENS are from a synthetic plant derived source. The estrogen components are the same as the main other equine or synthetic derived products. Therefore, we expect similar pharmacology. pms-CONJUGATED ESTROGENS contains: 46.0- 70.0% sodium estrone sulfate, 18.5-37.5% sodium equilin sulfate, and 6.5-21.0% sodium 17"- dihydroequilin sulfate. Results of studies based on equine products are presented below.

Clinical Trials

Effects on Vasomotor Symptoms

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805 postmenopausal women (average age 53.3 +- 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least 7 moderate to severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before randomization. Equine conjugated estrogen (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the conjugated estrogen 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.

TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY- MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF 1

T

reatment

(No. of Patients) --------------- No. of Hot Flushes/Day ------------------

Time Period Baseline Observed Mean p-Values (week) Mean +- SD Mean +- SD Change +- SD vs. Placeboa

0.625 mg CE

(n = 27)

4 12.29 +- 3.89 1.95 +- 2.77 -10.34 +- 4.73 <0.001

12 12.29 +- 3.89 0.75 +- 1.82 -11.54 +- 4.62 <0.001

0.45 mg CE

(n = 32)

0.3 mg CE

(n = 30)

Placebo (n = 28)

a: Based on analysis of covariance with treatment as factor and baseline as covariate.

Effects on Vulvar and Vaginal Atrophy

Last Observation Carried Forward.

The first part of the HOPE study reports results from the first year of the study on the efficacy of three lower dosage combinations of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. This study was a randomized, double-blind, placebo-controlled trial (The Women's Health, Osteoporosis, Progestin, Estrogen study, or HOPE). Two thousand, six hundred, seventy-three healthy, postmenopausal women with intact uterus, including an efficacy-evaluable population (n=241 at baseline) took part in the study. Patients received for 1 year (13 cycles; in miligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE 0.45; CEE 0.45 and MPA 2.5; CEE 0.45 and MPA 1.5; CEE 0.3; CEE 0.3 and MPA 1.5; or placebo. The main outcome measures were the number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p<0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).

Effects on Bone Mineral Density

Health and Osteoporosis, Progestin and Estrogen (HOPE) Study

The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 +- 4.9 years) were 2.3 +- 0.9 years, on average, since menopause, and took one 600-mg tablet of elemental calcium (Caltrate) daily. Subjects were not given vitamin D supplements. They were treated with conjugated equine estrogen 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.

Intent-to-treat Subjects

All active treatment groups showed significant differences from placebo in each of the 4 BMD endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 2.46% with 0.625 mg, 2.26% with 0.45 mg, and 1.13% with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45%. These results show that the lower dosages of conjugated estrogen were effective in increasing L2 to L4 BMD compared with placebo and, therefore, support the efficacy of the lower doses. The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L2 to L4 and changes in femoral neck and total body that were generally smaller than those seen for L2 to L4. Significant differences between groups indicated that each of the conjugated estrogen treatments was more effective than placebo for all 3 of these additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all showed mean percent increases in BMD while placebo treatment was accompanied by mean percent decreases. For femoral trochanter, each of the conjugated estrogen dose groups showed a mean percent increase that was significantly greater than the small increase seen in the placebo group. The percent changes from baseline to final evaluation are shown in Table 3.

TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION,

LAST OBSERVATION CARRIED FORWARD

a

: Identified by dosage (mg) of conjugated equine estrogen or placebo.

Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater than the value shown on the x-axis. Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN CONJUGATED EQUINE ESTROGEN AND PLACEBO GROUPS T h e mean percent change from baseline in L2 to L4 BMD for women who completed the bone density study is shown with standard error bars by treatment group in Figure 2. Significant differences between each of the conjugated estrogens dosage groups and placebo were found at cycles 6, 13, 19, and 26. Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN CONJUGATED EQUINE ESTROGEN GROUPS AND PLACEBO The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (P<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.

Women's Health Initiative Studies

The Women's Heath Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of conjugated equine estrogen (0.625 mg per day) alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of conjugated estrogen or conjugated estrogen/medroxyprogesterone acetate on menopausal symptoms. The conjugated estrogen-only substudy is continuing and results have not been reported. The conjugated estrogen/medroxyprogesterone acetate substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". Results of the conjugated estrogen/medroxyprogesterone acetate substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 4 below.

a: adapted from JAMA, 2002; 288:321-333

b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer

c: a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture or death due to other causes

d: not included in Global Index

* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with Conjugated Estrogen/Medroxyprogesterone were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per I 0,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Pharmacokinetics of pms-CONJUGATED ESTROGENS

Conjugated estrogens used in therapy are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However, pms-CONJUGATED ESTROGENS contains a modified-release formulation of conjugated estrogens that slowly releases estrogens over several hours. Estrogens used in therapy are also well absorbed through the skin and mucous membranes. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Administered estrogens and their esters are handled within the body essentially the same way as the endogenous hormones. 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. Although naturally-occuring estrogens circulate in the blood largely bound to sex hormone- binding globulin (SHBG) and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile, then reabsorbed from the intestine and returned to the liver through the portal venous system. 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). 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. 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.

Pivotal Clinical Trails

No information is available on pivotal clinical trials conducted with pms-CONJUGATED ESTROGENS.

CONTRAINDICATIONS

Conjugated Estrogens Tablets, C.S.D. should not be administered to patients with any of the following conditions:

• personal history of known or suspected estrogen-dependent neoplasia such as breast or endometrial cancer

• undiagnosed abnormal genital bleeding

• known or suspected pregnancy

• active hepatic dysfunction or disease, especially of the obstructive type

• active or past history of confirmed venous thromboembolism (such as deep venous thrombosis or pulmonary embolism) or active thrombophlebitis.

• endometrial hyperplasia

• active or past history of arterial thromboembolic disease (eg. cerebrovascular accident, myocardial infarction, coronary heart disease)

• classical migraine

• partial or complete loss of vision due to ophthalmic vascular disease

• pms-CONJUGATED ESTROGENS should not be used in patients that are hypersensitive to any of its components.

• Lactation

WARNINGS

See Boxed Warnings at the front page.

CARDIOVASCULAR DISORDERS

Available epidemiological data indicate that use of estrogen with or without progestin is associated with an increased risk of stroke, and coronary heart disease. WHI- trial's results concluded that there are more risks than benefits among women using combined Hormone Replacement Therapy (HRT), compared to the group using placebo. In 10,000 women on combined HRT (conjugated equine estrogens/medroxyprogesterone acetate) over one year period, there were seven more cases of coronary heart disease (37 on combined HRT versus 30 on placebo) and eight more cases of strokes(29 vs 21). 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 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, 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.

BREAST CANCER

Current epidemiological data indicate that the use of combined HRT is associated with an increased risk of invasive breast cancer. WHI- trial's results concluded that there are more risks than benefits among women using combined HRT (conjugated equine estrogens/medroxyprogesterone acetate), compared to the group using placebo. In 10,000 women on combined HRT over one year period, there were eight more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo). The WHI study reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD], 1.7cm [1.1] vs 1.5cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The WHI trial also reported that 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. It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease. 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 HRT(as reported in the results of 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.

VENOUS THROMBOEMBOLISM

Recent epidemiological data indicate that use of estrogen with or without progestin is associated with an increased risk of developing venous thromboembolism (VTE). WHI- trial's results concluded that there are more risks than benefits among women using combined HRT (conjugated equine estrogens/medroxyprogesterone acetate), compared to the group using placebo. In 10,000 women on combined HRT over a period of one year, there were eighteen more cases of total blood clots in the lungs and legs (34 on combined HRT versus 16 on placebo). 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) and severe obesity (body mass index > 30 kg/m2). The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major elective surgery or posttraumatic surgery, or major trauma(if feasible, estrogens 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). 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.

ENDOMETRIAL HYPERPLASIA & ENDOMETRIAL CARCINOMA

Estrogen-only HRT increases the risk of endometrial hyperplasia (if taken by women with intact uteri). There is evidence from several studies that estrogens unopposed by progestins ( if taken by women with intact uteri) increases the risk of endometrial hyperplasia and the risk of endometrial carcinoma. Endometrial hyperplasia may be a precursor to endometrial carcinoma. The addition of a progestin to estrogen therapy (in women with intact uteri) has been shown to reduce the incidence of endometrial hyperplasia.

GALLBLADDER DISEASES

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

DEMENTIA

Current epidemiological evidence indicates that the use of combined HRT is associated with a significantly increased risk of developing probable dementia. The Women's Health Initiative Memory Study, a clinical substudy of the WHI, followed 4532 post-menopausal women age 65 and over and free of dementia at baseline. There was a reported two-fold increase in the relative risk of developing probable dementia after an average follow-up of 4.05 years in the group treated with daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone versus those treated with placebo (hazard ratio [HR] 2.05, 95% confidence interval [CI], 1.21-3.48). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year (45 vs 22 per 10 000 person-years; P=.01)

PRECAUTIONS

Before pms-CONJUGATED ESTROGENS is administered, the patient should have a complete physical examination including blood pressure determination. Breasts and pelvic organs should be examined and a Papanicolaou smear should be taken. Endometrial biopsy should be done 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 three to six months after of initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals

at least once a year and should include at least those procedures outlined above.

It is important that patients are encouraged to practice frequent self-examination of the breasts.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt diagnostic measures like hysteroscopy, endometrial biopsy or curettage to rule out the possibility of uterine malignancy and the treatment should be re-evaluated. Pre-existing uterine leiomyoma may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyoma requires discontinuation of medication. Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use. Caution is advised in patients with a history of estrogen-related jaundice and pruritus. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out. Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication. If feasible, estrogens 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. Women using hormonal replacement therapy (HRT) 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 therapy may have to be discontinued. Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. Treatment should be stopped if there is an increase in epileptic seizures. 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. 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. A worsening of glucose tolerance and lipid metabolism have 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. Women with familial hypertriglyceridemia or porphyria need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started. 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 the section under Laboratory Tests. Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive-tract disorders. In females there is an increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and cancer later in life; in the male, of urogenital abnormalities. Although some of these changes are benign, it is not known whether they are precursors of malignancy.

Drug Interactions

Estrogens may diminish the effectiveness of anticoagulants, antidiabetic and antihypertensive agents. Preparations affecting liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens. The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the public literature. It is unknown whether such interactions occur with drug products containing other types of estrogens.

1. The metabolism of ethinyl estradiol is increased by rifampin and anticonvulsants such as phenobarbital, phenytoin and carbamazepine. Coadministration of troglitazone and certain ethinyl estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol) reduce the plasma concentrations of ethinyl estradiol by 30 percent.

Ascorbic acid and acetaminophen may increase AUC and/or plasma concentrations of ethinyl estradiol. Coadministration of atorvastatin and certain ethinyl estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol) 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 products containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (e.g., oral contraceptives containing ethinyl estradiol). In addition, these drugs 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 (e.g., oral contraceptives containing ethinyl estradiol). Concomitant administration of aminoglutethimide with medroxyprogestrone acetate (MPA), may significantly reduce the bioavailability of MPA. It was found that some herbal products (e.g St. John's wort) which are available as OTC products might affect metabolism, and therefore, 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.

Laboratory Tests

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 norepinephrine- induced platelet aggregability; decreased antithrombin III; increased thyroxin-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by column or radiominnunassay; free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered; 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; reduced response to the metyrapone test; reduced serum folate concentration;

• increased serum triglyceride and phospholipid concentration, increased plasma HDL and HDL-2 subfraction concentration, reduced LDL cholesterol concentration, increased triglyceride levels;

impaired glucose tolerance 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 HRT therapy when relevant specimens are submitted.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms

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. Over dosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.

Treatment

All of the ingested drug should be removed by gastric lavage and symptomatic treatment given.

DOSAGE AND ADMINISITRATION

pms-CONJUGATED ESTROGENS 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 and therefore minimize the occurrence of endometrial hyperplasia. 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.

Usual Dosage Range

Menopausal symptoms

: 0.625 -1.25 mg 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): 0.625 mg daily. Hypoestrogenism due to:

A. Female hypogonadism

: 0.3 mg to 0.625 mg daily, administered cyclically (e.g., 3 weeks on and I week off) or continuously as required. Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.

1. 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

: 0.3 mg to 1.25 mg daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.

Vulvar Atrophy

: 0.3 mg to 1.25 mg daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.

PHARMACEUTICAL INFORMATION

Availability of Dosage Forms

pms-CONJUGATED ESTROGENS are available as: 0.3 mg (green) oval-shaped sugar coated tablets in bottles of 100. 0.625mg (red) oval-shaped sugar coated tablets in bottles of 100, 500. 0.9 mg (pink) oval-shaped sugar coated tablets in bottles of 100. 1.25 mg (yellow) oval-shaped sugar coated tablets in bottles of 100, 500.

Medicinal Ingredient

: conjugated estrogens (46.0-70.0% sodium estrone sulfate, 18.5-37.5% sodium equilin sulfate, and 6.5-21.0% sodium 17"-dihydroequilin sulfate).

Non-medicinal ingredients

: acacia, calcium light, candy varnish, carnauba wax, colloidal silicon, microcrystalline cellulose, stearic acid, talc, sucrose, purified water,

0.3 mg tablets also contain: titanium dioxide and Opalux green AS-3385. 0.625 tablets also contain: Opalux maroon AS-3911. 0.9 mg tablets also contain: titanium dioxide and Opalux pink AS-1481 1.25 mg tablets also contain: titanium dioxide and Opalux yellow AS-2110

STORAGE RECOMMENDATIONS

pms-CONJUGATED ESTROGENS tablets should be stored between 15 and 30o C. Keep out of the reach of children.

INFORMATION FOR THE CONSUMER USING pms-CONJUGATED ESTROGENS

This leaflet describes when and how to use pms-CONJUGATED ESTROGENS and the risks of estrogen treatment. Please read this INFORMATION FOR THE CONSUMER carefully before you start taking pms-CONJUGATED ESTROGENS and each time you refill your prescription. If you want to know more or have any questions, please ask your doctor or pharmacist.

Warning

The results of the Women's Health Initiative (WHI) study indicated increased risk of myocardial infarction (heart attack), stroke, invasive breast cancer, pulmonary emboli (blood clots in the lungs) and deep venous thrombosis (blood clots in the leg veins) in postmenopausal women receiving treatment with combined conjugated equine estrogens and medroxyprogesterone acetate (a progestin medication). Therefore, you should consider the following:

• pms-CONJUGATED ESTROGENS should not be used for preventing heart disease or stroke.

• The use of estrogens, with or without progestins, may increase your risk of developing invasive breast cancer, heart attack, stroke and blood clots in the legs and lungs.

• pms-CONJUGATED ESTROGENS should be prescribed at the lowest effective dose and for the shortest period of time.

INTRODUCTION

WHAT IS pms-CONJUGATED ESTROGENS?

pms-CONJUGATED ESTROGENS (conjugated estrogens) contains a mixture of estrogens obtained exclusively from natural sources.

Estrogen Drugs

Estrogens have several important uses but also some risks. pms-CONJUGATED ESTROGENS should be used only under a doctor's supervision. You should see your doctor at least once a year while you are taking pms-CONJUGATED ESTROGENS. Your visit may include a blood pressure check, a breast exam and a Pap smear and pelvic exam. Your doctor may suggest scheduling regular mammograms (breast x-rays), and may recommend some blood tests. You should decide with your doctor if the potential benefits of estrogen treatment outweigh the possible risks for you. If you decide to start taking estrogens, check with your doctor to make sure you are using the lowest possible effective dose. The length of your treatment with estrogens will depend on the reason for use and your response to treatment. You should regularly discuss the length of your treatment with your doctor.

WARNINGS AND PRECAUTIONS

The use of estrogens has been reported to increase the risk of endometrial hyperplasia (overgrowth of the lining of the uterus) and endometrial carcinoma (cancer of the lining of the uterus). A recent study has indicated that the use of combined hormone replacement therapy (combined estrogen and progestin therapy) is associated with an increased risk of invasive breast cancer. Estrogens should not be taken by women who have a personal history of breast cancer. In addition, women with a family history of breast cancer or women with a history of breast lumps, breast biopsies or abnormal mammograms (breast x-rays) should consult with their doctor before starting hormone replacement therapy (HRT). Women should have a mammogram before starting HRT and at regular intervals during treatment as recommended by their treating physician.

Regular breast examinations by a physician and regular breast self-examinations are recommended for all women.

Recent studies indicate that the use of estrogen with or without progestin is associated with an increased risk of developing venous thromboembolism (blood clots in the veins). This risk also increases with age, if you or a family member has had blood clots, if you smoke or if you are severely overweight. The risk of blood clots is also temporarily increased if you are immobilized for long periods of time and with major surgery. Your doctor may recommend that you temporarily discontinue taking hormone replacement therapy in advance of expected hospitalizations or surgery. The use of estrogen therapy with or without progestin therapy has been associated with an increased risk of stroke and heart attack. The use of oral estrogens after menopause has been reported to increase the risk of gallbladder disease requiring surgery. Current studies indicate that the use of combined estrogen and progestin in women age 65 and over may increase the risk of developing probable dementia (loss of memory and intellectual function). To help your doctor decide whether you should use pms-CONJUGATED ESTROGENS and what precautions should be taken during use, tell your doctor: what other prescription and nonprescription medicines, if any, you are taking. There are some medicines which interfere with the effects of estrogens and estrogens may interfere with the effects of other medicines. about your allergies or sensitivities to medicines or any other substances; if you have ever had any of the following: high blood pressure heart, kidney, or liver disease asthma epilepsy (seizures) or other neurological disorders diabetes depression abnormalities of the breast or uterus including cancer and endometriosis breast disease, breast biopsies uterine fibroids phlebitis (inflamed veins) stroke, heart attack or blood clot migraine headache high triglyceride levels. jaundice porphyria -systemic lupus erythematosus abnormal calcium levels

How Supplied

pms-CONJUGATED ESTROGENS for oral administration are available as follows:

SELECTED BIBLIOGRAPHY

1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002; 288(3):321-333.

2. Hulley S, Grady D, Bush T, et al for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women, JAMA. 1998; 280(7):605- 613.

3. Grady S, Herrington D, Bittner V, et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/progestin replacement study follow-up (HERS II). JAMA. 2002; 288(1):49-57.

4. Chlebowski RT, Hendrix SL, Langer RD, et al. The Women's Health Initiative randomized trial. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA. 2003; 289(24):3243-3253.

5. Shumaker S.A, Legault, C, Rapp SR, et al. The Women's Health Initiative Memory Study: A randomized controlled trial. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA. 2003; 289(20):2651-2662.

6. Canadian Menopause Consensus ConferenceJ Soc Obstet Gynecol Can 1994; 16: 1-40.

7. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-27.

8. Lindsay R, Tohme JF. Estrogen treatment of patients with established menopausal osteoporosis, Obstet Gynecol 1990; 76:290-5.

9. Lobo RA. Treatment of the postmenopausal women: basic and clinical aspects. New York: Raven Press, 1994.

10. Medical Management of the Menopause. A Report by the Special Advisory Committee on Reproductive Physiology to the Drugs Directorate. Health Protection Branch. Health Canada.1995

11. Primary Care Guidelines for the diagnosis and management of osteoporosis. Scientific Advisory Board to the Osteoporosis Society of Canada. Submitted for publication: Can Med Assoc J, May 1996.

12. Writing Group for the PEPI Trial. Effects of hormones therapy on bone mineral density. Results from the Postmenopausal Estogen/Progestin Interventions (PEPI) Trial. JAMA 1996; 276(17):1389-1396.

13. TPD Working Paper for Product Monographs of Non-Contraceptive Estrogen & Estrogen+ Progestin Products, February 2003.

14. HOPE (Women's Health, Osteoporosis, Progestin, Estrogen trial) Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001; 75:1080-1087.

15. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and wiithout medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002; 287:2668-2676.

16. Pickar JH, Yeh I, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 76:25-31.

17. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75:1065-1079.

18. Prescribing Information for Premarin(r), website premarin.com.