Premplus

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. 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.

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

A single dose study in healthy, postmenopausal women was conducted to investigate any potential drug interaction when 2×0.625 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.

Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.

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;

  
  

• impaired glucose tolerance;

  
  

• increased serum triglycerides and phospholipids concentration.

  
  

• increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone (T₄), as measured bycolumn or radioimmunoassay; T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ concentrationis 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;

  
  

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.

In vitro and in vivo studies have shown that 17β-estradiol, one of the components of conjugated estrogens, is metabolized partially by Cytochrome P450 3A4 (CYP3A4). Therefore, strong CYP3A4 inducers such as phenobarbitol, phenytoin, carbamazepine, rifampicin and dexamethasome may reduce plasma concentrations of 17β-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, and ritonavir may increase plasma concentrations of 17β-estradiol and may result in side effects.

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.

Preparations inducing liver enzymes (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens.

Use of estrogens alone or in combination with progestins therapy should be limited to 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.

A dose of one maroon 0.625 mg conjugated estrogens (Premarin) tablet administered for 28 days at the same time each day and one peach 10 mg MPA tablet to be taken at the same time from day 15-28 of a 28-day cycle, when a cyclic regimen where a higher dose of medroxyprogesterone acetate is needed and regular withdrawal bleeding is medically appropriate on an individualized basis.

Additional factors which should be taken into consideration when adjusting the dose should include the patient’s medical history, occurrence of adverse events, laboratory results and physical and gynecological examination. Patients should be re-evaluated at regular intervals.

Oral.

If a patient misses a dose, it should be taken as soon as possible. If it is close to the patient’s next scheduled dose, the missed dose should be skipped, and the patient should continue with her normal schedule. The patient should not take two doses at the same time.

anorgasmia, breast engorgement, cervix carcinoma, endometrial carcinoma, endometrial hyperplasia, fibrocystic breast, genital edema, labial edema, mastitis, salpingitis, uterine enlargement, uterine fibroids enlarged, uterine neoplasm, vulvovaginitis.

abnormal vision, abnormality of accommodation, amblyopia, conjunctivitis, diplopia, dry eyes, eye haemorrhage, eye pain, lacrimation, visual field defect.

goiter, hypothyroidism, pituitary activity increased.

Enlargement of hepatic hemangiomas; angioedema, increased triglycerides.

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

anorexia, bilirubinemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperlipemia, hypocalcemia, obesity, increased appetite.

fever, hypothermia, malaise, moniliasis, ulcer.

angina pectoris, extrasystoles, palpitation, phlebitis, postural hypotension, spider angioma, tachycardia, varicose vein.

breast neoplasm, cervix neoplasm.

asthma, bronchitis, dyspnea, epistaxis, pharyngitis, pneumonia, rhinitis, sinusitis.

abnormal dreams, agitation, amnesia, anxiety, hyperesthesia, hypoesthesia, neurosis, paresthesia, reflexes decreased, somnolence, tinnitus, thinking abnormal, tremor, vertigo.

hematuria, nocturia, oliguria, polyuria, urinary incontinence, urinary tract infection, urinary urgency.

bladder pain, cystitis.

contact dermatitis, dry skin, eczema, fungal dermatitis, hair discolouration, herpes simplex, herpes zoster, hirsutism, maculopapular rash, skin carcinoma, skin discoloration, skin benign neoplasm, skin hypertrophy, sweating, urticaria.

flu syndrome.

arthralgia, arthritis, bursitis, myalgia, myasthenia, tenosynovitis, muscle twitching, neck pain.

cholecystitis, cholelithiasis.

hypertension, vasodilatation, thrombophlebitis.

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

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

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.

fibrinolysis increased, serum glutamic oxaloacetic transaminase (AST) increased.

anaemia, hypochromic anaemia, leucopenia, lymphocytosis, lymphadenopathy.

allergic reaction, face edema.

hostility, libido decreased, anorgasmia.

colitis, constipation, dry mouth, enterocolitis, eructation, gastritis, gingivitis, glossitis, increased appetite, mouth ulceration, periodontal abscess, rectal hemorrhage, salivary gland enlargement, stomach ulcer, taste perversion, tenesmus, thirst, tongue edema, vomiting.

See above indications.

Premplus and Premplus Cycle are not indicated for use in children.

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. Overdosage with MPA, in female patients, may result in a period of amenorrhea of variable length and may be followed by irregular menses for several cycles. No cases of overdosage in male patients have been reported. However, such overdosage, if it were to occur, would not likely result in any particular symptomatology.

Symptomatic treatment should be given in the case of estrogen overdosage. There is no known therapy for overdosage of medroxyprogesterone. Doses as high as 1000 mg of medroxyprogesterone for the therapy of endometrial carcinoma have been used without adverse effect.

Each oval, maroon tablet, branded “0.625” on one side in white ink, contains: conjugated estrogens C.S.D. 0.625 mg. Each oval, white MPA tablet, scored on one side, debossed with 2 opposing “C”s on the other side, contains: medroxyprogesterone acetate 2.5 mg. Nonmedicinal ingredients: maroon Premarin tablet: calcium sulfate, carnauba wax, edible ink, erythrosine aluminum lake, FD&C Blue No. 2, FD&C Yellow No. 6, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pharmaceutical glaze, polyethylene glycol, povidone, sodium benzoate, stearic acid, sucrose and titanium dioxide; white MPA tablet: lactose, magnesium stearate, methylcellulose and microcrystalline cellulose. Blister cards (×2) of 14 Premarin and 14 MPA, cartons totalling 56 tablets.

Each oval, maroon tablet, branded “0.625” on one side in white ink, contains: conjugated estrogens C.S.D. 0.625 mg. Each oval, purple MPA tablet, scored on one side, debossed with 2 opposing “C”s on the other side, contains: medroxyprogesterone acetate 5 mg. Nonmedicinal ingredients: maroon Premarin tablet: calcium sulfate, carnauba wax, edible ink, erythrosine aluminum lake, FD&C Blue No. 2, FD&C Yellow No. 6, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pharmaceutical glaze, polyethylene glycol, povidone, sodium benzoate, stearic acid, sucrose and titanium dioxide; purple MPA tablet: D&C Blue No. 1 aluminum lake, D&C Red No. 30 aluminum lake, lactose, magnesium stearate, methylcellulose and microcrystalline cellulose. Blister cards (×2) of 14 Premarin and 14 MPA, cartons totalling 56 tablets.

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, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

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

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.

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.

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

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.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication 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, medication should be withdrawn.

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

Estrogens/progestins should not be used during pregnancy.

Of the total number of subjects in the conjugated equine estrogens in combination with medroxyprogesterone acetate substudy of the Women’s Health Initiative study (WHI), 44% (n=7320) were 65 years and over, while 6.6% (n=1095) were 75 and over. No significant differences in relative risks were observed between subjects 65 years and over compared to younger subjects. There was a higher relative risk of stroke and invasive breast cancer in women 75 and over compared to younger subjects.

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.

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

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

Women with porphyria need special surveillance.

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. Estrogen-containing products have been shown to increase plasma HDL and HDL-2 subfraction concentrations, reduce LDL cholesterol concentration, and increase triglyceride levels.

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

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.

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 with or without progestins 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 with or without progestins for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).

Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.

It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

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.

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.

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.

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).

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

The role of progestin, when combined with estrogen, is to help prevent endometrial hyperplasia/carcinoma in women with intact uteri.

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. Most studies show no significant increased risk associated with the use of estrogens for less than one year. 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 estrogen therapy is discontinued.

In a subset of WHI no increased risk of endometrial cancer after an average of 5.2 years of treatment with combined estrogen plus progestin HRT compared to placebo was observed.

Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1% or less with CEE or CEE/MPA in two large clinical trials [Health and Osteoporosis, Progestin and Estrogen (n=2153) and Menopausal Study Group (n=1385)]. In these two clinical trials two cases of endometrial cancer were reported to occur among women taking combination CEE/MPA.

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.

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

Premplus and Premplus Cycle are not indicated for use in children.

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

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

The estrogen plus progestin substudy of WHI (CE/MPA versus placebo) reported a non-statistically significant increased risk of ovarian cancer. However, limitations of this study include only 5.6 years of follow-up, and the low number of ovarian cancer cases (20 of 8506 subjects in the estrogen plus progestin group and 12 of 8102 subjects in the placebo group were diagnosed with invasive ovarian cancer).

Before Premplus or Premplus Cycle 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. 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.

Estrogens with or without progestins 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.

Premplus and Premplus Cycle contain lactose. In patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the severity of the condition should be taken into careful consideration before prescribing Premplus or Premplus Cycle. The patients should be closely monitored.

HRT has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, HRT should be discontinued immediately.

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

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.

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.

Estrogen should not be used during lactation.

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

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.

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 concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin albumin (50-80% bound to plasma proteins). MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.

Coadministration of conjugated estrogens with MPA does not affect the pharmacokinetic profile of MPA; similarly, MPA does not affect the pharmacokinetic profile of the conjugated or unconjugated estrogens.

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. A double-blind, randomized, parallel study has confirmed a significant reduction in hot flushes experienced by menopausal women taking Premplus or Premplus Cycle.

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

By a direct action, endogenous estrogens 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. Indirectly, they also contribute to the shaping of the skeleton, maintenance of tone and elasticity through the increase of collagen production in the supportive tissues of the heart, skin and urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair and pigmentation of the nipples and genital tissues. Decline of ovarian estrogenic and progestogenic activity at the end of the menstrual cycle can result in menstruation, although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However, in the preovulatory or anovulatory cycle, estrogen is the primary determinant in the onset of menstruation.

Estrogen products act by regulating the transcription of a limited number of genes. 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 tissues of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women.

Progesterone is secreted by the ovary mainly from the corpus luteum during the second half of the menstrual cycle. Progesterone released during the luteal phase of the cycle leads to the development of a secretory endometrium. Estrogen precedes and accompanies progesterone in its action upon the endometrium and is essential to the development of the normal endometrial pattern.

Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.

The purpose of adding a progestin medication to long-term estrogen therapy is to reduce the risk of endometrial hyperplasia in women with intact uteri.

Some estrogens are excreted in bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates with only minor amounts excreted as sulfates.

The apparent terminal-phase disposition half-life (t_½) of the various estrogens is prolonged by the slow absorption from Premarin/MPA and ranges from 10 to 24 hours. MPA has a mean t_½ of 38 hours.

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. 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. Data from a large clinical trial indicate that MPA administered in the recommended dose to women receiving Premarin 0.625 mg reduces the incidence of hyperplastic changes and hence reduces the risk of developing adenocarcinoma. This is the clinical rationale for combining conjugated estrogens found in Premarin tablets with MPA in product presentations of Premplus and Premplus Cycle.

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. Studies also suggest that estrogen reduces the rate of vertebral fractures. One clinical study 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.

Studies to date suggest that the addition of MPA to estrogen replacement therapy does not interfere with the beneficial effects of Premarin on bone.

Metabolism and inactivation of estrogens occur primarily in the liver. Metabolism and elimination of MPA occurs primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

This pharmacokinetic study was conducted to investigate potential interactions between single doses of Premarin and MPA given concomitantly. The results demonstrated that single-dose coadministration of 2×0.625 mg Premarin tablets with 2×5.0 mg MPA encapsulated tablets does not significantly affect the pharmacokinetics of estrone, equilin, total estrone, total equilin, or MPA.

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. These bleeding patterns may resolve with the continued use of Premplus. During a 1-year clinical trial the occurrence of bleeding or spotting was measured for the last 7 cycles of treatment with a continuous regimen of Premarin and MPA. Results demonstrated that a significantly greater percentage of women taking Premarin and MPA (0.625 mg/5.0 mg) continuous therapy had no bleeding or spotting compared to the Premarin and MPA (0.625 mg/2.5 mg) continuous therapy.

With a cyclic therapy of Premarin and MPA, it is customary to experience withdrawal bleeding or withdrawal spotting. This withdrawal bleeding or spotting may begin between day 20 of one 28-day cycle and day 5 of the next 28-day cycle. During a 1-year clinical trial, the overall incidence of withdrawal bleeding (with or without spotting) or withdrawal spotting was 62.6% of cycles.

In addition to withdrawal bleeding, irregular bleeding may occur with cyclic therapy. In a 1-year clinical trial, the reported mean number of days of irregular bleeding and irregular spotting for each cycle were 4.8 days and 2.5 days, respectively.

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, secreted by the adrenal cortex, to estrone by 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.

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. Like estrogens, progestogens diffuse freely into the cell nucleus where they bind to the progesterone receptor and influence the transcription of a limited set of genes. Progesterone receptors are primarily located in the female reproductive tract. Medroxyprogesterone acetate (MPA) differs considerably in its metabolic and pharmacologic effects from natural progesterone. Androgenic and anabolic effects of MPA have been noted with high doses, but the drug is apparently devoid of significant estrogenic activity.