PREMARIN®

Natural conjugated estrogens as 0.3 mg, 0.625 mg and 1.25 mg tablets.

Presentation

Natural conjugated estrogens in:

• 0.3 mg tablets: green oval, sugar coated tablets.
• 0.625 mg tablets: maroon, oval, sugar coated tablets.
• 1.25 mg tablets: yellow, oval, sugar coated tablets.

Uses

Actions

Estrogen production occurs primarily in the ovarian follicles in women from the menarche to the menopause and is important in the development and maintenance of the female urogenital system and secondary sex characteristics.

During the menopause the ovarian-estrogen production decreases and in post-menopausal women, when the ovaries have ceased to function, only a small amount of estrogen is still produced.

This decrease and eventual cessation of estrogen production in peri-menopausal and post-menopausal women, respectively, results in vasomotor symptoms (sweating, hot flushes) and atrophic vaginitis. In addition to relieving or eliminating these disorders, estrogen replacement therapy has also been demonstrated to retard or halt the post-menopausal bone mass loss (osteoporosis).

The pharmacologic effects of orally administered conjugated estrogens are similar to those of endogenous estrogens.

Oral administration of estrogen to postmenopausal women increases serum high density lipoprotein (HDL-cholesterol) and decreases low density lipoprotein (LDL-cholesterol) and total cholesterol levels. This improvement in lipid profile may be one of the factors contributing to the beneficial effect of estrogen on the risk of coronary heart disease in postmenopausal women. Estrogen decreases vascular resistance, increases blood flow and decreases the pulsatility index which represents the impedance to blood flow in the uterine and internal carotid arteries. Estrogen has been shown to increase the production of prostacyclin in the endothelium of blood vessels and to decrease the production of thromboxane A₂ by platelets thereby reducing platelet adhesiveness.

Pharmacokinetics

Conjugated estrogens are soluble in water are well absorbed from the gastrointestinal tract.

Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionised in body fluids, which favour excretion through the kidneys since tubular reabsorption is minimal.

Indications

PREMARIN tablets are indicated:

1. As replacement therapy for estrogen deficiency states associated with the climacteric in women most commonly manifested by:

a) Moderate to severe vasomotor symptoms associated with estrogen deficiency in natural and surgical menopause (sweating, hot flushes).
b) Atrophic vaginitis.
c) Atrophic urethritis

2. For the prevention and management of osteoporosis. Estrogen replacement therapy is the most effective single modality for the prevention of osteoporosis in postmenopausal women.
3. For a reduction in the risk of coronary heart disease (CHD) in women with no current or prior evidence of CHD.
4. For female hypoestrogenism

Dosage and Administration

Concomitant Progestogen Use: The addition of a progestogen during estrogen administration reduces the risk of endometrial hyperplasia and endometrial carcinoma, which has been associated with use of unopposed estrogens. Morphological and biochemical studies of the endometrium suggest that at least 10-14 days of an adequate dose of progestogen are needed to significantly reduce any hyperplastic changes. Since progestogens are administered to reduce the risk of hyperplastic changes of the endometrium, patients without a uterus do not require a progestogen.

The lowest dose that will control symptoms should be chosen. Doses of PREMARIN should not exceed the recommended doses.

Administration may be continuous (e.g. without a break in therapy) or cyclic (e.g. three weeks on and one week off).

Continuous therapy may be started arbitrarily; however, commencement on the first day of bleeding may be preferred if the patient is menstruating regularly.

Cyclic administration is started arbitrarily if the patient has not menstruated within the last two months or more. If the patient is menstruating, cyclic administration is started on day 5 of bleeding.

With both cyclic and continuous regimens, the addition of a progestogen is recommended in women with an intact uterus to reduce the risk of endometrial hyperplasia and endometrial carcinoma.

Usual dosage ranges:

VASOMOTOR SYMPTOMS, ATROPHIC VAGINITIS AND ATROPHIC URETHRITIS: 0.3 mg - 1.25 mg daily. Estrogen deficient women who are being treated for these conditions should be evaluated at regular intervals (3 - 6 months).

OSTEOPOROSIS: 0.625 mg daily. This dose is required for bone mass conservation.

CORONARY HEART DISEASE: 0.625 mg daily.

FEMALE HYPOESTROGENISM: 0.3 - 1.25 mg daily. Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium. Doses of 0.15 mg have been used in girls and are associated with the onset of development of secondary sex characteristics. Dose should be individualised to achieve optimum patient response.

Contraindications

1. Active thrombophlebitis or thromboembolic disease or a documented history of these conditions.
2. Known or suspected malignancy of the breast or genital organs.
3. Undiagnosed abnormal genital bleeding.
4. Known or suspected pregnancy.
5. Known or suspected estrogen-dependent neoplasia.
6. PREMARIN should not be taken by patients who are hypersensitive to any of its ingredients.

Warnings and Precautions

There is no evidence that estrogens are effective for nervous symptoms or depression which may occur during menopause and they should not be used to treat such conditions.

PREMARIN products are not contraceptive agents and should not be used as such. Women of child bearing potential desiring contraception should be advised to adhere to non-hormonal contraceptive methods.

A complete medical and family history should be obtained prior to the initiation of any estrogen therapy. The pre-treatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear.

If a decision to use PREMARIN is made it should be used with other important measures such as dietary changes, exercise and cessation of smoking.

Monotherapy with estrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women with an intact uterus. Studies have indicated that this risk is reduced with = 10 days of an adequate dose of progestogen therapy per cycle. Patients with a uterus should be monitored at least annually for signs of endometrial hyperplasia or endometrial cancer. When concurrent progestogen therapy is not used in women with a uterus, monitoring should include endometrial sampling.

Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding or mastodynia. In the event of abnormal vaginal bleeding adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy. Where no pathological cause is found for abnormal vaginal bleeding, dose reduction or cycling may be indicated.

Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor such as asthma, epilepsy, migraine, and cardiac or renal dysfunction require careful observation.

Some studies have suggested a possible increased incidence of breast cancer diagnosis in women on hormone replacement therapy taking higher doses for prolonged periods of time. The risk may increase with duration of use but returns to the normal level within five years of discontinuation of use. The majority of studies, however, have not shown an association with the usual doses used for estrogen replacement therapy. Breast cancers diagnosed in current or recent users of estrogen replacement therapy are more likely to be localized to the breast than those found in non-users. The role of progestogens in the risk of breast cancer is unknown. Women on hormone replacement therapy should have regular breast examination, instruction in breast self-examination, and mammography when considered appropriate by the treating physician.

In the Heart and Estrogen-progestin Replacement Study (HERS), 2763 postmenopausal women with documented coronary heart disease (CHD) who were taking their usual cardiac medications were randomised to conjugated estrogens (CE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg daily or placebo. Documented CHD was defined as the presence of one or more of the following: previous myocardial infarction, previous percutaneous mechanical revascularization, previous coronary artery bypass graft surgery, or angiographic evidence of greater than 50% occlusion of one or more major coronary arteries. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of recurrent coronary heart disease events, defined as CHD death or nonfatal myocardial infarctions, in this elderly population (average age 66.7 years) with established coronary disease. There was an early increase in recurrent CHD events in the first year in the CE plus MPA group, but after two years of treatment with CE plus MPA, a decrease in recurrent CHD events was reported.

GALLBLADDER DISEASE - There is an increase in the risk of gallbladder disease in women receiving postmenopausal estrogens.

SURGERY - If feasible estrogens should be discontinued at least four weeks before surgery of the type associated with increased risk of thromboembolism or during periods of prolonged immobilisation.

Estrogens may be poorly metabolised in patients with impaired liver function and they should be administered with caution in such patients.

Estrogens should be used with caution in patients with metabolic bone diseases associated with hypercalcaemia.

Pre-existing uterine leiomyomata may increase in size during estrogen use.

Studies have suggested that hormone replacement therapy may be associated with an increased relative risk of developing venous thromboembolism (i.e. deep venous thrombosis or pulmonary embolism). Risk / benefit should therefore be carefully weighed in consultation with the patient when prescribing hormone replacement therapy to women with a risk factor for venous thromboembolism. If any signs of thromboembolic processes occur, treatment should be discontinued immediately.

Generally recognised risk factors for venous thromboembolism include a personal history, a family history (the occurrence of venous thromboembolism in a direct relative at a relatively early age may indicate genetic predisposition), severe varicose veins and severe obesity. The risk of venous thromboembolism also increases with age. The risk of venous thromboembolism may be temporarily increased with prolonged immobilisation, major elective or post-traumatic surgery or major trauma. Depending on the nature of the event and the duration of the immobilisation consideration should be given to a temporary discontinuation of hormone replacement therapy.

If concomitant progestogen therapy is used, potential risks may include adverse effects on carbohydrate and lipid metabolism. The choice of progestogen and dosage may be important in minimising these adverse effects.

Estrogen therapy may be associated with elevations of plasma triglycerides. This may lead to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.

Patients should be advised that the resumption of menses associated with estrogen replacement therapy in postmenopausal women is not indicative of fertility.

Mutagenicity and Carcinogenicity

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinoma of the breast, cervix, vagina and liver.

Use during Pregnancy

ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the male and female foetus, an increased risk of vaginal adenosis, squamous-cell dysplasia of the cervix, and vaginal cancer in the female later in life. There is no indication for estrogen therapy during pregnancy. Estrogens are ineffective in the prevention or treatment of threatened or habitual abortion.

Use during Lactation

As a general principle the administration of any medication to nursing mothers should be done only when clearly necessary since many medications are excreted in human milk.

Adverse Effects

The most serious adverse reactions associated with the use of PREMARIN are indicated under WARNINGS AND PRECAUTIONS. The following additional adverse reactions have been reported with estrogenic therapy.

GENITOURINARY SYSTEM: Breakthrough bleeding, spotting, change in menstrual flow, amenorrhoea.

BREASTS: Tenderness, enlargement, secretion.

GASTROINTESTINAL: Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice.

SKIN: Chloasma or melasma which may persist when the medication is discontinued, alopecia, rash.

EYES: Steepening of the corneal curvature, intolerance to contact lenses.

CENTRAL NERVOUS SYSTEM: Headache, migraine, dizziness, chorea.

MISCELLANEOUS: Increase or decrease in weight, oedema, changes in libido, aggravation of porphyria.

Interactions

Rifampicin reportedly decreases estrogenic activity during concomitant use with estrogens. This effect has been attributed to enhanced metabolism of estrogen, presumably by induction of hepatic microsomal enzymes.

Overdosage

Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.

Pharmaceutical Precautions

Store below 30°C.

Medicine Classification

Prescription Medicine.

Package Quantities

PREMARIN 0.3 mg X 28 tablets
PREMARIN 0.625 mg x 28 tablets
PREMARIN 1.25 mg x 28 tablets

Further Information

PREMARIN (conjugated estrogens) is a mixture of estrogens, obtained exclusively from natural sources, blended to represent the average composition of material derived from pregnant mares' urine. It contains the sodium salts of water-soluble sulphate esters of estrone, equilin, and 17 alpha-dihydroequilin, together with smaller amounts of 17 alpha-estradiol, equilenin, 17 alpha-dihydroequilenin, 17 beta-dihydroequilin, 17 beta-dihydro-equilenin, 17 beta-estradiol and delta 8,9 dihydroestrone.

^®Registered Trade Mark

Name and Address

Wyeth (N.Z.) Limited