ESTROFEM

17ß-oestradiol

Presentation

ESTROFEM 1mg calendar dial pack contains 28 tablets as described below:

ESTROFEM 2mg calendar dial pack contains 28 tablets as described below:

28 blue, round, film coated tablets with diameter 6mm and stamped "Novo 280" on one side. The other side is plain. Each tablet contains 2mg of 17ß-oestradiol and weighs about 80mg.

Uses

Actions

The oestrogen, 17ß-oestradiol, is chemically and biologically identical to the endogenous human 17ß-oestradiol and is therefore classified as a human oestrogen.

Endogenous 17ß-oestradiol induces and maintains the primary and secondary sexual characteristics. The biological effect of oestradiol is carried out through a number of specific oestrogen receptors . The steroid receptor complex is bound to the cell's DNA and induces synthesis of specific proteins.

The oestradiol has an influence on metabolic processes and among others LDL-C (low-density lipoprotein cholesterol) is reduced and HDL-C (high-density lipoprotein cholesterol) and triglycerides are increased.

17ß-oestradiol increases SHBG-BC (sex-hormone-binding-globulin binding capacity) and CBG-BC (corticosteroid-binding-globulin binding capacity). The gonadotrophins FSH (follicle stimulating hormone) and LH (luteinizing hormone) are suppressed.

Pharmacokinetics

Novo Nordisk's orally administered micronised 17ß-oestradiol is rapidly and efficiently absorbed from the gastrointestinal tract, reaching a peak plasma concentration within 4-6 hours. Following the administration of ESTROFEM, the steady plasma level of 17ß-oestradiol ranges between 70-100 pg/ml. 17ß-oestradiol has a half life of approximately 14-16 hours. In the blood stream more than 90% of 17ß-oestradiol is bound to plasma proteins.

17ß-oestradiol is oxidised to oestrone, which in turn is converted to oestriol. Both transformations take place mainly in the liver. Oestrogens are excreted into the bile and then undergo reabsorption from the intestine. During this enterohepatic circulation, degradation occurs. They are excreted in the urine (90-95%) as biologically inactive glucoronide and sulphate conjugates, or in the faeces (5-10%), mostly unconjugated.

Indications

ESTROFEM is indicated for treatment of oestrogen deficiency syndrome, including prevention of bone mineral content loss in postmenopausal women at increased risk of developing fractures.

In women with an intact uterus, use of opposed therapy must be considered.

Dosage And Administration

ESTROFEM is administered orally, one tablet daily, preferably at the same time each day, without interruption.

Treatment of hysterectomised women and postmenopausal women may be started on any convenient day. If the woman is menstruating, treatment is started on Day 5 of bleeding.

Initial dose is 1 to 2mg for relief of symptoms of oestrogen deficiency. Treatment is usually initiated with 2mg. The dose may be reduced to 1mg. Sufficient inhibition of bone mineral content loss occurs with 1 to 2mg.

Contraindications

Warnings And Precautions

Warnings

Use of HRT for more than five years could lead to an increased risk of breast cancer. The risk increases with the time of exposure and decreases after treatment has stopped so that it is back to the average risk of breast cancer five years after withdrawal. Breast cancer found in women on HRT tend to be more limited than those not associated with HRT. The findings may be due to an earlier diagnosis, the biological effect of HRT or both. The absolute increase in risk could be expressed as follows: "During the period between 50 and 70 years of age about 45 cases of breast cancer will be detected in every 1000 women. Among those who use HRT for 5 years, 2 extra cases of breast cancer on every 1000 women will be detected during the same period of age. For those who use HRT for 10 and 15 years there will be 6 and 12 extra cases of breast cancer respectively in every 1000 women in this age group. Regular breast examinations and where appropriate mammography should be carried out in women on HRT. Breast status should also be closely monitored in women with a history of or known breast nodules or fibrocystic disease.

Prolonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women. Studies have found that protection from this effect is achieved with = 10 days progestogen therapy per month.

Epidemiological studies have suggested that hormone replacement therapy (HRT) may be associated with an increased relative risk of developing venous thromboembolism (VTE), ie. deep venous thrombosis or pulmonary embolism. Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing HRT to women with a risk factor for VTE.

Generally recognised 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), varicose veins and severe obesity. The risk of VTE also increases with age.

The risk of VTE 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 HRT.

Special Precautions

Before initiating therapy

A physical examination and a complete medical and family history should be taken prior to the initiation of any oestrogen replacement therapy with special reference to blood pressure, examination of the breasts and the abdomen and a gynaecological examination.

Women with an intact uterus with abnormal genital bleeding of unknown etiology or women with an intact uterus who have previously been treated with unopposed oestrogens should be examined with special care in order to investigate a possible hyperstimulation/malignancy of the endometrium before initiation of treatment with ESTROFEM.

Women suffering from acute or chronic liver disease or who have a history of liver disease, where the liver function tests have failed to return to normal, should be monitored regularly with liver function tests during treatment with ESTROFEM.

Women in antihypertensive treatment or patients with epilepsy, migraine, diabetes, asthma or cardiac failure should be monitored regularly.

Pre-existing uterine fibroids may increase in size during oestrogen therapy and symptoms of endometriosis may be exacerbated.

During therapy

If abnormal or irregular bleedings occur during or shortly after therapy, diagnostic aspiration biopsy or curettage should be performed to rule out the possibility of uterine malignancy.

Duration of treatment

As a general rule, oestrogens should not be prescribed for longer than one year without another physical examination, including a gynaecological examination.

The long-term prevention of bone mineral content loss should be restricted to women at increased risk of developing fractures.

Reasons for immediate withdrawal

The indications for immediate withdrawal of therapy are:

• Venous thromboembolic disorders
• The appearance of jaundice
• The emergence of migraine-type headache
• Sudden visual disturbances
• Significant increase in blood pressure.

Contraception

ESTROFEM has no contraceptive effect.

Pregnancy And Lactation

Known or suspected pregnancy is a contraindication of ESTROFEM therapy.

Lactation is not relevant in women receiving ESTROFEM. However, oestrogens and norethisterone acetate are excreted in the milk of nursing mothers.

Effects On Ability To Drive And Use Machines

No effects known.

Adverse Effects

During the first few months of treatment with ESTROFEM breast tenderness, nausea and oedema may occur in a dose dependent manner, in up to about 10% of women treated. Symptoms are normally transient.

Breast cancer, thromboembolic disorders as well as changes in hepatic function have been reported.

Interactions

Liver enzyme inducing drugs increase the metabolism of oestrogens. This may reduce the oestrogen effect. Interactions with oestrogens are documented for the following liver enzyme inducing drugs: barbiturates, phenytoin, rifampicin, carbamazepine.

Overdosage

Symptoms

Nausea and vomiting.

Treatment

There is no specific antidote and treatment should be symptomatic.

Pharmaceutical Precautions

Store below 25°C

Do not refrigerate

Store in a dry place

Protect from light

Keep out of reach of children.

Medicine Classification

Prescription Medicine.

Package Quantities

ESTROFEM 1mg and 2mg tablets are supplied in a calendar dial pack containing 28 tablets.

Further Information

Nature of the container

The calendar dial pack with 28 tablets consists of the following three parts:

The base made of coloured non-transparent polypropylene

The ring-shaped lid made of transparent polystyrene

The centre-dial made of coloured non-transparent polystyrene.

Instructions for use

List of excipients

Lactose monohydrate Ph.Eur
Maize starch Ph.Eur
Gelatin Ph.Eur
Talc Ph.Eur
Magnesium Stearate Ph.Eur
Titanium Dioxide Ph.Eur
Methylhydroxypropylcellulose Ph.Eur
E132 or E172

Preclinical safety data