PROGYNOVA ®

Oestradiol valerate 1mg and 2mg tablets.

Presentation

PROGYNOVA 1mg: beige, biconvex, round, lustrous sugar coated tablets, 6.8mm in diameter, each containing 1 mg estradiol valerate.

PROGYNOVA 2mg: blue, biconvex, round, lustrous sugar coated tablets, 6.8mm in diameter, each containing 2 mg estradiol valerate.

Uses

Actions

From the beginning of the female climacteric, there is a noticeable decline in estrogen production in the ovaries. This leads to an estrogen deficiency in the female body, which gives rise to various complaints and disturbances in general well being, until the body has adapted itself to the diminished estrogen production.

Estrogen deficiency and its accompanying symptoms in the postmenopausal are rapidly and reliably eliminated by regular administration of the lacking hormone in the form of PROGYNOVA.

Pharmacokinetics

Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time, estradiol undergoes extensive further metabolism, e.g. into estrone, estriol and estrone sulphate.

Maximum concentrations of estradiol in plasma are generally reached between 4-6 hours after tablet intake. In relation to the single dose, approximately two times higher serum levels of estradiol are observed after multiple administration. On average, the concentration of estradiol varies between 30 (minimum levels) and 60 pg/mL (maximum levels). Estrone, as a further estrogenic metabolite, reaches about 8-times higher concentrations in plasma. After stopping the treatment with PROGYNOVA, pre-treatment levels of estradiol and estrone are reached within 2-3 days.

Estradiol binds to albumin and the sex hormone binding globulin (SHBG). The unbound proportion of estradiol in plasma is about 1-1.5 % and the SHBG-bound proportion is in the range of 30-40 %.

After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. The metabolic clearance of estradiol has been found to be about 30 mL/min/kg. The metabolites of estradiol are excreted with a half-life of about 1 day; by about 90 % via the kidneys and by about 10 % with the bile.

Estradiol and its metabolites are excreted into milk only to a minor extent.

After oral administration of estradiol valerate, about 3 % of estradiol becomes bioavailable.

Indications

Climacteric complaints after the cessation of monthly bleeding, or deficiency symptoms after oophorectomy or radiological castration for non-carcinomatous diseases, such as hot flushes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, dizziness.

PROGYNOVA also has a favourable influence on the irritable bladder - a not infrequent occurrence in the climacteric; signs of cutaneous and mucosal involution (particularly in the genital region) which normally occur with advancing age, and on osteoporotic complaints.

Dosage and Administration

Before starting PROGYNOVA, a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out.

As a precaution, clinical follow-up should be conducted at intervals of about 6 months.

1 tablet PROGYNOVA 2 mg is taken daily after a meal. The tablets are to be swallowed whole with some liquid. The treatment is continuous. The next pack follows immediately without a break.

In the course of treatment, the dosage may be reduced to 1 tablet PROGYNOVA 1 mg daily.

In women with an intact uterus, the additional administration of a progestogen is necessary.

Contraindications

Pregnancy, severe disturbances of liver function, jaundice or persistent pruritus during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours, active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions, sickle-cell anaemia, existing or suspected hormone-dependent tumours of the, uterus or mammae, endometriosis, severe diabetes with vascular changes, congenital disturbances of lipometabolism, otosclerosis with deterioration during pregnancy.

Warnings and Precautions

If, in exceptional cases, uterine bleeding occurs, this requires a differential-diagnostic clarification.

Epidemiological studies have suggested that hormone replacement therapy (HRT) may be associated with an increased relative risk of developing venous thromboembolism (VTE), i.e. 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 disposition) and severe obesity. The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.

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.

In case of diabetes, high blood pressure, varicose veins, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor and also where there is a history of phlebitis, strict medical supervision is necessary.

A meta-analysis from 51 epidemiological studies reported that there is a modest increase in the risk of having breast cancer diagnosed in women who have used HRT for more than five years. The findings may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with duration of treatment (by 2.3 % per year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause. The increased risk gradually disappears during the course of the first five years after cessation of HRT. Breast cancers found in women using HRT are more likely to be localised to the breast than those found in non-users.

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 breast disease.

In rare cases, benign and in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intraabdominal haemorrhage have been observed after the use of hormonal substances such as the one contained in PROGYNOVA. If severe upper abdominal complaints, liver enlargement or signs of intraabdominal haemorrhage occur, a liver tumour should be included in the differential-diagnostic considerations.

The benefit of treatment with estrogen-containing preparations is undisputed and scientifically proven. Recently, however, the opinion has been expressed that long-term use of unopposed estrogens during the climacteric may increase the incidence of endometrial carcinoma. Since this suspected risk cannot be entirely ruled out, endometrial hyperplasia should be avoided in unopposed estrogen treatment, e. g. by the additional administration of a progestogen.

Reasons for immediate discontinuation of PROGYNOVA are:

Occurrence for the first time of migrainous headaches or more frequent occurrence of unusually severe headaches, sudden perceptual disorders (e.g. disturbances of vision or hearing), first signs of thrombophlebitis or thromboembolic symptoms (for example, unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason), a feeling of pain and tightness in the chest, onset of jaundice, onset of anicteric hepatitis, itching of the whole body, increase in epileptic seizures, significant rise in blood pressure.

Preclinical safety data

Besides the studies with the active ingredient estradiol valerate, data which were recorded for the actual pharmacologically active metabolite of estradiol valerate, 17ß-estradiol, were also taken into consideration for the toxicological evaluation of the risk from use of PROGYNOVA.

In animal experimental studies on systemic tolerance with repeated oral administration including studies for evaluation of a tumorigenic activity, no systemic intolerance reactions were observed which would raise objections to the use of the preparation in therapeutic dosages.

On principle, however, it should be kept in mind that sexual steroids might stimulate the growth of hormone-dependent tissues and tumours.

Reproduction toxicological investigations with estradiol valerate gave no indications of a teratogenic potential. As no non-physiological estradiol-plasma-concentrations are produced by administration of estradiol valerate, this preparation does not present a risk to the foetus.

If inadvertent treatment occurs during pregnancy, the intake of PROGYNOVA should immediately be terminated.

In vitro studies with 17ß-estradiol gave no indications of a mutagenic potential.

Pregnancy and lactation

Use in Pregnancy

The administration of PROGYNOVA during pregnancy is contraindicated.

Use in Lactation

Only a small portion of estradiol and its metabolites enters the mother's milk.

Adverse Effects

In rare cases, a feeling of tension in the breasts, gastric upsets, nausea, headaches, increase in body weight, and uterine bleeding can occur.

Interactions

The regular intake of other medical preparations (e. g. barbiturates, phenylbutazone, hydantoins, rifampicin) can impair the action of PROGYNOVA.

Reduced substance levels have been observed under the simultaneous use of certain antibiotics (e. g. ampicillin), possibly due to changes in the intestinal flora.

The requirement for oral antidiabetics or insulin can change.

Overdosage

Acute toxicity studies with estradiol valerate indicated that, even in the case of inadvertent intake of a multiple of the therapeutic dose, no acute toxicity risk is to be expected.

Pharmaceutical Precautions

Shelf life: 5 years.

Special precautions for storage: Not applicable.

Medicine Classification

Prescription Medicine

Package Quantities

Two calendar packs containing 28 tablets.

Further Information

List of excipients

Lactose, maize starch, polyvidone 25,000, talc, magnesium stearate, sucrose, polyvidone 700,000, polyethylene glycol 6,000, calcium carbonate, glycerol, titanium dioxide (E 171), ferric oxide pigment yellow (E 172), indigotine lake (E 132), montanglycol wax.

Nature and contents of container

Blister packs of deep-drawn strips made of polyvinyl chloride film with counter sealing foil made of aluminium with heat sealable coating, containing 28 sugar coated tablets.

Instructions for use/handling

Store all drugs properly and keep them out of reach of children.