Composition

Calendar-pack containing 11 tablets of 2 mg estradiol-17-valerate each, plus 10 tablets of 2 mg estradiol-17-valerate and 1 mg cyproterone acetate each.

Inactive ingredients

sucrose, titanium dioxide, ferric oxide pigment

Pharmacological properties

The hormones of the follicle and corpus luteum in the ovary cease being produced in the climacteric. This loss is accompanied not only by the cessation of menstrual cycles, but also by deficiency symptoms with subjective complaints such as hot flushes, outbreaks of sweating, sleep disorders, depressive moods and adverse effects on metabolic functions. In this connection, disturbances of bone metabolism leading to an increasing loss of bone substance are of particular importance.

Estradiol valerate can be regarded as a prodrug of estradiol-17 b , and the object of the use is to make up for the loss of endogenous estradiol-17 b secretion - the main contributory factor to the above mentioned deficiency symptoms.

The progestogen cyproterone acetate contained in Climen has antiandrogenic properties and leaves the serum lipoprotein levels unaffected. Consequently, the favourable effect of estradiol on lipometabolism can be exploited to the full, an advantage as regards arteriosclerotic changes of the cardiovascular system.

Estradiol valerate is combined cyclically with cyproterone acetate in order to suppress the mitogenic effect of the estrogen in the endometrium. This is expected to provide a protective effect in respect of the development of endometrial carcinoma.

Pharmacokinetics

Cyproterone acetate and estradiol valerate are completely absorbed after oral administration. The natural substance estradiol is formed from estradiol valerate during absorption and the first pass through the liver. Both substances reach their maximum plasma levels after 1 - 3 hours. The estrogen values are distinctly elevated for about 24 hours. The concentration of cyproterone acetate falls in two phases with half-lives of 3 - 4 hours and 2 - 3 days. On daily repeated administration, no increase of estradiol is likely, while a 2 - 4-fold increase of the minimum plasma levels of cyproterone acetate can be expected.

The two substances are excreted for the greater part as metabolites: cyproterone acetate to the extent of 30 % via the kidneys and 70 % via the liver with a half-life of 2 days, estradiol to the extent of 90 % with the urine and 10 % with the faeces, the half-life being 1 day.

Indications

• Hormonal replacement therapy in climacteric complaints, signs of involution of the skin and urogenital tract, depressive moods in the climacteric, deficiency symptoms after ovariectomy for non-carcinomatous diseases;
• prevention of postmenopausal osteoporosis;
• primary and secondary amenorrhoea (after pregnancy has been ruled out);
• other cycle disturbances

Contraindications

• pregnancy
• lactation
• severe disturbances-of liver function
• jaundice or persistent itching during a previous pregnancy
• previous or existing liver tumours
• tumours of the uterus
• ovaries or breast or a suspicion of such tumours
• endometriosis
• active deep venous thrombosis
• thromboembolic disorders or a documented history of these conditions
• severe diabetes mellitus with vascular changes
• sickle-cell anaemia
• disturbances of lipometabolism
• a history of herpes of pregnancy
• otosclerosis with deterioration during pregnancy

Special notes

Climen is not a contraceptive.

Where applicable, contraception should be practised with non-hormonal methods (with the exception of the rhythm and temperature methods).

The frequency with which bleeding fails to occur in the tablet-free interval increases as the duration of treatment increases. If there is a chance that pregnancy has occurred, tablet taking must be interrupted until it has been ruled out.

If bleeding occurs repeatedly within the 3 weeks in which Climen is taken, the doctor should be consulted but tablet taking should not be interrupted beforehand.

Before the start of treatment for secondary amenorrhoea, it should be ascertained that no prolactin- producing pituitary tumour is present, since according to the present state of knowledge - the possibility cannot be ruled out that macroadenomas will grow if they are exposed to the influence of higher doses of estrogen for a prolonged time.

Epidemiological studies have suggested that hormone replacement therapy (HRT) may be associated with an increased relative risk or developing venous thromboembolism (VTE), i.e. deep venous 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 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 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 immobilization, major elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of the immobilization, consideration should be given to a temporary discontinuation of HRT.

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 gradually disappears during the course of the first five years after cessation of HRT. Breast cancer found in women using HRT is more likely to be localized 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.

The benefit of treatment with estrogen-containing preparations has been proven scientifically. The use of estrogens alone at higher doses and over a prolonged period during the climacteric can lead to excessive development of the lining of the uterus and, in this connection, can increase the incidence of cancer of the uterus. This risk can best be avoided by the additional administration of a progestogen, as is done in treatment with Climen. The general result of this is transformation and shedding of the lining of the uterus and, therefore, menstruation-like bleeding.

The doctor should be informed if the patient suffers from the following disorders: diabetes, high blood pressure, varicose veins, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor. In all these cases, and also where there is a history of phlebitis, strict medical supervision is necessary.

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 those contained in Climen. The doctor must therefore be informed of the occurrence of unusual upper abdominal complaints that do not disappear spontaneously within a short time, as it may then be necessary to withdraw the preparation.

Reasons for immediate discontinuation

• 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 hepatitis
• Itching of the whole body
• Increase in epileptic seizures
• Significant rise in blood pressure, pregnancy

Side effects

A feeling of tension in the breasts, intermenstrual bleeding, gastric complaints, nausea and changes of body weight and libido occasionally occur. Oedema, headache and depressive moods occur in individual cases.

The frequency with which bleeding fails to occur in the tablet-free interval increases as the duration of treatment increases.

In the case of unexpected side effects please consult your doctor.

Interactions

The doctor should be informed if other medical preparations are taken regularly (e. g., barbiturates, phenylbutazone, hydantoins, rifampicin, ampicillin) since they can impair the action of Climen.

The requirement for oral antidiabetics or insulin can change.

Dosage and Administration

Before starting Climen a thorough general medical and gynaecological examination (including the breasts) should be carried out and pregnancy must be excluded.

As a precaution, control examinations should be conducted at intervals of about 6 months during long-term treatment with Climen.

The pack contains an adhesive disc marked with the days of the week. After removing the protective foil the round disc should be stuck onto the tablet pack, so that the day of the week on which tablet taking starts is directly under the section marked "Start”; for example, if the first tablet is to be taken on a Wednesday, the "Start" section should be lined up with a day marked "Wed". Each tablet is thus marked with the corresponding day of the week and one can see at a glance whether the tablet for that day has been taken or not.

Tablet taking is always started from the, blister marked "Start" and continued daily in the direction of the arrows until all 21 tablets have been taken. The tablets are to be swallowed whole with some liquid.

Climen is started on the 5th day of the cycle (1st day of menstrual bleeding - 1st day of the cycle).

Patients with amenorrhoea or bleeding at very irregular intervals can start Climen treatment immediately upon medical prescription as pregnancy has been ruled out.

Following 21 days of tablet-taking, there will be a tablet-free interval of 7 days during which time about 2 - 4 days after the last tablet was taken a withdrawal bleeding of menstrual character will occur. If not otherwise prescribed by the doctor, a new pack of Climen should be started after the 7-day tablet-free interval on the same the day of the week as the previous one - regardless of whether the bleeding has already ceased or is still continuing.

It does not matter at what time of the day the patient takes her tablet, but once she has selected a particular time - e. g after her breakfast she should keep to it every day. If she forgets to take a tablet at the usual time, she should take it within the following 12 hours.

Storage conditions

Do not store above 30°C (86°F).

Presentation

Calendar-packs of 21 tablets.