Special Warning : אזהרת שימוש

4.4.   Special warnings and precautions for use

•   For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risk and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

•   Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up:

•   Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below).
Investigations, including appropriate imaging tools, e.g mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision:

•   If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Progynova, in particular: 
-       Leiomyoma (uterine fibroids) or endometriosis
-       Risk factors for, thromboembolic disorders (see below)
-       Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer
-       Hypertension
-      Liver disorders (e.g. liver adenoma)
-      Diabetes mellitus with or without vascular involvement
-      Cholelithiasis
-      Migraine or (severe) headache
-      Systemic lupus erythematosus
-      A history of endometrial hyperplasia (see below)
-      Epilepsy
-      Asthma
-      Otosclerosis
-      Hereditary angioedema.


Reasons for immediate withdrawal of therapy:
Therapy should be discontinued in case a contraindication is discovered and in the following situations:

-      Jaundice or deterioration in liver function
-      Significant increase in blood pressure
-      New onset of migraine-type headache
-      Pregnancy.

Endometrial hyperplasia and carcinoma
•   In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see Section 4.8). ). After stopping treatment risk may remain elevated for at least 10 years.

•   The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non- hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

•   For oral doses of estradiol > 2mg, conjugated equine oestrogens > 0.625 mg and patches > 50 micrograms/day the endometrial safety of added progestogens has not been demonstrated.

•   Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

•       Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.


Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestoagen therapy
• The randomised placebo-controlled trial the Women’s Health Initiative study (WHI) , and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8).

Oestrogen-only therapy
• The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations (see Section 4.8).

•   The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

•   HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

•   Ovarian cancer is much rarer than breast cancer.
•   Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
•   Some other studies including the WHI trial suggest that the use of combined HRTs may be associated with a similar, or slightly smaller, risk (see Section 4.8).

Venous thromboembolism

•   HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.
The occurrence of such an event is more likely in the first year of HRT than later (see Section 4.8).

•   Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30kg/m2),
pregnancy/post-partum period, systemic lupus erythematosus (SLE), and cancer.
There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

•   Patients with known thromboembolic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3)

•   In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g.
antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

•   Those women already on anti-coagulant treatment require careful consideration of the benefit-risk of use of HRT.

•   If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

•   There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.

Combined oestrogen-progestogen therapy
The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.


Ischaemic stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8).


Other conditions
•   Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

•   Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

•   Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio- immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged.
Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I- antitrypsin, ceruloplasmin).

•   Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.

•   HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

•   Progynova is not suitable as a contraceptive. If appropriate, contraception should be practised with non-hormonal methods.

•   Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine .

•   Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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