Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
For the treatment of postmenopausal symptoms, HRT should only be initiated f or symptoms that adversely affect quality of life. In all cases, a caref ul appraisal of the risks and benef its should be undertaken at least annually and HRT should only be continued as long as the benef it 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 benef its and risks f or these women may be more f avourable than in older women.

Medical examination/f ollow-up

Bef ore 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 f or 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.
Investigations, including appropriate imaging tools, e.g mammography, should be carried out in accordance with currently accepted screening practices, modif ied 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 Angeliq, in particular:
•          Leiomyoma (uterine f ibroids) or endometriosis,
•          Risk f actors f or, thromboembolic disorders (see below)
•          Risk f actors for oestrogen dependent tumours, e.g. 1st degree heredity f or 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 
Reasons f or immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the f ollowing situations:
•         Jaundice or deterioration in liver f unction
•         Signif icant 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 f or prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies f rom 2- to 12-f old greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). Af ter stopping treatment risk may remain elevated f or at least 10 years.
The addition of a progestogen cyclically f or 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.

Breakthrough bleeding and spotting may occur during the f irst months of treatment. If breakthrough bleeding or spotting appears af ter some time on therapy, or continues af ter treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestagen therapy
The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in f inding an increased risk of breast cancer in women taking combined oestrogen-progestogen f or HRT that becomes apparent af ter about 3 (1-4) years (see section 4.8).

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

Results f rom a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken f or more than 5 years, the risk may persist f or 10 years or more.
HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.


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 f irst year of HRT than later (see section 4.8).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, a personal history or family history obesity (BMI > 30 kg/m2) pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is theref ore contraindicated in these patients (see Section 4.3).

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE f ollowing 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 mobilized.

In women with no personal history of VTE but with a f irst degree relative with a history of thrombosis at young age, screening may be of f ered af ter caref ul counselling regarding its limitations (only a proportion of thrombophilic def ects are identif ied by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the def ect is ‘severe’ (e.g. antithrombin, protein S, or protein C def iciencies or a combination of def ects) HRT is contraindicated.
Women already on chronic anticoagulant 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. painf ul swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence f rom randomised controlled trials of protection against myocardial inf arction in women with or without existing CAD who received combined oestrogen and progestogen or oestrogen-only HRT.

The relative risk of CAD during use of combined oestrogen and 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 and progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5-f old 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).

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-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time af ter stopping.

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).

Hepatitis C

During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were signif icantly more f requent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.


Other conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysf unction should be caref ully observed.

Women with pre-existing hypertriglyceridemia should be f ollowed 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.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.


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 radioimmunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, ref lecting 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).

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

The progestin component in Angeliq is an aldosterone antagonist exhibiting weak potassium sparing properties. In most cases, no increase of serum potassium levels is to be expected. In a clinical study, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products (such as ACE inhibitors, angiotensin II receptor antagonists or NSAIDs) serum potassium levels slightly, but not signif icantly increased during drospirenone intake. Theref ore, it is recommended to check serum potassium during the f irst month of treatment in patients presenting with renal insuf f iciency and pretreatment serum potassium in the upper ref erence range, and particularly during concomitant use of potassium sparing medicinal products (see also section 4.5).

Women with elevated blood pressure may experience a decrease in blood pressure under treatment with Angeliq due to the aldosterone antagonist activity of drospirenone (see section 5.1). Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

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

Each tablet of this medicinal product contains 48.2mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase def iciency or glucose-galactose malabsorption should not take this medicine.

Effects on Driving

4.7   Effects on ability to drive and use machines

Angeliq has no inf luence on the ability to drive and use machines.