Estramon 50 transdermal patch 50 mcg/day sachet No. 6

Instructions for use Estramon 50 transdermal patch 50 mcg/day sachet No. 6

Composition

active ingredient: estradiol;

1 patch measuring 20 cm2 with an average estradiol release rate of 50 mcg per day contains 4 mg of estradiol;

excipients: da-tocopherol concentrate, acrylate copolymer, Pegoterat substrate.

Dosage form

Transdermal patch.

Main physicochemical properties: ellipsoidal matte colorless patch, fixed on a colorless protective film.

Pharmacotherapeutic group

Sex hormone and drugs used in genital pathology. ATX code G03C A03.

Pharmacological properties

Pharmacodynamics.

The transdermal system contains estradiol (17ß-estradiol), which is chemically and biologically similar to endogenous human estradiol. Estradiol replaces the loss of estrogen production in menopausal women and alleviates menopausal symptoms. Estrogens prevent bone loss after menopause or oophorectomy.

Clinical trial data

Improvement of symptoms caused by estrogen deficiency and effect on bleeding. Relief of menopausal symptoms is achieved within the first weeks of treatment.

Osteoporosis prevention.

• Estrogen deficiency in menopause is accompanied by increased bone metabolism and bone mass loss.

• The effect of estrogen on bone density is dose-dependent. It is clear that protection is provided as long as treatment is ongoing. After stopping HRT (hormone replacement therapy), bone loss is comparable to that in untreated women.

• Results from the Women's Health Initiative (WHI) trial and meta-analyses of other studies suggest that current use of HRT, alone or in combination with a progestogen, in generally healthy women reduces the risk of hip, spine or other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the information on this is limited.

Pharmacokinetics.

Resorption.

The use of estradiol in the form of a transdermal system ensures a long and uniform delivery of estradiol to the body. The concentration of estradiol in the blood plasma can be controlled, preventing overdose. After attaching the Estramon 50 patch, estradiol is well absorbed through intact skin, which ensures its stable level in the bloodstream during treatment. The calculated average daily rate of estradiol release is 50 μg per day. Unlike oral dosage forms, transdermal use of estradiol prevents its intensive metabolism during the first passage through the liver.

Bioavailability.

With continuous use of the Estramon 50 patch, the average concentration of estradiol in the blood plasma is about 34 pg/ml, the maximum concentration is about 48 pg/ml. After removing the patch, the estradiol content returns to the initial level within 12-24 hours.

Distribution.

Estradiol is more than 50% bound to plasma proteins such as sex hormone binding globulin and albumin. Only 2% of estradiol remains free and biologically active.

Biotransformation.

Transdermally applied estradiol is metabolized in the same way as the endogenous hormone. Estradiol is metabolized primarily in the liver, where it is converted to estrone and then to estriol, epi-estriol and catechol-estrogens, which are then conjugated to sulfates and glucuronides. The cytochrome P-450 isoforms CYP1A2 and CYP3A4 catalyze the hydroxylation of the estradiol-binding estriol. In humans, estriol is glucuronized by UGT1A1 and UGT2B7. Estradiol metabolites are also transformed by enterohepatic circulation.

Breeding.

The sulfates and glucuronic acid esters, together with a small proportion of estradiol and various other metabolites, are excreted in the urine. Only a small amount is excreted in the feces. Since the half-life of estradiol is short (about 1 hour), within 24 hours after removal of the patch, the concentration of estradiol and estrone in the serum returns to baseline.

Indication

Hormone replacement therapy (HRT) for symptoms of estrogen deficiency in postmenopausal women.

HRT to eliminate symptoms caused by estrogen deficiency in women in the menopausal period no earlier than 12 months after the last menstruation.

Prevention of osteoporosis in postmenopausal women at high risk of fractures in case of intolerance or contraindications to the use of other drugs prescribed for the prevention of osteoporosis.

Experience in treating women aged 65 years and over is limited.

Contraindication

– Diagnosed, predicted breast cancer or a history of breast cancer;

– previously diagnosed or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer);

– vaginal bleeding of unknown origin;

– current venous thromboembolism (deep vein thrombosis, pulmonary embolism) or venous thromboembolism in the past;

– known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see section “Special warnings and precautions for use”);

– arterial thromboembolic diseases at present or in history (e.g., ischemic heart disease, stroke);

– acute liver diseases, as well as the presence of liver diseases in the past, if liver function tests have not normalized;

– known hypersensitivity to the active substances or to any of the components of the drug;

– porphyria.

Interaction with other medicinal products and other types of interactions

The metabolism of estrogens (and progestogens) may be enhanced by concomitant use of substances that induce enzymes involved in drug metabolism, especially enzymes of the cytochrome P450 system. Such substances include anticonvulsants (e.g. phenobarbital, carbamazepine, phenytoin) and antimicrobials (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Although ritonavir and nelvinavir are known to be potent CYP450 inhibitors, when used simultaneously with steroid hormones, they, on the contrary, activate these enzymes.

Herbal preparations containing St. John's wort (Hypericum perforatum) may enhance the metabolism of estrogens (and progestogens).

Estradiol is metabolized primarily by the CYP3A4 isoenzyme, therefore concomitant use of CYP3A4 inhibitors, such as ketoconazole, erythromycin, and ritonavir, may lead to increased exposure to estradiol.

With transdermal administration, the first-pass effect through the liver is absent, so estrogens (and progestogens) applied transdermally may be less harmful than orally administered hormones due to enzyme inducers. It has been clinically proven that increased metabolism of estrogens and progestogens can lead to a weakening of their effect and a change in the uterine bleeding profile.

Estrogen therapy may affect the results of some laboratory tests, such as glucose tolerance or thyroid function tests.

Application features

HRT should only be initiated for the treatment of postmenopausal symptoms that adversely affect quality of life. A careful benefit-risk assessment of therapy should be performed at least annually before initiating or continuing the use of Estramone 50, and treatment should only be continued if the benefits outweigh the risks. Data on the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit-risk ratio in such women is more favorable than in older women.

Medical examination/consultation. Before starting or resuming the use of Estramon 50 after a break, the patient's medical history (including family history) should be carefully studied. Physical examination (including gynecological examination and breast examination) should be performed, taking into account contraindications (section "Contraindications") and precautions (section "Special instructions for use"). Regular examinations are recommended during treatment, the frequency and extent of which are determined individually. Women should be informed about which changes in the breasts should be reported to their doctor (see section "Breast cancer" below). Regular examination, including appropriate imaging methods, such as mammography, should be performed in accordance with current guidelines for healthy women, taking into account the medical needs of each woman individually.
Situations in which it is necessary to monitor the condition of patients. If any of the following diseases are present, have been present in the past and/or have worsened during pregnancy or previous hormone therapy, patients should be closely monitored. It should be borne in mind that these conditions may recur or worsen during treatment with Estramon 50. These include:

- leiomyoma (uterine fibroids) or endometriosis;

- risk factors for thromboembolic diseases (see below);

- risk factors for estrogen-sensitive tumors, such as a first-degree hereditary predisposition to breast cancer;

- arterial hypertension;

- liver disease (e.g. liver adenoma);

- diabetes mellitus with or without vascular complications;

- gallstone disease;

- migraine or (severe) headache;

- systemic lupus erythematosus;

- history of endometrial hyperplasia (see below);

- epilepsy;

- bronchial asthma;

- otosclerosis.

Reasons for immediate discontinuation of therapy. HRT should be discontinued immediately if a contraindication is identified, as well as in the following situations:

- the appearance of jaundice or impaired liver function;

- significant increase in blood pressure;

- the appearance of a headache like a migraine for the first time;

Endometrial hyperplasia and carcinoma. In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when estrogens are used alone for long periods. The observed increased risk of endometrial cancer in women taking estrogens alone compared with those not taking them ranges from 2- to 12-fold, depending on the duration of treatment and the dose of estrogen (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.

Additional cyclic administration of a progestogen for at least 12 days per month or 28-day cycle, or continuous combined estrogen-progestogen therapy in women with a preserved uterus, can prevent the excess risk associated with estrogen-only HRT. During the first months of treatment, breakthrough uterine bleeding associated with a sudden decrease in sex hormone levels ("withdrawal bleeding") or spotting may occur. If they occur during treatment for some time or persist after discontinuation of therapy, the cause should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. Unrestricted estrogen stimulation may lead to premalignant or malignant transformation of residual foci of endometriosis. Therefore, the need for progestogen in addition to estrogen replacement therapy should be considered in cases where hysterectomy has been performed due to endometriosis and in the presence of residual endometriosis.

Breast cancer: All available evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen HRT and probably also in women taking estrogen-only HRT. This risk depends on the duration of use.

Combined estrogen-progestogen therapy. The randomized placebo-controlled Women's Health Initiative study (WHI) and epidemiological studies have shown an increased risk of breast cancer in women taking combined estrogen-progestogen HRT, which becomes apparent after about 3 years.

Estrogen monotherapy. The WHI trial did not find an increased risk of breast cancer in hysterectomised women taking oestrogen-only HRT. Observational studies have mostly reported a small increased risk of breast cancer, which is significantly lower than in patients taking combined oestrogen-progestagen. The increased risk becomes apparent after a few years of use and increases with increasing duration of use, but returns to baseline within a few (at most 5) years after stopping treatment. HRT, especially combined oestrogen-progestagen therapy, increases the density of mammographic images, which may adversely affect the radiological detection of breast cancer.

Ovarian cancer. Ovarian cancer is much less common than breast cancer. Epidemiological evidence from a large meta-analysis has shown a slightly increased risk in women using oestrogen-only or combined oestrogen-progestagen hormone replacement therapy; this risk becomes apparent within 5 years of use and decreases over time after discontinuation of therapy. Some other studies, including the WHI study, suggest that the use of combined HRT may be associated with the same or a slightly lower risk (see section 4.8).

Venous thromboembolism. HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This is more likely to occur during the first year of HRT than later. Patients with known thrombophilic conditions are at increased risk of VTE, and HRT may further increase this risk. Therefore, hormone replacement therapy is contraindicated in this group of patients (see section 4.3).

The generally accepted risk factors for VTE are: estrogen use, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and carcinoma. There is no consensus on the role of varicose veins in the development of VTE. As for all post-operative patients, precautions should be taken to prevent VTE after surgery. If prolonged immobilisation is expected after elective surgery, it is recommended that HRT be temporarily discontinued 4–6 weeks before surgery. Treatment should not be resumed until the woman has regained full mobility.

Women without a history of VTE but with a first-degree relative who has had thrombosis at a young age may be offered screening after careful discussion of its limitations (screening only detects a subset of thrombophilic disorders).

If a congenital thrombophilic disorder is identified, accompanied by a family history of thrombosis, or if the disorder is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of disorders), HRT is contraindicated.

If VTE develops after initiation of therapy, the drug should be discontinued immediately. Patients should be advised to seek immediate medical attention if they develop potential symptoms of thromboembolism (e.g., painful swelling of a leg, sudden chest pain, shortness of breath).

Coronary heart disease (CHD): There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without coronary heart disease who take combined oestrogen-progestagen or oestrogen-only HRT.

Combined estrogen-progestogen therapy. The relative risk of CHD with combined estrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CHD is largely age-dependent, the number of additional cases of CHD due to estrogen and progestogen use is very small in healthy women close to menopause, but will increase with age.

Estrogen monotherapy: Data from randomized controlled trials have not shown an increased risk of CHD in hysterectomized women taking estrogen monotherapy.

Ischaemic stroke. Combined oestrogen-progestagen therapy and oestrogen-only therapy are associated with an increased risk of ischaemic stroke of up to 1.5 times. The relative risk does not change with age or time since menopause. However, as the baseline absolute risk of stroke is largely age-dependent, the overall risk of stroke in women taking HRT will increase with age.

Severe anaphylactic/anaphylactoid reactions: Cases of anaphylactic/anaphylactoid reactions have been reported in post-marketing experience, some of which have occurred during treatment with estradiol and required urgent medical intervention.

Angioedema: Estrogens may cause or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Patients who have developed angioedema after treatment with estradiol should not be re-treated with Estramon 50.

Other states.

- Estrogens may cause fluid retention, and therefore patients with impaired cardiac or renal function should be carefully monitored.

- Women with pre-existing hypertriglyceridemia should be closely monitored during estrogen replacement therapy or hormone replacement therapy, as rarely in women with this pathology, plasma triglyceride levels have increased significantly during estrogen treatment, leading to pancreatitis.

- Estrogens increase thyroxine-binding globulin (TBG), leading to increased circulating thyroid hormones as measured by protein-bound iodine (PBI), T4 levels (by column assay or radioimmunoassay), or T3 levels (by radioimmunoassay). Triiodothyronine (T3) uptake is reduced as a result of increased TGB levels. Free triiodothyronine (T3) and thyroxine (T4) concentrations are not altered. Serum levels of other binding proteins, corticoid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may be increased, leading to increased serum concentrations of corticosteroids and sex hormones. Free or biologically active hormone concentrations are not altered. Concentrations of other plasma proteins (angiotensin-renin substrate, alpha-I-antitrypsin, ceruloplasmin) may increase.

- Cognitive abilities are not improved with HRT. There is evidence of an increased risk of dementia in women who are over 65 years of age at the start of continuous combined HRT or estrogen monotherapy.

- Contact sensitization is known to occur with all topically applied medicinal products. Although extremely rare, women who develop contact sensitization to one of the components of Estramon 50 should be informed of the possibility of a severe hypersensitivity reaction if they continue to use the substance that caused the contact sensitization.

- Although available information does not indicate that estrogens, including transdermal estradiol, disrupt carbohydrate metabolism, women with diabetes should be monitored at the beginning of therapy until further information is available.

- Thyroid function should be regularly checked in patients who require thyroid hormone replacement therapy and estrogen therapy simultaneously, in order to monitor the level of thyroid hormones in the blood plasma.

Therapy with Estramon 50 does not prevent fertilization.

Use during pregnancy or breastfeeding

Pregnancy

The use of Estramon 50 is contraindicated during pregnancy. If pregnancy occurs during treatment with the drug, its use must be discontinued immediately.

The available results of most epidemiological studies involving unintentional fetal exposure to estrogen do not indicate a teratogenic or fetotoxic effect of the drug.

Lactation period

The use of Estramon 50 is contraindicated during lactation.

Ability to influence reaction speed when driving vehicles or other mechanisms

Unknown.

Method of administration and doses

The duration and treatment regimen are determined by the doctor individually. The patch is used as mono- or combination therapy.

Dosage

It is recommended to apply 1 patch at intervals of 3-4 days (on average 2 times a week).

Symptoms of estrogen deficiency:

Both at the beginning and for the continuation of treatment, it is necessary to start with the lowest effective dose, and to use it for the shortest possible period.

Depending on the clinical response, the dose can be adjusted, taking into account the individual patient's condition. If after 3 months of using the patch, the symptoms of estrogen deficiency are not eliminated, the dose can be increased, but the maximum dose should not exceed 100 mcg per day. If symptoms of overdose appear (for example, a feeling of tension in the mammary glands), the dose should be reduced.

Prevention of osteoporosis in postmenopausal women:

For the prevention of postmenopausal osteoporosis in women, the patch should be used at a dose of 50 mcg per day (1 patch with an interval of 3–4 days).

General remarks

Estramon 50 can be used both cyclically and continuously.

For women with an intact uterus, regardless of the treatment regimen chosen, estrogen should be combined with a progestogen that is approved for use with estrogen for at least 12-14 days of each 28-day cycle to effectively reduce estrogen-induced endometrial hyperplasia.

For women after hysterectomy, the addition of progestogen is not recommended, except in cases where endometriosis has been diagnosed.

Beginning of therapy.

In women not using HRT or in women switching from continuous combined HRT, treatment can be started on any convenient day. In women switching from cyclic or continuous sequential estrogen-progestogen HRT, treatment should be started immediately on the day after the end of the previous cycle.

Options for estrogen monotherapy and combined estrogen/progestogen therapy.

Cyclically or cyclically sequentially:

Cyclical use of estrogen with a break in treatment, usually the drug is used for 21 days, after which a break in treatment lasts for 7 days. For the treatment of women with a uterus, a progestogen is additionally used sequentially for the last 12–14 days of treatment.

Continuously or continuously in sequence:

Continuous estrogen use. For the treatment of women with a uterus, a progestogen is additionally used continuously for 12–14 days of each 28-day cycle.

Progestogen can be added, for example, in the form of drugs such as norethisterone, norethisterone acetate, medroxyprogesterone acetate or progesterone (for more detailed information, see the instructions for medical use of these drugs).

Continuous, non-cyclic treatment may be used for women after hysterectomy, or if significant symptoms of estrogen deficiency recur during a treatment break.

Method of application

1. Each transdermal patch is individually packaged. Immediately before use, open the sachet by cutting it closer to the edge and remove the patch without damaging it.

2. The patch should be carefully folded up and down along the perforation until most of the protective film separates along the perforated strip from the adhesive surface of the patch. This part of the protective film is removed by one of the resulting tips.

3. Apply the exposed adhesive surface of the patch to a healthy, clean, dry area of skin on the outer surface of the thigh.

4. Slightly lift the loose part of the patch to remove the remaining protective film and secure the patch completely.

5. After the patch is completely fixed, it must be pressed with your hand for 10 seconds.

The patch should not be applied to the mammary glands! When using a new patch, the application site should be changed. A new patch can be re-applied to the same site at least a week later. Immediately before application, the skin area should be degreased, it should not be damaged or irritated. The patch should not be attached to areas where it can slide when sitting. The patch should not be attached to the waist area, as friction from contact with tight clothing may cause the patch to come off. The patch should be applied immediately after opening the package and removing the protective film. After fixing the patch, make sure that it is well fixed, especially at the edges. If the patch does not hold, it should be pressed harder to secure it.

If the patch is applied correctly, the patient can bathe or shower as usual. However, it may come off the skin if it comes into contact with very hot water or in a sauna. The patch should be protected from direct sunlight.

If the patch has come off partially or completely prematurely (less than 3-4 days), a new patch should be applied. If another patch application is missed, a new patch should be applied as soon as possible. The next patch replacement should be carried out in accordance with the original treatment regimen. Interruption of treatment may increase the likelihood of uterine bleeding or spotting.

Experience with the use of the Estramon 50 patch in women aged 65 years and older is limited.

Children

The medicine should not be used in children.

Overdose

The most common symptoms of overdose in clinical use are breast tenderness and/or vaginal bleeding. If such symptoms occur, a dose reduction should be considered. To quickly reverse the effects of overdose, the patch should be removed.

Adverse reactions

Mild erythema at the application site is the most commonly reported adverse reaction (16.6%). Mild redness has been observed after removal of the patch from the skin at the application site. Mild pruritus and a small rash around the application site have also been reported.

Adverse effects are classified according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (< 1/10000), unknown (frequency cannot be estimated due to lack of data).

Benign, malignant and non-specific neoplasms (including cysts and polyps): uncommon - breast cancer.

On the part of the immune system: rare - hypersensitivity; rare - urticaria, anaphylactic reactions (including angioedema), anaphylactoid reactions.

Metabolism and nutrition: infrequent - hypercholesterolemia; rare - changes in carbohydrate tolerance, worsening of porphyria.

Psychiatric disorders: common – depression, nervousness, affective lability; uncommon – anxiety; rare – libido disorders; rare – exacerbation of epilepsy.

Nervous system: very common - headache; common - drowsiness, insomnia, mood swings, irritability, hot flashes; uncommon - migraine, dizziness; rare - paresthesia; rare - chorea.

On the part of the organs of vision: infrequent - visual impairment, feeling of dryness in the eyes; rare - intolerance to contact lenses.

Cardiovascular system: infrequent - arterial hypertension, embolism, tachycardia, loss of consciousness; rare - venous thromboembolism, feeling of heaviness in the legs, varicose veins; unknown - embolism.

From the digestive tract and hepatobiliary system: frequent - nausea, dyspepsia, flatulence, diarrhea, abdominal pain, feeling of fullness; increased appetite; infrequent - vomiting, constipation, increased liver enzymes; rare - impaired liver function and impaired bile outflow (formation of stones in the gallbladder), cholestatic jaundice, cholelithiasis, impaired gallbladder function.

Skin and subcutaneous tissue disorders: very common - application site reactions, including local bleeding, bruising, burning, eczema, oedema, inflammation, pain, papules, paresthesia, swelling, vesicles; skin irritation, erythema; common - acne, skin rash, dry skin, itching; uncommon - skin discoloration; rare - contact dermatitis, pigmentation, alopecia; rare - skin necrosis, excess hair, erythema multiforme, erythema nodosum and hemorrhagic rash, chloasma or melanosis, vascular purpura, generalized exanthema; unknown - urticaria.

Musculoskeletal and connective tissue disorders: common: back pain; uncommon: arthralgia, muscle cramps, joint pain, pain in extremities (leg pain*); rare: myasthenia gravis.

* Does not apply to thromboembolism, is usually transient and lasts 3–6 weeks. If symptoms persist, the estrogen dose should be reduced.

Respiratory disorders: uncommon – sore throat.

From the urinary system: infrequently - dysuria, urinary tract infections.

Reproductive system and breast disorders: very common - breast tenderness and pain, dysmenorrhea, menstrual disorders; common - breast enlargement, uterine spasms, endometrial hyperplasia, vaginal infections, discharge (leucorrhoea), increased cervical secretion, cervical neoplasm, uterine pathology, uterine/vaginal bleeding, including spotting, pelvic pain, endometrial pathology, vulvovaginitis, vaginal candidiasis, vaginal dryness, breast cancer, ovarian cyst, fibrocystic breast disease, breast cyst, abnormal cytological smear, uterine prolapse; rare - uterine leiomyoma, extratubal cyst formation, endocervical polyps, galactorrhea, breast discharge; unknown - fibrocystic mastopathy.

General disorders: frequent - pain, dorsalgia, asthenia, peripheral edema, weight change (increase or decrease); infrequent - allergic reactions, malaise, water or salt retention in the body, loss of appetite; rare - nosebleeds.

Investigations: uncommon – increased transaminases; not known – abnormal liver function test results.

The following adverse reactions have been reported with some estrogen-progestogen therapy: estrogen-dependent malignant and benign neoplasms, e.g. endometrial cancer, liver neoplasms; venous thromboembolism, e.g. deep vein thrombosis, pelvic venous thrombosis and pulmonary embolism; stroke; myocardial infarction; dementia; dry eyes; changes in the composition of the tear film; the appearance or exacerbation of phlebitis; ectropion; epistaxis; porphyria; eczema; cystitis-like symptoms, increase in the size of uterine fibroids; cervical erosion.

Breast cancer

• The increased risk for patients receiving estrogen monotherapy was significantly smaller than for patients receiving combined estrogen and progestogen preparations.

• The level of risk depends on the duration of drug use.

• The results of the largest randomized, placebo-controlled trial, the Women's Health Initiative (WHI), and the largest epidemiological study, the Million Women Study (MWS), are presented in Tables 1 and 2.

Table 1. Million-Women-Study (MWS): estimated additional risk of breast cancer after 5 years of HRT

Table 2. US Women's Health Initiative (WHI) study: additional risk of breast cancer after 5 years of HRT use

Endometrial carcinoma

Postmenopausal women with an intact uterus.

About 5 in 1,000 women with an intact uterus who were not taking HRT developed endometrial carcinoma. Estrogen monotherapy is not recommended in women with an intact uterus because it increases the risk of endometrial carcinoma.

Depending on the duration of estrogen monotherapy and estrogen dose, the increased risk of endometrial carcinoma in epidemiological studies ranged from 5 to 55 additional cases diagnosed per 1,000 women aged 50 to 65 years.

By adding progestogen