Angelique Micro tablet film 0.25 mg+0.50 mg x28 146797

Compound

Film-coated tablets	1 table
core
active substances:
estradiol hemihydrate (micronized) in terms of estradiol	0.5 mg
drospirenone (micronized)	0.25 mg
excipients: lactose monohydrate - 50.45 mg; corn starch - 14.4 mg; pregelatinized corn starch - 9.6 mg; povidone - 4 mg; magnesium stearate - 0.8 mg
film shell: yellow varnish (hypromellose (5cP) - 1.0112 mg, macrogol 6000 - 0.2024 mg; talc - 0.2024 mg, titanium dioxide - 0.464 mg, yellow iron oxide dye - 0.12 mg) - 2 mg

Pharmacodynamics

The drug Angeliq® Micro contains 17β-estradiol, chemically and biologically identical to endogenous human estradiol, and the synthetic progestogen drospirenone. 17β-estradiol provides hormone replacement during and after menopause. The addition of drospirenone provides control of bleeding and counteracts the development of estrogen-induced endometrial hyperplasia.

Effects of estradiol

The decline of ovarian function, accompanied by a decrease in the production of estrogen and progesterone, leads to the development of menopausal syndrome, which is characterized by vasomotor and organic symptoms. Hormone replacement therapy (HRT) is indicated to treat these symptoms.

Of all natural estrogens, estradiol is the most active and has the greatest affinity (binding strength) for estrogen receptors. Target organs for estrogen include, but are not limited to, the uterus, hypothalamus, pituitary gland, vagina, mammary glands, and bones (osteoclasts).

Other effects of estrogens include reductions in blood insulin and glucose concentrations, receptor-mediated vasoactive effects, and receptor-independent effects on vascular smooth muscle cells. Estrogen receptors have been identified in the heart and coronary arteries.

Oral administration of natural estrogens has advantages in cases of hypercholesterolemia due to a more favorable effect on lipid metabolism in the liver.

Estrogen monotherapy has a dose-dependent stimulating effect on endometrial mitosis and proliferation and, thus, increases the incidence of endometrial hyperplasia and, consequently, the risk of developing endometrial cancer. To avoid the development of endometrial hyperplasia, a combination with progestogens is necessary.

Effects of drospirenone

Drospirenone has pharmacodynamic effects very similar to natural progesterone.

Progestogenic activity

Drospirenone is a potent progestogen with a central inhibitory effect on the hypothalamic-pituitary-gonadal axis. In women of reproductive age, drospirenone has a contraceptive effect; When drospirenone is administered as a single drug, ovulation is suppressed. The threshold dose of drospirenone to suppress ovulation is 2 mg/day. Complete transformation of the endometrium previously exposed to estrogen occurs after taking a dose of 4 or 6 mg/day for 10 days (=40–60 mg per cycle). Continuous hormone replacement therapy with Angeliq® Micro allows you to avoid regular withdrawal bleeding, which is observed with cyclic or phase HRT. During the first months of treatment, bleeding and spotting are quite common, but their frequency decreases over time.

Antimineralocorticoid activity

Drospirenone has the ability to competitively antagonize aldosterone. Women who received drospirenone in addition to estradiol in a clinical study reported less peripheral edema than those who took estradiol alone.

Antiandrogenic activity

Like natural progesterone, drospirenone has antiandrogenic properties.

Effect on carbohydrate metabolism

Drospirenone has neither glucocorticoid nor antiglucocorticoid activity and does not affect glucose tolerance or insulin resistance. When using the drug Angeliq® Micro, glucose tolerance is not impaired.

Other properties

Observational studies suggest that among postmenopausal women, the incidence of colon cancer is reduced when using HRT. The mechanism of action is still unclear.

ANGELIQ MICRO film-coated tablets No. 28

Angeliq Micro is not used for contraception. If pregnancy is suspected, you should stop taking the pills until pregnancy is ruled out (see section “Use during pregnancy and breastfeeding”). If any of the following conditions/diseases or risk factors are present or worsening, before starting or continuing to take Angeliq Micro, you should evaluate the individual risk-benefit ratio of treatment, taking into account the possible need to discontinue it. When prescribing HRT to women who have several risk factors for the development of thrombosis or a high degree of severity of one of the risk factors, the possibility of mutually enhancing the effect of risk factors and the prescribed treatment on the development of thrombosis should be taken into account. In such cases, the total value of the existing risk factors increases. If there is a high risk, Angeliq Micro is contraindicated. Venous thromboembolism A number of controlled randomized and epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, against the background of HRT. Therefore, when prescribing Angeliq Micro to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient. High risk factors for developing VTE include individual and family history (the presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and obesity with a body mass index of more than 30 kg/m2. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial. The risk of VTE may temporarily increase with prolonged immobilization, “major” elective and post-traumatic operations, or major trauma. In case of prolonged immobilization or planned surgery, the drug should be stopped 4-6 weeks before surgery; resumption of use is possible only after the woman’s motor activity is completely restored. Treatment should be stopped immediately if symptoms of thrombotic disorders appear or if their occurrence is suspected. It is necessary to assess the ratio of individual risk and benefit of treatment in women using HRT drugs in conjunction with anticoagulants. Arterial thromboembolism Randomized controlled trials of long-term use of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) did not provide evidence of a beneficial effect on the cardiovascular system. Large-scale clinical trials of the combination of CLE and MPA revealed a possible increase in the risk of coronary heart disease (CHD) in the first year of use, followed by a lack of beneficial effect. One large clinical trial using CLE alone found a potential reduction in the incidence of CAD among women aged 50–59 years, but no overall benefit in the overall study population. As a secondary outcome, two large clinical trials using CLE either alone or in combination with MPA found a 30-40% increase in the risk of stroke. It is therefore unknown whether this increased risk applies to HRT preparations containing other types of estrogens and irogestogens or to non-oral routes of administration. Endometrial cancer Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. The addition of drospirenone prevents the development of endometrial hyperplasia caused by estrogen. If there is a history of endometrial hyperplasia, estrogens alone or in combination with gestagens should be used with caution. Breast cancer Clinical and observational studies have found an increase in the relative risk of developing breast cancer in women using HRT for several years. This may be due to earlier diagnosis, accelerated growth of an existing tumor during HRT, or a combination of both factors. The relative risk increases with duration of therapy but may be absent or reduced with estrogen-only treatment. This increase is comparable to the increased risk of breast cancer in women with a later onset of natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to normal levels over several years after stopping HRT. The increased risk of breast cancer has been suggested based on the results of more than 50 epidemiological studies (risk ranges from 1 to 2). Two large randomized trials of CLE alone or in combination with MPL reported estimated risk ratios of 0.77 (95% confidence interval: 0.59 to 1.01) or 1.24 (95% confidence interval: 1.01 to 1.54) after approximately 6 years of use HRT. It is unknown whether this increased risk also applies to other HRT drugs. HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer. When prescribing Angeliq Micro to women with risk factors for estrogen-dependent tumors (for example, first-degree relatives with breast cancer), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient. Ovarian cancer A study of estrogen in combination with progestin showed a statistically non-significant increase in the risk of ovarian cancer. The relative risk of developing ovarian cancer with conjugated estrogens with MPA compared with placebo was 1.58 (95% confidence interval: 0.77-3.24) after a median follow-up of 5.6 years. The absolute risk of conjugated estrogens with MPA compared with placebo was 4 versus 3 cases per 10,000 woman-years. Long-term use of estrogen-only HRT (5-10 years) was associated with a slightly increased risk of ovarian cancer. Long-term use of combination HRT drugs may have the same or slightly lower risk of developing ovarian cancer. Liver tumor During the use of sex hormones, which include drugs for HRT, benign, and even more rarely, malignant liver tumors have been observed in rare cases. In some cases, these tumors have led to intra-abdominal bleeding, which is life-threatening. If there is pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, the differential diagnosis should take into account the possibility of a liver tumor. Cholelithiasis It is known that estrogens increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times when treated with estrogen. Dementia There is limited clinical trial evidence of a possible increased risk of dementia in women starting CLE-containing medications aged 65 years or older. As observed in studies, the risk may be reduced if CLE-containing HRT medications are started in early menopause. Other conditions/diseases Treatment should be stopped immediately if migraine-like pain or frequent and unusually severe headaches appear for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain. The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT; clinically significant increases are rare. However, in some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered. In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect the concentration of potassium in the blood plasma in patients with mild to moderate forms of renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in the group of patients in whom the concentration of potassium in the blood plasma before treatment was determined at the upper limit of normal, and who additionally take potassium-sparing drugs. For mild liver dysfunction, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision is necessary, as well as periodic liver function tests. If liver function indicators deteriorate, Angeliq Micro should be discontinued. In case of recurrence of cholestatic jaundice or cholestatic itching, which was observed for the first time during pregnancy or previous treatment with sex hormones, taking Angeliq Micro should be stopped immediately. Special monitoring of women is necessary when triglyceride concentrations increase. In such cases, the use of HRT may cause a further increase in the concentration of triglycerides in the blood, which increases the risk of acute pancreatitis. Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen of diabetic patients when undergoing HRT. However, women with diabetes should be monitored when undergoing HRT. Some patients may develop undesirable effects of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for examination of the endometrium in order to exclude an organic disease. Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped. It is recommended to discontinue treatment if endometriosis relapses during HRT. If prolactinoma is suspected, this disease should be excluded before starting treatment. If prolactinoma is detected, the patient should be under close medical supervision (including periodic assessment of prolactin concentrations). In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During treatment with Angelique Micro, women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation. The following conditions/diseases may occur or worsen during HRT, and women with these conditions/diseases should be under medical supervision when undergoing HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus, chorea minor. In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema. Preclinical Safety Data Preclinical data obtained from routine repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of certain hormone-dependent tissues and tumors. Medical examination and counseling Before starting or resuming taking Angeliq Micro, you should familiarize yourself in detail with the patient’s medical history and conduct a general medical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but not less than once every 6 months) and should include measurement of blood pressure, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium. Impact on laboratory results. Taking sex hormones can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma concentrations of transport proteins such as sex hormone-binding globulin and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Angelique Micro does not have a negative effect on glucose tolerance. Effect on the ability to drive vehicles and machinery Not identified.

Pharmacokinetics

Estradiol

Absorption

After oral administration, estradiol is quickly and completely absorbed. During absorption and first passage through the liver, estradiol undergoes significant metabolization, for example into estrone, estriol and estrone sulfate. After oral administration, the bioavailability of estradiol is about 5%. Cmax of estradiol in plasma, approximately 16 pg/ml, is usually achieved 28 hours after taking the tablet. Food intake does not affect the bioavailability of estradiol.

Distribution

After oral administration of the drug Angeliq® Micro, a gradual change in the concentration of estradiol in the blood plasma is observed over 24 hours. Due to the circulation of estrogen sulfates and glucuronides in a wide range on the one hand, enterohepatic recirculation on the other, T1/2 of estradiol is a complex parameter , which depends on all these processes and is in the range of 13–20 hours after ingestion.

Estradiol binds nonspecifically to serum albumin and specifically to SHBG. The free fraction of estradiol in plasma is approximately 1–2%, and the fraction of the substance bound by SHBG is in the range of 40–45%. After oral administration, estradiol causes the formation of SHBG, which affects the distribution of serum proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound and unbound fractions, indicating the non-linearity of the pharmacokinetics of estradiol after taking the drug Angeliq® Micro. The apparent Vd of estradiol after a single intravenous injection is about 1 l/kg.

Metabolism

Estradiol is metabolized primarily in the liver, and also partially in the intestines, kidneys, skeletal muscles and target organs. These processes are accompanied by the formation of estrone, estriol, catechol estrogens, as well as sulfate and glucuronide conjugates of these compounds, each of which has significantly less estrogenic activity or no estrogenic activity at all. Plasma estrone concentrations are 6 times higher than estradiol. Plasma concentrations of estrone conjugates are 26 times higher than the corresponding concentrations of free estrone.

Elimination

Estradiol clearance from plasma is about 30 ml/min/kg. Estradiol metabolites are excreted by the kidneys and through the intestines with a T1/2 of approximately 24 hours.

Css

With daily use of the drug Angeliq® Micro Css of estradiol in the blood plasma is achieved after approximately 5 days. On average, the concentration of estradiol in blood plasma ranges from 12 pg/ml (minimum level) to 29 pg/ml (maximum level).

Drospirenone

Absorption

After oral administration, drospirenone is rapidly and completely absorbed. Bioavailability after oral administration is 76–85%. Food intake does not affect the bioavailability of drospirenone.

Distribution

Cmax of drospirenone in plasma, approximately 3.35 ng/ml, is achieved approximately 1 hour after single and multiple doses of 0.25 mg of drospirenone. After this, a biphasic decrease in the concentration of drospirenone in plasma is observed with a final T1/2 of about 35–39 hours. Drospirenone binds to serum albumin and does not bind to SHBG and corticoid-binding globulin. About 3–5% of the total plasma concentration of drospirenone is not bound to protein.

Metabolism

After oral administration, drospirenone is largely metabolized. The main metabolites in human plasma are the acid form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate. Both metabolites are formed without the participation of the cytochrome P450 system. Based on in vitro data, drospirenone is slightly metabolized by the cytochrome P4503A4 system.

Elimination

Plasma clearance of drospirenone is 1.2–1.5 ml/min/kg. Some of the dose received is excreted unchanged. Most of the dose is excreted by the kidneys and through the intestines in the form of metabolites in a ratio of 1.2:1.4 with T1/2 of about 40 hours.

Css

Achieved after approximately 10 days of daily use of the drug Angeliq® Micro. Due to the long T1/2 of drospirenone, Css is 2-3 times higher than the concentration after a single dose.

Contraindications

Taking Angeliq® Micro is contraindicated in the presence of any of the conditions/diseases listed below. If any of these conditions/diseases occur while taking Angeliq® Micro, you should immediately stop using the drug.

hypersensitivity to the components of the drug Angeliq® Micro;

bleeding from the vagina of unspecified etiology;

confirmed or suspected diagnosis of breast cancer or history of breast cancer;

confirmed or suspected diagnosis of a hormone-dependent precancerous disease or a hormone-dependent malignant tumor;

liver tumors currently or in history (benign or malignant);

severe liver disease;

severe kidney disease currently or in history or acute renal failure (until normalization of renal function indicators);

acute arterial thrombosis or thromboembolism (for example, myocardial infarction, stroke), angina pectoris;

deep vein thrombosis in the acute stage, venous thromboembolism (including pulmonary embolism) currently or in history;

the presence of a high risk of venous and arterial thrombosis (see “Special instructions”);

known predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant);

adrenal insufficiency;

untreated hyperplasia;

porphyria;

severe hypertriglyceridemia;

congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

pregnancy;

period of breastfeeding (see “Use during pregnancy and lactation”);

children and adolescents up to 18 years of age.

Carefully:

Angeliq® Micro should be prescribed with caution for the following diseases: congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itching during previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus (see “Special Instructions”) . It is necessary to take into account that estrogens alone or in combination with gestagens should be used with caution in the following diseases and conditions: the presence of risk factors for the development of thrombosis and thromboembolism in a family history (thromboembolic complications in close relatives at a young age), the presence of risk factors for the development of estrogen-dependent tumors (for example, 1st degree relatives with breast cancer), history of endometrial hyperplasia, smoking, hypercholesterolemia, obesity, systemic lupus erythematosus, dementia, gallbladder disease, retinal vascular thrombosis, moderate hypertriglyceridemia, edema in chronic heart failure, severe hypocalcemia, endometriosis, bronchial asthma, epilepsy, migraine, liver hemangiomas, hyperkalemia, conditions predisposing to the development of hyperkalemia, taking drugs that cause hyperkalemia - potassium-sparing diuretics, potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin.

Angeliq® Micro

Angeliq® Micro is not used for contraception.

If pregnancy is suspected, you should stop taking the pills until pregnancy is ruled out (see section “Use during pregnancy and breastfeeding”).

If any of the following conditions or diseases or risk factors are present or worsening, before starting or continuing to take Angeliq® Micro, you should evaluate the individual risk-benefit ratio of treatment, taking into account the possible need for its discontinuation.

When prescribing HRT to women who have several risk factors for the development of thrombosis or a high degree of severity of one of the risk factors, the possibility of mutually enhancing the effect of risk factors and the prescribed treatment on the development of thrombosis should be taken into account. In such cases, the total value of the existing risk factors increases. If there is a high risk, Angeliq® Micro is contraindicated.

Venous thromboembolism

A number of controlled randomized as well as epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, against the background of HRT. Therefore, when prescribing Angeliq® Micro to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

High risk factors for developing VTE include individual and family history (the presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and obesity with a body mass index of more than 30 kg/m2. m. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, “major” elective and post-traumatic operations, or major trauma. In case of prolonged immobilization or planned surgery, the drug should be stopped 4-6 weeks before surgery; resumption of use is possible only after the woman’s motor activity is completely restored.

Treatment should be stopped immediately if symptoms of thrombotic disorders appear or if their occurrence is suspected.

It is necessary to assess the ratio of individual risk and benefit of treatment in women using HRT drugs in conjunction with anticoagulants.

Arterial thromboembolism

Randomized controlled trials with long-term use of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) did not provide evidence of a beneficial effect on the cardiovascular system. Large-scale clinical trials of the combination of CLE and MPA revealed a possible increase in the risk of coronary heart disease (CHD) in the first year of use, followed by a lack of beneficial effect. One large clinical trial using CLE alone found a potential reduction in the incidence of CAD among women aged 50–59 years, but no overall benefit in the overall study population. As a secondary outcome, two large clinical trials using CLE either alone or in combination with MPA found a 30% to 40% increased risk of stroke. It is therefore unknown whether this increased risk applies to HRT products containing other types of estrogens and progestogens or to non-oral routes of administration.

Endometrial cancer

With long-term estrogen monotherapy, the risk of developing endometrial hyperplasia or carcinoma increases. The addition of drospirenone prevents the development of endometrial hyperplasia caused by estrogen. If there is a history of endometrial hyperplasia, estrogens alone or in combination with gestagens should be used with caution.

Mammary cancer

Clinical and observational studies have found an increase in the relative risk of developing breast cancer in women using HRT for several years. This may be due to earlier diagnosis, accelerated growth of an existing tumor during HRT, or a combination of both factors. The relative risk increases with duration of therapy but may be absent or reduced with estrogen-only treatment. This increase is comparable to the increased risk of breast cancer in women with a later onset of natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to normal levels over several years after stopping HRT.

The increased risk of breast cancer has been suggested based on the results of more than 50 epidemiological studies (risk ranges from 1 to 2).

Two large randomized trials of CLE alone or in combination with MPA yielded estimated risk ratios of 0.77 (95% CI: 0.59–1.01) or 1.24 (95% CI: 1 .01-1.54) after approximately 6 years of HRT use. It is unknown whether this increased risk also applies to other HRT drugs.

HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

When prescribing Angeliq® Micro to women with risk factors for estrogen-dependent tumors (for example, first-degree relatives with breast cancer), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Ovarian cancer

A study of estrogen in combination with a progestin showed a statistically non-significant increase in the risk of ovarian cancer. The relative risk of developing ovarian cancer with conjugated estrogens with MPA compared with placebo was 1.58 (95% confidence interval: 0.77-3.24) after a median follow-up of 5.6 years. The absolute risk of conjugated estrogens with MPA compared with placebo was 4 versus 3 cases per 10,000 woman-years. Long-term use of estrogen-only HRT (5-10 years) was associated with a slightly increased risk of ovarian cancer. Long-term use of combination HRT drugs may have the same or slightly lower risk of developing ovarian cancer.

Liver tumor

During the use of sex hormones, which also include drugs for HRT, in rare cases benign, and even more rarely, malignant liver tumors were observed. In some cases, these tumors have led to intra-abdominal bleeding, which is life-threatening. If there is pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, the differential diagnosis should take into account the possibility of a liver tumor.

Cholelithiasis

It is known that estrogens increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times when treated with estrogen.

Dementia

There is limited clinical trial data on a possible increased risk of dementia in women starting CLE-containing medications aged 65 years or older. As observed in studies, the risk may be reduced if CLE-containing HRT medications are started in early menopause.

Other conditions or diseases

Treatment should be stopped immediately if migraine-like pain or frequent and unusually severe headaches appear for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain.

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT; clinically significant increases are rare. However, in some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered.

In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect the concentration of potassium in the blood plasma in patients with mild to moderate forms of renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in the group of patients in whom the concentration of potassium in the blood plasma before treatment was determined at the upper limit of normal and who are additionally taking potassium-sparing drugs.

For mild liver dysfunction, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision is necessary, as well as periodic liver function tests.

If liver function indicators deteriorate, Angeliq® Micro should be discontinued.

In case of recurrence of cholestatic jaundice or cholestatic itching, observed for the first time during pregnancy or previous treatment with sex hormones, taking Angeliq® Micro should be stopped immediately.

Special monitoring of women is necessary when triglyceride concentrations increase. In such cases, the use of HRT may cause a further increase in the concentration of triglycerides in the blood, which increases the risk of acute pancreatitis.

Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen of diabetic patients when undergoing HRT. However, women with diabetes should be monitored when undergoing HRT.

Some patients may develop undesirable effects of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for examination of the endometrium in order to exclude an organic disease.

Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped.

It is recommended to discontinue treatment if endometriosis relapses during HRT.

If prolactinoma is suspected, this disease should be excluded before starting treatment. If prolactinoma is detected, the patient should be under close medical supervision (including periodic assessment of prolactin concentrations).

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During treatment with Angeliq® Micro, women prone to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.

The following conditions or diseases may occur or worsen during HRT, and women with these conditions or diseases should be under medical supervision when undergoing HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus, chorea minor.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Preclinical safety data

Preclinical data from routine repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of certain hormone-dependent tissues and tumors.

Medical examination and consultation

Before starting or resuming taking Angeliq® Micro, you should familiarize yourself in detail with the patient’s medical history and conduct a general medical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but at least once every 6 months) and include measurement of blood pressure, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

Impact on laboratory results.

Taking sex hormones can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma concentrations of transport proteins such as globulin that binds sex hormones and lipid or lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Angeliq® Micro does not have a negative effect on glucose tolerance.

Side effects

The most common adverse drug reactions (ADRs) observed when using Angeliq® Micro were breast tenderness, bleeding from the genital tract, and abdominal pain (in less than 2% of patients).

Irregular bleeding usually disappears with long-term therapy. The frequency of bleeding decreases with increasing duration of treatment.

Serious adverse reactions include arterial and venous thromboembolic complications and breast cancer.

ADRs described in clinical studies using Angeliq® Micro are presented below. To determine frequency, the following concepts are used: very often (≥1/10); often (from ≥1/100 to <1/10); uncommon (≥1/1000 to <1/100) and rare (≥1/10000 to <1/1000).

Mental disorders: often - emotional lability.

From the nervous system: infrequently - migraine.

Vascular disorders: uncommon - venous and arterial thromboembolic complications*.

From the gastrointestinal tract: often - abdominal pain.

From the genital organs and breast: often - pain (including discomfort in the mammary glands, bleeding from the genital tract; infrequently - cervical polyp, breast cancer**.

In clinical studies, adverse events were coded using the MedDRA dictionary. Different MedDRA terms that reflect the same medical phenomenon were grouped into one adverse event to avoid duplication or ambiguity in reporting the true effect.

*The concept of “venous and arterial thromboembolic complications” includes the following medical terms: peripheral deep vein occlusion, thrombosis and embolism/occlusion of pulmonary vessels, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke, excluding hemorrhagic.

** Data on the relationship with the use of the drug were obtained from post-marketing observations; Frequency data are obtained from clinical studies using the drug Angeliq® Micro.

Also about venous and arterial thromboembolic complications, breast cancer and migraine, see the sections “Contraindications” and “Special instructions”.

In one placebo-controlled study, adverse reactions were reported with an incidence of ≥2% - headache (6% of patients taking Angeliq® Micro and 5% of patients receiving placebo), nausea (3.3 and 1.1%, respectively). ), diarrhea (2.2 and 0.6%, respectively), vulvovaginal candidiasis (5.5 and 0.6%, respectively), peripheral edema (2.2 and 1.1%, respectively).

Adverse reactions that occur in isolated cases or symptoms that develop very long after the start of therapy and which are considered to be associated with the use of drugs from the group of combination drugs for continuous hormone replacement therapy are listed below:

- liver tumors (benign and malignant);

- hormone-dependent malignant tumors or hormone-dependent precancerous diseases (if it is known that the patient has such conditions/diseases, this is a contraindication to the use of the drug Angeliq® Micro);

- cholelithiasis;

- dementia;

- endometrial cancer;

- arterial hypertension;

- liver dysfunction;

- hypertriglyceridemia;

- changes in glucose tolerance or insulin resistance;

- increase in the size of uterine fibroids;

- reactivation of endometriosis;

- prolactinoma;

- chloasma;

- jaundice and/or itching associated with cholestasis;

- the occurrence or worsening of conditions/diseases for which the relationship with the use of HRT has not been clearly proven: epilepsy; benign diseases of the mammary glands; bronchial asthma; porphyria; systemic lupus erythematosus; otosclerosis, minor chorea;

- in women with hereditary angioedema, exogenous estrogens may exacerbate symptoms;

- hypersensitivity (including symptoms such as rash and urticaria).

For more information about serious adverse events associated with hormone replacement therapy, see the "Special Instructions" section.

Angelique Micro tablet film 0.25 mg+0.50 mg x28

ATX code: G03FA17 (Drospirenone and estrogen) Active substances estradiol (estradiol) Rec.INN registered by WHO drospirenone (drospirenone) Rec.INN registered by WHO Dosage form ANGELIQ® MICRO tab., coated. film-coated, 0.25 mg+0.5 mg: 28 or 84 pcs. reg. No.: LP-002845 from 01/27/15 - Valid Release form, composition and packaging Tablets, film-coated, yellow, round, biconvex, embossed “EL” in a regular hexagon on one side, on the cross section - a core from white to almost white and yellow shell.

1 tab. estradiol (in the form of hemihydrate) micronized 0.25 mg drospirenone (micronized) 0.5 mg

Excipients: lactose monohydrate - 50.45 mg, corn starch - 14.4 mg, pregelatinized corn starch - 9.6 mg, povidone - 4 mg, magnesium stearate - 0.8 mg.

Film shell composition: yellow varnish - 2 mg or (alternatively): hypromellose (5 cP) - 1.0112 mg, macrogol-6000 - 0.2024 mg, talc - 0.2024 mg, titanium dioxide - 0.464 mg, yellow iron oxide dye - 0.12 mg.

28 pcs. - blisters (1) - cardboard packs. 28 pcs. - blisters (3) - cardboard packs.

Clinical-pharmacological group: Anti-climacteric drug Pharmaco-therapeutic group: Anti-climacteric drug (estrogen + progestogen)

Indications: Hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with a non-removed uterus.

Dosage regimen If a woman does not take estrogen or switches to Angeliq Micro from another combination drug for continuous use, then she can begin treatment at any time.

Patients who switch to Angeliq Micro from a combination drug for a cyclic HRT regimen should begin taking it after the end of the current cycle of therapy.

Each package is designed for 28 days of use.

One tablet should be taken daily. After finishing taking 28 tablets from the current package, the next day they begin taking tablets from a new package of Angeliq Micro (continuous HRT), taking the first tablet on the same day of the week as the first tablet from the previous package.

The tablet is swallowed whole with a small amount of liquid. Tablets are taken regardless of meals. The time of day a woman takes the drug does not matter, however, if she started taking the pills at a specific time, she should continue to do so at that time.

The forgotten pill should be taken as soon as possible. If more than 24 hours have passed after the usual dosing time, you should not take an additional tablet. If you miss several tablets, you may develop bleeding from the vagina.

Use in certain groups of patients

In children

The drug is contraindicated for use in children and adolescents under 18 years of age.

In the elderly

There are no data indicating the need for dose adjustment in elderly patients. Information on the use of the drug in women aged 65 years and older is presented in the “Special Instructions” section.

For liver dysfunction

In women with mild to moderate liver dysfunction, drospirenone is well tolerated.

The drug is contraindicated for use in women with severe liver dysfunction (see section “Contraindications”).

For impaired renal function

A small increase in drospirenone exposure was observed in women with mild to moderate renal impairment but is not expected to be clinically significant.

The drug is contraindicated for use in women with severe renal impairment (see section “Contraindications”).

Side effects The most common adverse drug reactions (ADRs) observed when using Angeliq Micro were breast tenderness, bleeding from the genital tract, and abdominal pain (less than 2% of patients).

Irregular bleeding usually disappears with long-term therapy. The frequency of bleeding decreases with increasing duration of treatment.

Serious adverse reactions include arterial and venous thromboembolic complications and breast cancer.

ADRs described in clinical studies using Angeliq Micro are presented in the table below. To determine the frequency, the following concepts are used: very frequent (> 1/10), frequent (from > 1/100 to 1/1,000 to 1/10,000 to Class of organ systems Very frequent Frequent Infrequent Mental disorders emotional lability Nervous system disorders migraine Vascular disorders venous and arterial thromboembolic complications* Gastrointestinal disorders abdominal pain Disorders of the genital organs and breast pain in the mammary glands (including discomfort in the mammary glands) bleeding from the genital tract cervical polyp breast cancer**

* The concept of “venous and arterial thromboembolic complications” includes the following medical terms: peripheral deep vein occlusion, thrombosis and embolism/occlusion of pulmonary vessels, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke, excluding hemorrhagic.

** Data on the relationship with the use of the drug were obtained from the results of post-marketing observations, data on frequency were obtained from clinical studies using the drug Angeliq Micro.

Also about venous and arterial thromboembolic complications, breast cancer and migraine, see the sections “Contraindications” and “Special instructions”.

One placebo-controlled study reported adverse reactions occurring at a frequency of >2%: headache (6% of patients treated with Angeliq Micro and 5% of patients treated with placebo), nausea (3.3% and 1.1%, respectively), diarrhea ( 2.2% and 0.6%, respectively), vulvovaginal candidiasis (5.5% and 0.6%, respectively), peripheral edema (2.2% and 1.1%, respectively).

– liver tumors (benign and malignant),

- hormone-dependent malignant tumors or hormone-dependent precancerous diseases (if it is known that the patient has such conditions/diseases, this is a contraindication to the use of Angeliq Micro)

- cholelithiasis,

- dementia,

- endometrial cancer,

- arterial hypertension,

- liver dysfunction,

- hypertriglyceridemia,

- changes in glucose tolerance or insulin resistance,

- increase in the size of uterine fibroids,

- reactivation of endometriosis,

- prolactinoma,

- chloasma,

- jaundice and/or itching associated with cholestasis,

- the occurrence or worsening of conditions/diseases for which the relationship with the use of HRT has not been clearly proven: epilepsy, benign diseases of the mammary glands, bronchial asthma, porphyria, systemic lupus erythematosus, otosclerosis, chorea minor,

- in women with hereditary angioedema, exogenous estrogens may exacerbate symptoms,

- hypersensitivity (including symptoms such as rash and urticaria).

For more information about serious adverse events associated with hormone replacement therapy, see the "Special Instructions" section.

Contraindications for use Taking Angeliq Micro is contraindicated in the presence of any of the conditions/diseases listed below. If any of these conditions/diseases occur while taking Angeliq Micro, you should immediately stop using the drug.

— pregnancy or breastfeeding (see section “Use during pregnancy and breastfeeding”),

- bleeding from the vagina of unspecified etiology,

- confirmed or suspected diagnosis of breast cancer or a history of breast cancer,

- confirmed or suspected diagnosis of a hormone-dependent precancerous disease or hormone-dependent malignant tumor,

- liver tumors currently or in history (benign or malignant),

- severe liver diseases,

- severe kidney disease currently or in history or acute renal failure (until normalization of renal function indicators),

- acute arterial thrombosis or thromboembolism (for example, myocardial infarction, stroke), angina pectoris,

- deep vein thrombosis in the acute stage, venous thromboembolism (including pulmonary embolism) currently or in history,

— the presence of a high risk of venous and arterial thrombosis (see section “Special instructions”),

- identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant),

- adrenal insufficiency,

- untreated hyperplasia,

- porphyria,

- severe hypertriglyceridemia,

- hypersensitivity to the components of the drug Angeliq Micro,

- children and adolescents up to 18 years of age,

- congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution: Angeliq Micro should be prescribed with caution in the following diseases: congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during a previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus (see "Special Instructions" ).

It is necessary to take into account that estrogens alone or in combination with gestagens should be used with caution in the following diseases and conditions: the presence of risk factors for the development of thrombosis and thromboembolism in a family history (thromboembolic complications in close relatives at a young age), the presence of risk factors for the development of estrogen-dependent tumors (for example, 1st degree relatives with breast cancer), history of endometrial hyperplasia, smoking, hypercholesterolemia, obesity, systemic lupus erythematosus, dementia, gallbladder disease, retinal vascular thrombosis, moderate hypertriglyceridemia, edema in chronic heart failure, severe hyiocalcemia, endometriosis, bronchial asthma, epilepsy, migraine, liver hemangiomas, hyperkalemia, conditions predisposing to the development of hyperkalemia, taking medications that cause hyperkalemia - potassium-sparing diuretics, potassium supplements, ACE inhibitors, apgiotheisin II receptor antagonists and heparin.

Use during pregnancy and breastfeeding HRT is contraindicated during pregnancy or breastfeeding. If pregnancy is detected while taking Angeliq Micro, the drug should be discontinued immediately.

Small amounts of sex hormones can be excreted in breast milk.

Use for liver dysfunction In women with mild to moderate liver dysfunction, drospirenone is well tolerated.

The drug is contraindicated for use in women with severe liver dysfunction

Use in Renal Impairment: A small increase in drospirenone exposure was observed in women with mild to moderate renal impairment but is not expected to be clinically significant.

The drug is contraindicated for use in women with severe renal impairment

Use in children The drug is contraindicated for use in children and adolescents under 18 years of age. Special instructions Angeliq Micro is not used for contraception.

If pregnancy is suspected, you should stop taking the pills until pregnancy is ruled out (see section “Use during pregnancy and breastfeeding”).

If any of the following conditions/diseases or risk factors are present or worsening, before starting or continuing to take Angeliq Micro, you should evaluate the individual risk-benefit ratio of treatment, taking into account the possible need to discontinue it.

Venous thromboembolism

A number of controlled randomized as well as epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, against the background of HRT. Therefore, when prescribing Angeliq Micro to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

The possible role of varicose veins in the development of VTE remains controversial.

Treatment should be stopped immediately if symptoms of thrombotic disorders appear or if their occurrence is suspected.

It is necessary to assess the ratio of individual risk and benefit of treatment in women using HRT drugs in conjunction with anticoagulants.

Arterial thromboembolism

Randomized controlled trials with long-term use of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) did not provide evidence of a beneficial effect on the cardiovascular system. Large-scale clinical trials of the combination of CLE and MPA revealed a possible increase in the risk of coronary heart disease (CHD) in the first year of use, followed by a lack of beneficial effect. One large clinical trial using CLE alone found a potential reduction in the incidence of CAD among women aged 50–59 years, but no overall benefit in the overall study population. As a secondary outcome, two large clinical trials using CLE either alone or in combination with MPA found a 30-40% increase in the risk of stroke. It is therefore unknown whether this increased risk applies to HRT preparations containing other types of estrogens and irogestogens or to non-oral routes of administration.

Endometrial cancer

Mammary cancer

The increased risk of breast cancer has been suggested based on the results of more than 50 epidemiological studies (risk ranges from 1 to 2).

Two large randomized trials of CLE alone or in combination with MPL reported estimated risk ratios of 0.77 (95% confidence interval: 0.59 to 1.01) or 1.24 (95% confidence interval: 1.01 to 1.54) after approximately 6 years of use HRT. It is unknown whether this increased risk also applies to other HRT drugs. HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

When prescribing Angeliq Micro to women with risk factors for estrogen-dependent tumors (for example, first-degree relatives with breast cancer), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Ovarian cancer

Liver tumor

Cholelithiasis

It is known that estrogens increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times when treated with estrogen.

Dementia

Other conditions/diseases

In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect the concentration of potassium in the blood plasma in patients with mild to moderate forms of renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in the group of patients in whom the concentration of potassium in the blood plasma before treatment was determined at the upper limit of normal, and who additionally take potassium-sparing drugs.

If liver function indicators deteriorate, Angeliq Micro should be discontinued.

In case of recurrence of cholestatic jaundice or cholestatic itching, which was observed for the first time during pregnancy or previous treatment with sex hormones, taking Angeliq Micro should be stopped immediately.

Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped.

It is recommended to discontinue treatment if endometriosis relapses during HRT.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During treatment with Angelique Micro, women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.

The following conditions/diseases may occur or be aggravated during HRT, and women with these conditions/diseases should be under medical supervision when undergoing HRT: epilepsy, benign breast tumor, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, chorea minor .

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Preclinical safety data

Medical examination and consultation

Before starting or resuming taking the drug Angeliq Micro, you should familiarize yourself in detail with the patient’s medical history and conduct a general medical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but not less than once every 6 months) and should include measurement of blood pressure, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

Impact on laboratory results.

Taking sex hormones can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma concentrations of transport proteins such as sex hormone-binding globulin and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis.

Angelique Micro does not have a negative effect on glucose tolerance.

Impact on the ability to drive vehicles and machinery

Not found.

Overdose Acute toxicity studies have not revealed a risk of acute side effects when accidentally taking the drug in quantities many times higher than the daily therapeutic dose.

In clinical studies, the use of drospirenone up to 100 mg or combined estrogen/progestin drugs containing 4 mg estradiol was well tolerated.

Symptoms that may occur in case of overdose: nausea, vomiting, bleeding from the vagina.

There is no specific antidote, treatment is symptomatic.

Drug interactions Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical effectiveness, which is manifested by irregular bleeding. A similar property to induce liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and the presence of this feature is also suggested in oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually observed no earlier than 2-3 weeks, but it may then persist for at least 4 weeks after discontinuation of the drug.

In rare cases, against the background of concomitant use of certain antibiotics (for example, penicillin and tetracycline groups), a decrease in the concentration of estradiol was observed.

The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely. However, CYP3A4 inhibitors (eg, cimetidine, ketoconazole, etc.) may inhibit the metabolism of estradiol.

Interaction of the drug Angeliq Micro with other drugs

Based on in vitro interaction studies, as well as an in vivo study in female volunteers taking 3 mg of drospirenone per day in combination with omeprazole, simvastatin or midazolam, it can be concluded that a clinically significant interaction of drospirenone with cytochrome P450 on the metabolism of other medicinal substances is unlikely.

Pharmacodynamic interaction with antihypertensive drugs and nonsteroidal anti-inflammatory drugs (NSAIDs)

An increase in serum potassium concentration with the combined use of Angeliq Micro and non-steroidal anti-inflammatory drugs (NSAIDs) or antihypertensive drugs is unlikely. The combined use of the above three types of drugs may lead to a slight increase in serum potassium concentrations, more pronounced in women with diabetes mellitus.

Interaction with alcohol

Excessive alcohol consumption during HRT may increase circulating estradiol concentrations.

Conditions for dispensing from pharmacies By prescription. Storage conditions and periods At a temperature not exceeding 30°C. Keep out of the reach of children. Shelf life: 3 years. Do not use after the expiration date stated on the package.

Interaction

Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical effectiveness, which is manifested by irregular bleeding. A similar property to induce liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and the presence of this feature is also suggested in oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually observed no earlier than 2–3 weeks, but may then persist for at least 4 weeks after discontinuation of the drug.

In rare cases, during concomitant use of certain antibiotics (for example, penicillin and tetracycline groups), a decrease in the concentration of estradiol was observed.

The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely. However, CYP3A4 inhibitors (eg cimetidine, ketoconazole, etc.) may inhibit the metabolism of estradiol.

Interaction of the drug Angeliq® Micro with other drugs

Pharmacodynamic interaction with antihypertensive drugs and NSAIDs

An increase in serum potassium concentration when taking Angeliq® Micro and NSAIDs or antihypertensive drugs in combination is unlikely. The combined use of the above three types of drugs may lead to a slight increase in serum potassium concentrations, more pronounced in women with diabetes mellitus.

Interaction with alcohol

Excessive alcohol consumption during HRT may increase circulating estradiol concentrations.

Instructions for use ANGELIQ® (ANGELIQ)

Angelique should be prescribed with caution in case of arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itching during previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus.

If any of these conditions are present or worsening, before starting or continuing HRT, the ratio of individual risk to benefit of treatment should be assessed.

Before starting or resuming HRT, a woman is recommended to undergo a thorough general and gynecological examination (including examination of the mammary glands and cytological examination of cervical mucus) and exclude pregnancy. In addition, disorders of the blood coagulation system should be excluded. Control examinations should be carried out periodically.

A number of controlled randomized and epidemiological studies have revealed an increased relative risk of developing venous thromboembolism

(VTE) against the background of HRT. When prescribing HRT to women with risk factors for VTE (deep vein thrombosis or pulmonary embolism), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient. Risk factors for developing VTE include a history of VTE (including familial VTE in close relatives at a relatively young age may indicate a genetic predisposition) and severe obesity. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial. The risk of VTE may temporarily increase with prolonged immobilization, extensive surgery, or trauma. Depending on the cause or duration of immobilization, the question of the advisability of temporarily stopping HRT should be decided.

Treatment should be stopped immediately if symptoms of thrombosis appear or are suspected.

Randomized controlled trials of long-term use of combined conjugated estrogens and medroxyprogesterone acetate did not provide evidence of a beneficial effect on the cardiovascular system. An increased risk of stroke was also found. To date, no long-term randomized controlled trials have been conducted with other HRT drugs to identify beneficial effects on cardiovascular morbidity and mortality. It is therefore unknown whether this increased risk applies to HRT products containing other types of estrogens and progestogens.

Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma.

. Studies have confirmed that the addition of gestagens reduces the risk of endometrial hyperplasia and cancer.

breast cancer has been found in clinical trials and observational studies.

in women using HRT for several years. This may be due to earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with the duration of treatment (by 2.3% per year of use). This is comparable to the increase in the risk of breast cancer in women with each year of delay in the onset of natural menopause (by 2.8% per year of delay). The increased risk gradually decreases to normal levels during the first 5 years after stopping HRT. Breast cancer found in women taking HRT is usually more localized than in women not taking it.

HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

During the use of sex steroids, which also include drugs for HRT, benign and even more rarely malignant liver tumors

, which in some cases led to life-threatening intra-abdominal bleeding. If there is pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding, the differential diagnosis should take into account the possibility of a liver tumor.

It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to developing gallstones when treated with estrogen.

You should immediately stop using the drug if you experience migraine-like or frequent and unusually severe headaches for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain.

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT (a clinically significant increase is rare). In some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered.

With renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect serum potassium concentrations in patients with mild to moderate renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in those patients whose serum potassium concentration before treatment was determined at the upper limit of normal and who are additionally taking potassium-sparing drugs.

For mild liver dysfunction, including various forms of hyperbilirubinemia (including Dubin-Johnson syndrome or Rotor syndrome), medical supervision is necessary, as well as periodic liver function tests. If liver function tests worsen, HRT should be discontinued.

If cholestatic jaundice or cholestatic pruritus recurs, which was observed for the first time during pregnancy or during previous treatment with sex steroid hormones, HRT should be stopped immediately.

Special monitoring is required for women with moderately elevated triglyceride levels. In such cases, the use of HRT may cause a further increase in blood triglyceride levels, which increases the risk of acute pancreatitis.

Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to adjust the dosage regimen in patients with diabetes mellitus. Nevertheless, this category of patients should be monitored during HRT.

Some patients under the influence of HRT may develop undesirable manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for endometrial examination.

If treatment for irregular menstrual cycles does not produce results, an examination should be performed to exclude an organic disease.

Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped.

It is recommended to discontinue treatment if endometriosis relapses during HRT.

If prolactinoma is suspected, this disease should be excluded before starting treatment.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During HRT, women with a tendency to develop chloasma should avoid prolonged exposure to the sun or UV radiation.

Epilepsy, benign tumor of the mammary gland, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, minor chorea may first appear or worsen during HRT. Although a direct relationship with HRT has not been proven, patients with these diseases (or with a predisposition to them) should be under medical supervision when undergoing HRT.

Taking sex steroids can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma levels of transport proteins such as SHBG, lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Angelique does not have a negative effect on glucose tolerance.

Excessive alcohol consumption during HRT may increase circulating estradiol levels.

Directions for use and doses

Orally, regardless of food intake, swallow whole, with a small amount of liquid.

If a woman does not take estrogens or switches to Angeliq® Micro from another combination drug for continuous use, she can begin treatment at any time. Patients who switch to Angeliq® Micro from a combination drug for a cyclic HRT regimen should begin taking it after the end of the current cycle of therapy.

Each package is designed for 28 days of use.

You should take 1 tablet daily. After finishing taking 28 tablets. from the current package, the next day they begin taking tablets from a new package of Angeliq® Micro (continuous HRT), taking the first tablet on the same day of the week as the first tablet from the previous package.

The time of day a woman takes the drug does not matter, but if she starts taking the pills at a specific time, she should continue to do so at that time. The forgotten pill should be taken as soon as possible. If more than 24 hours have passed after the usual dosing time, you should not take an additional tablet. If you miss several tablets, you may develop bleeding from the vagina.

Use in certain patient groups

In children. The drug is contraindicated for use in children and adolescents under 18 years of age.

In the elderly. There are no data indicating the need for dose adjustment in elderly patients. Information on the use of the drug in women aged 65 years and older is presented in the “Special Instructions” section.

For liver dysfunction. In women with mild to moderate liver dysfunction, drospirenone is well tolerated. The drug is contraindicated for use in women with severe liver dysfunction (see “Contraindications”).

For renal dysfunction. A small increase in drospirenone exposure was observed in women with mild to moderate renal impairment but is not expected to be clinically significant. The drug is contraindicated for use in women with severe renal impairment (see “Contraindications”).

Overdose

Acute toxicity studies have not revealed a risk of acute side effects when accidentally taking the drug in quantities many times higher than the daily therapeutic dose.

In clinical studies, the use of drospirenone up to 100 mg or combined estrogen/progestin drugs containing 4 mg estradiol was well tolerated. Symptoms that may occur in case of overdose: nausea, vomiting, vaginal bleeding. There is no specific antidote, treatment is symptomatic.