Angeliq, 2 mg+1 mg, film-coated tablets, 28 pcs.

Pharmacological properties of the drug Angeliq

The drug Angelique contains 17β-estradiol, which is identical in its chemical and biological properties to estradiol produced in the human body, and a synthetic progestogen, drospirenone. 17β-Estradiol provides hormone replacement therapy during and after the menopausal period. The additional inclusion of drospirenone helps regulate bleeding and prevents the development of endometrial hyperplasia caused by estrogen. Effect of estradiol. Inhibition of ovarian function, accompanied by a decrease in the production of estrogens and progestogens in the body, predetermines menopausal syndrome, characterized by vasomotor and organic symptoms. To eliminate these disorders, hormone replacement therapy (HRT) is prescribed. Estradiol is the most effective of all physiological estrogens and has the greatest affinity for estrogen receptors. The target organs affected by estrogen include the uterus, hypothalamus, pituitary gland, vagina, mammary glands, bones (namely osteoclast cells). Other effects of estrogen include decreased blood insulin and glucose concentrations, local receptor-mediated vasoactive effects, and receptor-independent effects on vascular muscle. Estrogen receptors have been identified in the heart and coronary arteries. Oral administration of natural estrogens has a beneficial effect in some cases of hypercholesterolemia, maximizing the metabolic effect of the liver on lipids. After one year of treatment with Angeliq, the mean changes in HDL cholesterol concentrations were insignificant. With simultaneous use of 1 mg of drospirenone, a slight increase in these indicators by 1.1% was determined; when using 2 and 3 mg of drospirenone, this figure decreased by 1.6 and 3.4%, respectively. Serum LDL-C concentrations decreased by an average of 11 (1 mg drospirenone), 14 (2 mg drospirenone), and 13% (3 mg drospirenone) compared with a 9% decrease after one year of 1 mg estradiol monotherapy. It is likely that combination drugs with drospirenone attenuate the increase in TG concentrations caused by monotherapy with 1 mg estradiol. After one year of treatment with 1 mg estradiol, TG concentrations in patients averaged approximately 18% higher than baseline, compared with an average increase of 9 (1 mg drospirenone), 5 (2 mg drospirenone), and 4% with the combination of 1 mg estradiol and drospirenone. . Therapy with Angeliq for 2 years leads to an increase in bone mineral density throughout the body, in the lumbar spine and pelvic bones by approximately 3-5%. Long-term HRT reduces the risk of peripheral bone fractures in postmenopausal women. HRT also has a positive effect on the collagen content of the skin, skin density and can delay the formation of wrinkles. Estrogen monotherapy, depending on the dose, stimulates mitotic activity and proliferation of the endometrium, which leads to an increase in the number of cases of endometrial hyperplasia and an increased risk of developing endometrial carcinoma. To prevent endometrial hyperplasia, it is necessary to combine estrogen with any progestogen. Effect of drospirenone. The pharmacodynamic properties of drospirenone are similar to those of natural progesterone. Progestogenic effect Drospirenone is a strong progestogen that has a central inhibitory effect on the hypothalamic-pituitary-gonad system. In women of childbearing age, drospirenone provides a contraceptive effect; monotherapy with drospirenone inhibits the ovulation process. The minimum dose of drospirenone required to inhibit ovulation is 2 mg/day. Complete transformation of the endometrium under the influence of estrogen is achieved at doses of 4–6 mg/day for 10 days (40–60 mg per cycle). Angelique is a combination drug for continuous HRT, which allows you to avoid regular withdrawal bleeding observed with cyclic or phase HRT. Bleeding and spotting are quite common in the first months of treatment, but over time their number decreases. While taking Angelique (2 mg drospirenone), the incidence of amenorrhea quickly increased to 81% in the 6th cycle, then to 86% in the 12th cycle and to 91% in the 24th cycle. After 12 months of treatment with Angeliq, 72–82% of women reported endometrial atrophy. The combination of components of the drug Angeliq effectively prevents the development of endometrial hyperplasia caused by estrogen. In clinical studies, no endometrial hyperplasia was detected in women receiving different doses of the active substance of the drug. Antimineralocorticoid activity Drospirenone has a competing antagonistic effect with aldosterone. The antihypertensive effect is most pronounced in women with hypertension with increasing doses of drospirenone. After 12 weeks of therapy with 1 mg estradiol/3 mg drospirenone, mean blood pressure decreased (systolic/diastolic by 14-8 mm Hg, compared with placebo - 6-3 mm Hg). No corresponding changes in blood pressure are expected in women with normal blood pressure. When using the drug Angeliq, the average body weight decreased during 12 months of treatment by 1.1–1.2 kg (2 mg of drospirenone daily), while in patients receiving estradiol monotherapy, an increase in body weight of 0.5 kg was noted. During a clinical study, women receiving drospirenone in combination with estradiol had a lower incidence of peripheral edema compared to patients receiving estradiol monotherapy. Antiandrogenic activity Like natural progesterones, drospirenone has antiandrogenic properties. Effect on carbohydrate metabolism Drospirenone does not have glucocorticoid or antiglucocorticoid activity and does not affect glucose tolerance and insulin resistance. When using Angelique, glucose tolerance does not change. Other properties Angelique has a positive effect on health and quality of life. According to the survey, the beneficial effects of the drug Angeliq significantly exceeded the effect compared with estradiol monotherapy. This high rate is mainly due to an improvement in somatic symptoms, a decrease in the severity of anxiety/fear, and cognitive impairment. According to numerous studies, the use of a combination of conjugated equine estrogens with medroxyprogesterone acetate suggests that the incidence of colon cancer in women receiving HRT is reduced. With monotherapy with conjugated equine estrogens, no reduction in the risk of developing this pathology was observed. Drospirenone Following oral administration, drospirenone is rapidly and almost completely absorbed. As indicated in the table below, maximum serum concentrations are achieved approximately 1 hour after single and multiple oral administration of Angeliq. The pharmacokinetic characteristics of drospirenone depend on the dose received, ranging from 1 to 4 mg. Bioavailability is 76–85% and is independent of food intake.

*Data for Angelique 2 mg and Angelique 3 mg were calculated by interpolating the studied doses of 1 mg drospirenone + 1 mg estradiol and 4 mg drospirenone + 1 mg estradiol.

After oral administration, the serum concentration of drospirenone decreases over two phases with a mean terminal half-life of approximately 35–39 hours. Drospirenone binds to serum albumin, but does not bind to sex steroid binding globulin (SHBG) and corticoid binding globulin (GSK, CBG). Only 3–5% of the total concentration of drospirenone is present in the blood serum as a free steroid. The average apparent volume of distribution of drospirenone is 3.7–4.2 L/kg. After oral administration, drospirenone is significantly metabolized. The main metabolites in plasma are the acid form of drospirenone, obtained due to the opening of the lactone ring, as well as 4,5 dihydro-drospirenone - 3-sulfate. Both metabolites are formed without the participation of the P450-dependent system. in vitro studies , drospirenone is slightly metabolized by cytochrome P450 3A4. The total clearance of drospirenone from serum is 1.2–1.5 ml/min/kg. Only very small amounts of drospirenone are excreted unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of about 1.2:1.4. The half-life of metabolites in urine and feces is up to 40 hours. The table above shows the maximum equilibrium concentrations (AUC) of drospirenone in the blood serum achieved during treatment. AUC is achieved after approximately 10 days of daily use of Angeliq. Estradiol After oral administration, estradiol is rapidly and completely absorbed. During absorption and first passage through the liver, estradiol is significantly metabolized, which reduces the absolute bioavailability of estrogen after oral administration to approximately 5% of the received dose. The maximum concentration, about 22 pg/ml, was achieved 6–8 hours after a single oral dose of Angeliq. The bioavailability of estradiol is not affected by food intake. When taking Angeliq orally during the 24-hour interval between doses of the drug, only a gradual change in the concentration of estradiol in the serum is noted. Due to the large volume of circulating estrogen sulfates and glucuronides, on the one hand, and enterohepatic recirculation, on the other, the terminal half-life of estradiol lasts about 13–20 hours after oral administration. Estradiol binds nonspecifically to serum albumin and specifically to sex steroid binding globulin (SHBG). Only 1–2% of estradiol circulates as a free steroid, 40–45% is associated with SHBG. Orally administered estradiol induces the formation of SHBG, which affects the distribution of serum proteins. As a result, the part of estradiol bound to SHBG increases, and the part bound to albumin and free decreases, indicating the non-linear nature of the pharmacokinetics of estradiol after oral administration of the drug Angeliq. The apparent volume of distribution of estradiol after a single intravenous injection is about 1 l/kg. Estradiol is rapidly metabolized, and in addition to estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are known as pharmacologically active metabolites of estradiol. Only estrone was detected in significant concentrations in blood plasma. The serum estrone content is approximately 6 times higher than the estradiol concentration. Serum concentrations of estrone conjugates are approximately 26 times higher than the corresponding concentrations of free estrone. Metabolic clearance is about 30 ml/min/kg. Estradiol metabolites are excreted in urine and bile with a half-life of approximately 1 day. After daily oral administration of the drug Angeliq, the equilibrium concentration of estradiol is achieved after 5 days. The concentration of estradiol in serum accumulates approximately 2 times. At a 24-hour dosing interval, serum AUC of estradiol ranges from 20–43 mg/ml after taking Angeliq.

Angeliq, 2 mg+1 mg, film-coated tablets, 28 pcs.

Angeliq® is not used for contraception.

HRT drugs should be prescribed only to treat symptoms caused by postmenopausal estrogen deficiency that affect quality of life. HRT should be continued only as long as the benefits outweigh the risks of the drug.

If you suspect pregnancy, you should stop taking the pills until pregnancy has been ruled out (see “Use during pregnancy and lactation”).

If any of the following conditions or risk factors are present or worsening, the individual risk-benefit ratio of treatment should be assessed before starting or continuing to take Angeliq.

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® is contraindicated.

VTE

A number of controlled randomized and epidemiological studies have revealed an increased relative risk (RR) of developing VTE during HRT, i.e. DVT or pulmonary embolism. Therefore, when prescribing Angeliq® to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Risk factors for developing VTE include individual and family history (the presence of VTE in first-degree 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.

Risk factors for the development of VTE are also the use of estrogens, thrombophilic diseases/conditions, SLE, and cancer.

It is necessary to assess the relationship between the individual risk and benefit of treatment with HRT drugs in patients taking anticoagulant drugs on a regular basis.

The risk of VTE may temporarily increase with prolonged immobilization, after surgery, major trauma, surgery on the lower extremities or pelvis, or neurosurgery. In case of prolonged immobilization or planned surgery, taking the drug for HRT should be stopped 4-6 weeks before surgery; resumption of use is possible only after the woman has completely restored her motor activity.

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

Arterial thromboembolism

Controlled randomized studies of the use of combined or estrogen-only drugs for HRT did not reveal evidence of their protective effect against myocardial infarction, regardless of the presence or absence of a history of coronary artery disease. The risk of developing coronary artery disease is slightly increased when using combined drugs for HRT; the risk increases with age. The use of combined drugs for HRT increases the risk of stroke by 1.5 times.

Endometrial cancer

With long-term estrogen monotherapy, the risk of developing endometrial hyperplasia or carcinoma increases. Studies have confirmed that the addition of gestagens prevents the increased risk of endometrial hyperplasia and cancer. 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 trial data and observational studies have found an increased RR for 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 RR 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 within a few (mostly five) 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 CBE alone or continuously combined with MPA yielded estimated risk ratios of 0.77 (95% CI: 0.59–1.01) or 1.24 (95% CI: 1.01–1.01). 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.

Ovarian cancer

Ovarian cancer is less common in the population than breast cancer. A meta-analysis of 52 epidemiological studies suggests a slightly increased RR for ovarian cancer in women treated with HRT compared with never-treated women (prospective studies: RR: 1.2, 95% CI: 1.15–1. 26; all studies: RR: 1.14, 95% CI: 1.1–1.19). Women continuing to take HRT had a slightly increased risk of developing ovarian cancer (RR 1.43, 95% CI 1.31–1.56).

Other studies, including the WHI

, indicate that the use of combination drugs for HRT may be associated with a similar or slightly lower risk, but the risk may be more significant with long-term use (over several years).

Liver tumors

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 resulted in life-threatening intra-abdominal bleeding. 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. Some women are predisposed to developing gallstones when treated with estrogen.

Dementia

The use of HRT drugs does not improve cognitive function. There is evidence of an increased risk of developing dementia in women starting combination or single-drug HRT over the age of 65 years.

Other states

Treatment should be stopped immediately if migraine-like 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 women with high blood pressure, there may be a slight decrease in blood pressure while taking the drug Angeliq®. In women with normal blood pressure, there are no significant changes in blood pressure.

In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect serum potassium concentrations 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 whose serum potassium concentration before treatment was determined at ULN and who additionally take potassium-sparing drugs.

For mild liver dysfunction, incl. Various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, require medical supervision, as well as periodic liver function tests. If liver function indicators deteriorate, Angeliq® 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 should be stopped immediately.

Special monitoring of women is necessary when TG concentrations increase. In such cases, the use of HRT may cause a further increase in the level of TG 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 unwanted 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®, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following conditions may occur or be aggravated by HRT, and women with these conditions should be under medical supervision when undergoing HRT: epilepsy, benign breast tumor, bronchial asthma, migraine, otosclerosis, SLE, 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 steroids can promote the growth of certain hormone-dependent tissues and tumors.

Medical examination and consultation

Before starting or resuming taking Angeliq®, 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 organs and pelvic organs, including cytological examination of the cervical epithelium.

In the presence of prolactinoma, periodic determination of prolactin concentration is required.

Impact on the ability to drive a car and use machinery.

Not found.

Indications for use of the drug Angeliq

HRT for the treatment of menopausal syndrome in postmenopausal women, including vasomotor symptoms (hot flashes and bouts of sweating), sleep disturbances, depressive mood changes, nervousness and atrophic changes in the urogenital tract caused by insufficient production of endogenous estrogen due to natural menopause, hypogonadism, sterilization or primary ovarian dysfunction in women with a non-removed uterus. Prevention of postmenopausal osteoporosis.

Use of the drug Angeliq

If a woman is not taking estrogens or switching to Angeliq after taking another combination drug for continuous use, she can start treatment at any time. Patients who switch to taking Angeliq after using a cyclic combination drug for HRT should begin taking it after the end of the next menstrual-like bleeding. Take one tablet daily. Each blister pack is designed for a 28-day course of treatment. The tablets are swallowed without chewing, with a small amount of liquid, regardless of meals. Treatment is carried out continuously, that is, the next package of tablets begins immediately after the end of the previous one. It is advisable to take the tablets at the same time every day. The missed tablet should be taken as soon as possible. If you are more than 24 hours late in taking the pill, you do not need to take an additional pill. If you miss several doses of pills, bleeding may begin.

Contraindications to the use of the drug Angeliq

HRT should not be used for any of the following conditions. If any of these conditions occur during HRT, the drug should be stopped immediately. Vaginal bleeding of unknown etiology. Diagnosed or suspected breast cancer. Diagnosed precancerous conditions or malignant tumors dependent on sex steroids, or suspicion of their presence. Current or history of liver tumors (benign or malignant). Severe liver diseases. Current or past history of severe kidney disease until normalization of renal function tests. Arterial thromboembolism in the acute stage (for example, myocardial infarction, stroke). Exacerbation of deep vein thrombosis, current thromboembolic disorders or information about these diseases in the anamnesis. Severe form of hypertriglyceridemia. During pregnancy and breastfeeding. Hypersensitivity to the active substances or to any of the auxiliary components of the drug.

Side effects of the drug Angeliq

Below is the frequency distribution of various side effects when taking Angeliq. These rates are based on the incidence of adverse reactions recorded during four phase III clinical trials (1532 at-risk women). It is considered that an association between these reactions and the use of Angeliq (drospirenone content: 1.2 or 3 mg) is at least probable. At the beginning of therapy (the first few months), spotting may be noted. These phenomena are usually temporary and their frequency decreases as treatment continues. One of the common symptoms (noted in approximately every fifth woman) is pain in the mammary gland. Frequency: common (≥1/100, ≤1/10) From the body as a whole: abdominal pain or bloating, asthenia, pain in the extremities. From the digestive system : nausea. From the nervous system: headache, mood swings, hot flashes, nervousness. From the skin and subcutaneous tissues: benign neoplasms in the mammary glands, enlargement of the mammary glands. From the urogenital system : increase in uterine fibroids, cervical neoplasms, leukorrhea. Frequency: uncommon (≥1/1000, ≤1/100). From the body as a whole: pain in the back or pelvic area, chills, malaise, changes in laboratory parameters. From the cardiovascular system: migraine, hypertension, chest pain, palpitations, varicose veins, vein thrombosis, superficial thrombophlebitis, vasodilation. From the digestive system: gastrointestinal disorders, increased appetite, increased functional activity of the liver. Metabolism: generalized or local edema, weight gain, hyperlipidemia. From the musculoskeletal system: muscle cramps, arthralgia. From the nervous system: insomnia, dizziness, decreased libido, decreased ability to concentrate, paresthesia, increased sweating, anxiety, dry mouth, vertigo. From the respiratory system: shortness of breath. Skin and subcutaneous tissue disorders: alopecia, skin or hair diseases, hirsutism, breast carcinoma, breast engorgement. From the sensory organs: taste disturbance. From the urogenital system: vulvovaginitis, diseases of the endometrium and cervix, bleeding, dysmenorrhea, ovarian cyst, urinary tract infections or urinary incontinence. Extremely rarely, erythema nodosum, exudative erythema multiforme, chloasma and hemorrhagic dermatitis were detected in women receiving HRT.

Angeliq tablets p/o bl N28x1 Schering GmbH

The drug Angelique contains 17?-estradiol, chemically and biologically identical to endogenous human estradiol, and a synthetic progestogen, drospirenone. 17?-estradiol ensures the replacement of estrogens in the female body during and after menopause. The addition of drospirenone provides control of bleeding and prevents the development of estrogen-induced endometrial hyperplasia. • Effects of estradiol. The decline of ovarian function, accompanied by a decrease in the production of estrogens and progestogens in the body, predetermines menopausal syndrome, characterized by vasomotor and organic symptoms. To eliminate these disorders, hormone replacement therapy (HRT) is prescribed. Of all natural estrogens, estradiol is the most active and has the greatest affinity (binding strength) for estrogen receptors. Target organs for estrogens include, but are not limited to, the uterus, hypothalamus, pituitary gland, vagina, mammary glands, and bones (namely, osteoclast cells). Other effects of estrogens include reductions in blood insulin and glucose concentrations, local 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. After one year of therapy with a drug containing estradiol and drospirenone, the mean changes in high-density lipoprotein cholesterol (HDL-C) concentrations were insignificant. When taking a drug containing 2 mg of drospirenone in addition to estradiol, the concentration of high-density lipoprotein cholesterol (HDL-C) decreased by 1.6%, and the concentration of low-density lipoprotein cholesterol (LDL-C) in plasma decreased by an average of 14% compared with a decrease of 9% after one year of monotherapy with 1 mg estradiol. Combinations with drospirenone appear to attenuate the increase in triglyceride (TG) concentrations caused by 1 mg estradiol monotherapy. After one year of treatment with 1 mg estradiol, patients' TG concentrations averaged approximately 18% above baseline, compared with an average increase of 5% when combined with drospirenone 2 mg. Treatment with Angeliq for 2 years resulted in an increase in bone mineral density of approximately 3-5%, whereas placebo treatment resulted in a decrease in bone mineral density of approximately 0.5%. A significant statistical difference was found between pelvic bone mineral density in patients in the active treatment groups (with and without osteopenia) compared with placebo. There was also an increase in bone mineral density throughout the body and in the lumbar spine in patients in the active treatment group. Long-term HRT reduces the risk of peripheral bone fractures in postmenopausal women without osteoporosis. HRT also has a positive effect on the collagen content of the skin, skin density, and can delay the formation of wrinkles. Estrogen monotherapy has a dose-dependent stimulating effect on endometrial mitosis and proliferation and, thus, increases the incidence of endometrial hyperplasia. To avoid the development of endometrial hyperplasia, a combination of estrogen with any progestogens is necessary. • Effects of drospirenone. Drospirenone has pharmacodynamic effects similar to natural progesterone. Progestogenic activity. Drospirenone is a potent progestogen with a central inhibitory effect on the hypothalamic-pituitary-ovarian 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 4–6 mg/day for 10 days (40–60 mg per cycle). Continuous hormone replacement therapy with Angeliq allows you to avoid regular “withdrawal” bleeding that is observed with cyclic or phase HRT. During the first months of treatment, bleeding and spotting are quite common, but over time their frequency decreases. While taking Angeliq, the percentage of cases of amenorrhea quickly increases to 81% already on the 6th cycle, then to 86% on the 12th cycle and to 91% on the 24th cycle. The combination of active ingredients of the drug Angeliq effectively prevents the development of endometrial hyperplasia caused by estrogen. After 12 months of treatment with Angeliq, 71–77% of women experienced endometrial atrophy. Antimineralocorticoid activity. Drospirenone has the ability to competitively antagonize aldosterone. The hypotensive effect is most pronounced in women with high blood pressure (BP) with increasing doses of drospirenone. After 8 weeks of treatment with Angeliq, in patients with high blood pressure, systolic/diastolic blood pressure values ​​decreased markedly (decrease by 12 and 9 mm Hg compared to baseline values, compared with placebo - by 3/4 mm Hg. ; when assessing 24-hour ambulatory blood pressure parameters, a decrease of 5/3 mm Hg was noted compared to baseline values, and a decrease of 3/2 mm Hg compared to placebo). The effect of the drug becomes noticeable after 2 weeks, while the maximum effect is achieved within 6 weeks after the start of therapy. No corresponding changes in blood pressure are expected in women with normal blood pressure. In clinical studies of a drug containing a combination of estradiol with drospirenone, the average body weight of patients decreased during 12 months of treatment by 1.1–1.2 kg, while in patients receiving estradiol monotherapy, an increase in body weight of 0.5 kg was noted . Women who received drospirenone in addition to estradiol in a clinical study reported less peripheral edema than women who received estradiol alone. In patients with angina pectoris, after 6 weeks of treatment with Angeliq (containing 1 mg estradiol and 2 mg drospirenone), adaptation of coronary blood flow reserve in response to stress improves (relative change +14% compared to -15% in the placebo group). Antiandrogenic activity. Like natural progesterone, drospirenone has antiandrogenic properties. Effect on carbohydrate metabolism. Drospirenone has neither glucocorticoid nor antiglucocorticoid activity and has no effect on glucose tolerance or insulin resistance. When using the drug Angeliq, glucose tolerance is not impaired. Other properties. The drug Angelique has a positive effect on health and quality of life. According to the Women's Health Questionnaire, the beneficial effects of Angeliq significantly exceeded the effect compared to estradiol monotherapy (absolute value). This high rate is mainly due to an improvement in somatic symptoms, a decrease in the severity of anxiety/fear, and cognitive impairment. Observational studies and the WHI (Women's Health Initiative) study of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) suggest a reduction in the incidence of colon cancer in postmenopausal women taking HRT. In the WHI study, estrogen monotherapy with CEE did not reduce this risk. It is unknown whether the findings also apply to other HRT medications.

Special instructions for the use of Angeliq

Angelique is not used as a contraceptive. If any of the following diseases/risk factors are present or worsened, it is recommended that you carefully weigh the benefit-risk ratio of the drug before starting or continuing HRT. Venous thromboembolism. The results of epidemiological and randomized controlled studies suggest that HRT may be associated with an increased relative risk of developing venous thromboembolism (VTE), that is, deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with a risk factor for developing VTE, the risk-benefit ratio of the drug should be carefully weighed. Generally recognized risk factors for the development of VTE include: personal and family history (a case of VTE in a close relative at a relatively early 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 during prolonged immobilization, after elective or emergency surgery, or after severe trauma. The issue of temporary cessation of HRT should be decided depending on the nature of the intervention and the duration of immobilization. If symptoms of thrombotic disorders appear or are suspected, treatment should be stopped immediately. Arterial thromboembolism. Based on clinical studies, it has been shown that the use of a combination of conjugated equine estrogens and medroxyprogesterone acetate (MPA) for continuous use may be associated with a possible increase in the risk of developing coronary heart disease during the first year of their use and with continued treatment this risk did not change significantly, and also exists an increase in the risk of stroke by 30–40% with estrogen monotherapy or their use in combination with MPA. It has not been established whether this is a risk factor due to the use of other HRT drugs or routes of administration other than oral. Mammary cancer. The risk of developing breast cancer in women who have used HRT for several years increases with the duration of treatment. These facts may be due to earlier diagnosis, the biological effect of HRT on pre-existing tumors, or a combination of these factors. The risk of breast cancer growth is noted in cases of delay in the onset of natural menopause, drinking alcoholic beverages or obesity. Once you stop using HRT, this increased risk disappears within a few years. It is noted that tumors identified in women using or recently using HRT are more differentiated than tumors identified in women not using HRT. HRT increases image density in mammographic examinations, which may negatively affect the assessment of the results of radiological diagnosis of breast cancer. Endometrial cancer. Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. It can be assumed that the inclusion of progestogens in the treatment regimen reduces this increased risk. The additional inclusion of drospirenone in the treatment regimen prevents the development of endometrial hyperplasia caused by estrogen. Liver tumors. After using hormonal drugs, the components of which are contained in HRT preparations, in isolated cases the development of benign, and even less often, malignant liver tumors is noted. In some cases, these tumors led to intra-abdominal bleeding, which was life-threatening. When carrying out differential diagnosis in cases of pain in the upper abdomen, enlarged liver or signs of intra-abdominal bleeding, the likelihood of a liver tumor should be taken into account. Gallstones Estrogens increase the lithogenicity of bile, so some women are prone to developing gallstones during estrogen treatment. Dementia. The results of clinical studies using drugs containing conjugated equine estrogens have shown an increased risk of possible development of dementia if treatment is started in women aged 65 years and older. The risk can be reduced if treatment is started early in menopause. Other conditions. Treatment should be stopped immediately if migraine-like or frequent and unusually severe headaches appear for the first time, or if there are other symptoms that are likely signs of cerebral vascular occlusion. There has been no overall association between the use of HRT and the development of clinical hypertension. A slight increase in blood pressure has been reported in women receiving HRT, but clinically significant increases in blood pressure have rarely been reported. If in some cases persistent clinically significant hypertension develops during HRT, discontinuation of HRT should be considered. Depending on the dose of drospirenone, Angeliq has the ability to lower blood pressure in women with high blood pressure; therefore, it may be necessary to change the dosage of the antihypertensive drugs used. Corresponding changes in blood pressure cannot be expected in women with normal blood pressure. In patients with renal failure, the ability to excrete potassium may be reduced. It was found that taking drospirenone does not affect serum potassium concentrations in patients with mild to moderate renal failure. The risk of developing hyperkalemia is theoretically possible only in patients whose serum potassium concentration before treatment was at the upper limit of the control range, and who are additionally taking potassium-sparing drugs. For minor liver dysfunction, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, careful monitoring of the patient is necessary, as well as periodic determination of liver function. If liver function tests worsen, HRT should be discontinued. If cholestatic jaundice or cholestatic pruritus recurs, first observed during pregnancy or previous treatment with sex steroid hormones, HRT should be stopped immediately. Women with moderately elevated TG levels require special monitoring. In such cases, the use of HRT may cause a further increase in TG levels and a threat to the risk of developing acute pancreatitis. Although HRT may affect peripheral insulin resistance and glucose tolerance, there is generally no need to change the therapeutic regimen for diabetic patients using HRT. Such patients should be under close medical supervision. Some patients may develop undesirable manifestations of estrogen stimulation during HRT - pathological uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for examination of the condition of the endometrium. Under the influence of estrogens, uterine fibroids can increase in size, and therefore treatment must be stopped. It is recommended to discontinue treatment if a recurrence of endometriosis is detected during therapy. If you suspect the presence of prolactinoma, before starting treatment, you must exclude the possibility of such a disease. In some cases, chloasma may be noted, especially in women with a history of chloasma during pregnancy. When taking a course of HRT, women predisposed to chloasma should avoid exposure to the sun or ultraviolet radiation. It has been found that the following conditions and diseases may occur or worsen when using HRT. Although it cannot be confidently stated that these changes are directly related to the use of HRT, careful monitoring of patients undergoing HRT and who have been diagnosed with the following diseases is necessary: ​​epilepsy; benign tumor of the mammary glands; BA; migraine; porphyria; otosclerosis; systemic lupus erythematosus; chorea. Medical examination/consultation. Before starting or resuming HRT, the patient's medical history should be examined in detail and a physical examination should be performed, taking into account contraindications (see CONTRAINDICATIONS) and precautions (see APPLICATION), and such examinations should be repeated periodically. The frequency and nature of examinations should be based on existing standards of medical practice, taking into account the individual characteristics of the patient. As a rule, the pelvic organs are subject to examination, including standard cytological analysis of the cervix, examination of the abdominal cavity, mammary glands, and blood pressure measurement. During pregnancy and breastfeeding. The drug Angeliq is not prescribed during pregnancy and breastfeeding. If pregnancy occurs during treatment with Angeliq, its use should be discontinued immediately. There are no clinical data on the effects of Angeliq during pregnancy. The results of studies conducted on animals indicate a negative effect of the drug during pregnancy and lactation. The potential risk to humans is unknown. Based on the results of the studies, there was no evidence of a teratogenic effect of the estrogen/progestogen combination when used accidentally during pregnancy. A small amount of drospirenone is excreted in breast milk. Effect on the ability to drive vehicles and operate machinery: not noted.

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.

Interactions of the drug Angeliq

The influence of other medicinal products on Angelique. Increased clearance of sex hormones due to induction of liver enzymes may reduce the clinical effectiveness of therapy and cause untimely bleeding. Such liver enzyme inducing properties have been identified in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and the presence of these properties can also be expected in oxcarbazepine, topiramate, felbamate and griseofulvin. The mechanism of this interaction is based on the ability of these drugs to induce liver enzymes. Maximum enzyme induction, as a rule, is determined no earlier than 2-3 weeks from the start of use and it persists for 4 weeks after stopping the drug. In isolated cases, during concomitant use of certain types of antibiotics (for example, penicillin and tetracycline groups), a decrease in estradiol levels was noted. The main metabolites of drospirenone are formed without the participation of the cytochrome P450-dependent system. Therefore, it is unlikely that inhibitors of this system will influence the metabolism of drospirenone. However, other CYP3A4 inhibitors such as cimetidine, ketoconazole, etc. may inhibit the metabolism of estradiol. Excessive alcohol consumption during HRT may increase circulating estradiol levels. Interaction of the drug Angeliq with other medications. in vitro inhibitory studies , as well as an in vivo conducted in female volunteers using omeprazole as a marker substrate, showed that drospirenone does not show a significant tendency to interact with the metabolism of other drugs. Pharmacodynamic interaction with antihypertensive drugs and NSAIDs. Women taking Angeliq and antihypertensive drugs at the same time may experience a decrease in blood pressure. There is a possibility that the combined use of Angeliq and NSAIDs or antihypertensive drugs increases the concentration of potassium in the blood serum. Concomitant use of these three types of drugs may result in a slight increase in serum potassium concentrations, which is more pronounced in patients with diabetes. Effect on Laboratory Tests Intake of sex steroid hormones may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, and plasma levels of carrier proteins such as sex hormone-binding globulin. and lipid/lipoprotein fractions, as well as coagulation and fibrinolysis parameters. Changes are usually within acceptable limits. Taking Angeliq does not affect glucose tolerance.

Angelique

Use during pregnancy and breastfeeding

HRT is contraindicated during pregnancy and breastfeeding.
If pregnancy is detected while taking Angeliq®, the drug should be discontinued immediately. Small amounts of sex hormones can be excreted in breast milk.

Use for liver dysfunction

The use of the drug is contraindicated for benign or malignant liver tumors (including a history), severe liver diseases.

Angeliq should be prescribed with caution for congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itching. If liver function tests worsen, HRT should be discontinued.

Use for renal impairment

The use of the drug is contraindicated in case of severe kidney disease until laboratory parameters are normalized (including in medical history).

special instructions

Angeliq® is not used for contraception.

If contraception is necessary, non-hormonal methods should be used (with the exception of calendar and temperature methods). If you suspect pregnancy, you should stop taking the pills until pregnancy has been ruled out.

If any of the following conditions or risk factors are present or worsening, the individual risk-benefit ratio of treatment should be assessed before starting or continuing to take Angeliq.

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® 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) during HRT, i.e. deep vein thrombosis or pulmonary embolism. Therefore, when prescribing Angeliq® to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Risk factors for developing VTE include individual and family history (the presence of VTE in first-degree 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, “major” elective and trauma surgeries, or major trauma. Depending on the cause or duration of immobilization, the question of the advisability of temporarily stopping taking the drug Angeliq should be decided.

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

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. In large-scale clinical trials of this compound, a possible increase in the risk of coronary heart disease in the first year of use was identified, 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 as monotherapy 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 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. Studies have confirmed that the addition of gestagens reduces the risk of endometrial hyperplasia and cancer.

Mammary cancer

Clinical trial data 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 within a few (but most of five) 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 chronically combined with MPA reported 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 products.

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

Liver tumor

During the use of sex steroids, which include drugs for HRT, in rare cases benign, and even more rarely, malignant liver tumors were observed. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. 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. Some women are predisposed to developing gallstones 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. It is not known whether this applies to other HRT medications.

Other states

Treatment should be stopped immediately if migraine-like 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 women with high blood pressure, there may be a slight decrease in blood pressure while taking the drug Angeliq®. In women with normal blood pressure, significant changes in blood pressure are not expected.

In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect serum potassium concentrations 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 whose serum potassium concentration before treatment was determined at ULN and who additionally take potassium-sparing drugs.

For mild liver dysfunction, incl. Various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, require medical supervision, as well as periodic liver function tests. If liver function indicators deteriorate, Angeliq® 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 steroid hormones, taking Angeliq 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 under the influence of HRT may develop undesirable manifestations of estrogen stimulation, for example, 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 drug concentrations).

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

The following conditions may occur or be aggravated by HRT, and women with these conditions 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.

Additional Information

There is no data on the need for dose adjustment in women under 65 years of age. When using Angeliq® in women over 65 years of age, the information presented in the subsection “Dementia” should be taken into account.

Drospirenone is well tolerated in women with mild or moderate hepatic impairment.

In women with mild to moderate renal impairment, a slight slowdown in the elimination of drospirenone was observed, which was not clinically significant.

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 steroids can promote the growth of certain hormone-dependent tissues and tumors.

Medical examination

Before starting or resuming taking Angeliq®, you should review the patient's medical history in detail and conduct a physical 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 blood pressure measurement, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

In the presence of prolactinoma, periodic determination of prolactin concentration is required.

Impact on laboratory results

Taking sex steroids can affect the biochemical parameters of the liver, thyroid gland, adrenal glands and kidneys, the plasma content of transport proteins, such as globulin that binds sex hormones and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Angeliq® does not have a negative effect on glucose tolerance.

Impact on the ability to drive vehicles and operate machinery

Not found.