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

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.

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.

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.

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.

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.