For 1 tablet:
Active ingredients: estradiol hemihydrate (micronized) in terms of estradiol 0.500 mg, drospirenone (micronized) 0.250 mg;
Excipients: lactose monohydrate - 50.450 mg, corn starch - 14.400 mg, pregelatinized corn starch - 9.600 mg, povidone - 4.000 mg, magnesium stearate - 0.800 mg;
Yellow varnish 2.0000 mg or (alternatively): hypromellose (5 cP) 1.0112 mg, macrogol-6000 0.2024 mg, talc 0.2024 mg, titanium dioxide 0.4640 mg, iron dye yellow oxide 0.1200 mg .
The preparation Angelique Micro contains 17-estradiol, chemically and biologically identical to endogenous human estradiol, and the synthetic progestogen drospirenone. 17-estradiol provides hormone replacement during and after menopause. The addition of drospirenone provides control of bleeding and counteracts the development of estrogen-induced endometrial hyperplasia.
Effects of estradiol
Extinction of ovarian function, accompanied by a decrease in the production of estrogen and progesterone, leads to the development of menopausal syndrome, which is characterized by vasomotor and organic symptoms. Hormone replacement therapy (HRT) is indicated for the treatment of these symptoms.
Of all natural estrogens, estradiol is the most active and has the highest affinity (binding strength) for estrogen receptors. Target organs for estrogens include, but are not limited to, the uterus, hypothalamus, pituitary, vagina, mammary glands, bones (osteoclasts).
Other effects of estrogens include: a decrease in the concentration of insulin and glucose in the blood, vasoactive effects mediated by receptors, and effects on smooth muscle cells of blood vessels independent of receptors. 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 beneficial effect on lipid metabolism in the liver.
Estrogen monotherapy has a dose-dependent stimulating effect on mitosis and endometrial proliferation. thus, it increases the incidence of endometrial hyperplasia and, therefore, the risk of developing endometrial cancer. In order to avoid the development of endometrial hyperplasia, a combination with hierogestagens is necessary.
The effects of drospirenone
Drospirenone has very similar pharmacodynamic effects to natural progesterone.
Drospirenone is a potent progestogen with a central inhibitory effect on the hypothalamus-pituitary-gonadal system. In women of reproductive age, drospirenone has a contraceptive effect; with the introduction of drospirenone in the form of a single drug, ovulation is suppressed. The threshold dose of drospirenone to suppress ovulation is 2 mg / day. The complete transformation of the endometrium that had previously been exposed to estrogen occurs after taking a dose of 4 or 6 mg / day for 10 days (= 40-60 mg per cycle).
Continuous hormone replacement therapy with Angelik Micro helps to avoid regular “withdrawal” bleeding that occurs with cyclic or phase HRT. During the first months of treatment, bleeding and "spotting" discharge are quite common, but over time, their frequency decreases.
Drospirenone has the ability to compete antagonism with aldosterone. Women who received drospirenone in addition to estradiol as part of a clinical trial were less likely to experience peripheral edema than those taking estradiol alone.
Like natural progesterone, drospirenone has antiandrogenic properties.
Effect on carbohydrate metabolism
Drospirenone does not have pi glucocorticoid or antiglucocorticoid activity and does not affect glucose tolerance and insulin resistance. When using the drug Angelik Micro, glucose tolerance is not impaired.
Observational studies suggest that among postmenopausal women, when using HRT, the incidence of colon cancer decreases. The mechanism of action is still unclear.
- hormone replacement therapy for the treatment of moderate and severe vasomotor symptoms associated with menopause in women with an unexplained uterus.
Taking the drug Angelic Micro is contraindicated in the presence of any of the following conditions / diseases. If any of these conditions / diseases occurs while taking Angelik Micro, you should immediately stop using the drug.
- pregnancy or the period of breastfeeding (see the section "Use during pregnancy and during breastfeeding");
- bleeding from the vagina of unspecified etiology;
- a confirmed or suspected diagnosis of breast cancer or a history of breast cancer;
- confirmed or suspected diagnosis of hormone-dependent precancerous disease or hormone
dependent malignant tumor;
- liver tumors at present or in history (benign or malignant);
- severe liver disease;
- severe kidney disease at present or in the anamnesis or acute renal failure (until normalization of renal function);
- acute arterial thrombosis or thromboembolism (for example, myocardial infarction, stroke), angina pectoris;
- deep vein thrombosis in the acute stage, venous thromboembolism (including pulmonary embolism) at present or in the anamnesis;
- the presence of a high risk of venous and arterial thrombosis (see section "Special instructions");
- identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant);
- adrenal insufficiency;
- untreated hyperplasia;
- severe hypertriglyceridemia;
- Hypersensitivity to the components of the drug Angelik Micro;
- children's and teenage age up to 18 years;
- congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
With caution: Angelik Micro should be prescribed with caution in the following diseases: congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during a previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus (see "Special instructions" )
It must be taken into account that estrogens alone or in combination with progestogens should be used with caution in the following diseases and conditions: the presence of risk factors for thrombosis and thromboembolism in the family history (thromboembolic complications in close relatives at a young age), the presence of risk factors for the occurrence of estrogen-dependent tumors (for example, relatives of the 1st degree of kinship with breast cancer), a history of endometrial hyperplasia, smoking, hypercholesterolemia, obesity, systemic lupus erythematosus, dementia, gallbladder disease, retinal vascular thrombosis, moderate hypertriglyceridemia, edema in chronic heart failure, severe hyiocalcemia, endometriosis, bronchial asthma, epilepsy, migraine, liver hemangiomas, hyperkalemia, conditions that predispose to drug administration causing hyperkalemia - potassium-sparing diuretics, potassium preparations, ACE inhibitors, receptor antagonists apgiotheisin II and heparin.
Most often, when using the drug Angelik Micro, such undesirable drug reactions (NLR) were observed as soreness of the mammary glands, bleeding from the genital tract, abdominal pain (less than 2% of patients).
Irregular bleeding usually disappears with prolonged therapy. The frequency of bleeding decreases with increasing duration of treatment.
Serious adverse reactions include arterial and venous thromboembolic complications and breast cancer.
Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobials) can increase the clearance of sex hormones and reduce their clinical effectiveness, which is manifested by irregular bleeding. A similar property to induce liver enzymes was found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, the presence of this feature is also assumed in oxcarbazepine, topiramate, felbamate and griseofulvin. The maximum induction of enzymes is usually observed no earlier than 2-3 weeks, but then it can persist for at least 4 weeks after stopping the drug.
In rare cases, against the background of concomitant use of certain antibiotics (for example, penicillin and tetracycline groups), a decrease in the concentration of estradiol was observed.
The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely. However, CYP3A4 inhibitors (e.g. cimetidine, ketoconazole, etc.) can inhibit estradiol metabolism.
The interaction of the drug Angelik Micro with other drugs
Based on in vitro interaction studies, as well as an in vivo study on female volunteers taking 3 mg of drospirenone per day in combination with omeprazole, simvastatin or midazolam, it can be concluded that the clinically significant interaction of drospirenone with cytochrome P450 on the metabolism of other drug substances is unlikely.
Pharmacodynamic interaction with antihypertensive drugs and non-steroidal anti-inflammatory drugs (NSAIDs)
An increase in the concentration of serum potassium with the combined use of the drug Angelik Micro and non-steroidal anti-inflammatory drugs (NSAIDs) or antihypertensive drugs is unlikely. The combined use of the above three types of drugs can lead to a slight increase in the concentration of serum potassium, more pronounced in women with diabetes.
Excessive alcohol consumption during HRT may increase the concentration of circulating estradiol.
How to take, course of administration and dosage
If a woman does not take estrogen or switches to Angelik Micro from another combination drug for continuous use, then she can start treatment at any time.
Patients who switch to Angelik Micro with a combined preparation for cyclic HRT regimen should start taking it after the end of the current cycle of therapy.
Each package is designed for a 28-day reception.
Take one tablet daily. After taking 28 tablets from the current package, the next day they start taking tablets from a new package of the drug Angelik Micro (continuous HRT), taking the first tablet on the same day of the week as the first tablet from the previous package.
The tablet is swallowed whole, washed down with a small amount of liquid. Tablets are taken regardless of the meal. The time of day when a woman is taking the drug does not matter, however, if she started taking the pill at any particular time, she should adhere to this time further.
A forgotten pill should be taken as soon as possible. If after the usual time of administration more than 24 hours have passed, an additional tablet should not be taken. If several tablets are missed, bleeding from the vagina may develop.
Acute toxicity studies did not reveal a risk of acute side effects in case of accidental administration of the drug in an amount many times higher than the daily therapeutic dose.
In clinical studies, the use of drospirenone up to 100 mg or combined estrogen / progestogen preparations containing 4 mg of estradiol was well tolerated.
Symptoms that may occur with an overdose: nausea, vomiting, vaginal bleeding.
There is no specific antidote, the treatment is symptomatic.
The drug Angelique Micro is not used for contraception.
If pregnancy is suspected, pills should be stopped until pregnancy is excluded (see section "Use during pregnancy and during breast-feeding").
In the presence or worsening of any of the following conditions / diseases or risk factors, before starting or continuing taking the drug, Angelik Micro should evaluate the ratio of individual risk to the benefits of treatment, taking into account the possible need for its cancellation.
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, one should take into account the possibility of a mutual strengthening of the action of risk factors and the prescribed treatment for the development of thrombosis. In such cases, the total value of the available risk factors increases. In the presence of a high risk, the drug Angelik Micro is contraindicated.
A number of controlled randomized and epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, on the background of HRT. Therefore, when prescribing the drug Angelik Micro to women with risk factors for VTE, the ratio of risk and benefit of treatment should be carefully weighed and discussed with the patient.
High risk factors for the development of VTE include an individual and family history (the presence of VTE in immediate relatives at a relatively young age may indicate a genetic predisposition) and obesity with a body mass index of more than 30 kg / m. The risk of VTE also increases with age.
The question of the possible role of varicose veins in the development of VTE remains controversial.
The risk of VTE may temporarily increase with prolonged immobilization, "large" planned and post-traumatic operations, or extensive trauma. In the case of prolonged immobilization or planned surgical intervention, the drug should be discontinued 4-6 weeks before the operation, the resumption of administration is possible only after the full restoration of the motor activity of the woman.
Discontinue treatment immediately if symptoms of thrombotic disorders appear or if they are suspected.
It is necessary to assess the ratio of individual risk and benefit of treatment in women using HRT drugs in conjunction with anticoagulants.
In randomized controlled trials with prolonged use of conjugated equine estrogens (CLE) and medroxyprogesterone acetate (MPA), evidence of a positive effect on the cardiovascular system was not obtained. In large-scale clinical studies of the combination of CLE and MPA, a possible increase in the risk of coronary heart disease (CHD) in the first year of use was revealed with the subsequent absence of a positive effect. In one large clinical study using only CLE, a potential decrease in the number of cases of coronary heart disease among women aged 50-59 years was found in the absence of a general positive effect among the total study population. As a secondary result, in two large-scale clinical trials using CLE, both in the form of monotsrapia and in combination with MPA, an increase in the risk of stroke by 30-40% was revealed. Therefore, it is not known whether this increased risk extends to HRT preparations containing other types of estrogens and hierogestogens or to non-oral uses.
With prolonged estrogen monotherapy, the risk of developing hyperplasia or endometrial 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.
According to clinical and observational studies, an increase in the relative risk of developing breast cancer in women using HRT for several years was found. This may be due to earlier diagnosis, accelerated growth of an existing tumor on the background of HRT, or a combination of both factors. The relative risk increases with increasing duration of therapy, but may be absent or reduced when treated with estrogen alone. This increase is comparable to an increased risk of breast cancer in women with a later onset of natural menopause, as well as obesity and alcohol abuse. The increased risk gradually decreases to the usual level within a few years after the termination of HRT.
Assumptions regarding the increased risk of developing breast cancer are based on the results of more than 50 epidemiological studies (the risk varies from 1 to 2).
In two large-scale randomized trials with CLE as monotherapy or in combination with MPL, calculated risk values of 0.77 (95% confidence interval: 0.59 - 1.01) or 1.24 (95% confidence interval: 1.01 - 1.54) were obtained after approximately 6 years of use HRT. It is not known whether this increased risk also extends to other HRT drugs. HRT increases the mammographic density of the mammary glands, which in some cases can have a negative effect on the radiological detection of breast cancer.
When prescribing the drug Angelic Micro to women with risk factors for the occurrence of estrogen-dependent tumors (for example, relatives of the 1st degree of kinship with breast cancer), the ratio of risk and benefit from treatment should be carefully weighed and discussed with the patient.
A study of estrogen in combination with progestin showed a statistically insignificant increase in the risk of ovarian cancer. The relative risk of developing ovarian cancer with conjugated estrogens with MPA compared to placebo was 1.58
after an average observation period of 5.6 years. The absolute risk when using conjugated estrogens with MPA compared to placebo was 4 versus 3 cases per 10,000 women-years. Long-term use of estrogen-only HRT products (5–10 years) has been associated with a slightly increased risk of ovarian cancer. Long-term use of combination drugs for HRT may have the same or slightly lower risk of developing ovarian cancer.
Against the background of the use of sex hormones, which include hormone replacement therapy, in rare cases benign, and even less often, malignant liver tumors were observed. In some cases, these tumors led to intra-abdominal bleeding, which posed a threat to life. For pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, differential diagnosis should take into account the likelihood of a liver tumor.
Estrogens are known to increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times with estrogen treatment.
There is limited clinical evidence of a possible increase in the risk of dementia in women who start taking drugs containing CLE, aged 65 years and older. As observed in studies, the risk can be reduced if the use of HRT products containing CLE is started in early menopause.
Other conditions / diseases
Treatment should be discontinued immediately when a migraine-like pain first appears or a frequent and unusually severe headache occurs, as well as other symptoms appear that are possible harbingers of cerebral thrombotic stroke.
The relationship between HRT and the development of clinically expressed arterial hypertension has not been established. In women taking HRT, a slight increase in blood pressure is described, a clinically significant increase is rare. However, in some cases, with the development of persistent clinically significant arterial hypertension while taking HRT, cancellation of HRT can be considered.
In renal failure, potassium excretion may decrease. Taking drospirenone does not affect the concentration of potassium in the blood plasma in patients with mild or moderate forms of renal failure. Theoretically, the risk of developing hyperkaliempi cannot be excluded only in the group of patients in whom the concentration of potassium in the blood plasma was determined at the upper limit of the norm before treatment, and who additionally take potassium-sparing drugs.
In case of mild impairment of liver function, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision and periodic liver function tests are necessary.
If liver function indices worsen, Angelik Micro should be discontinued.
With a relapse of cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or prior treatment with sex hormones, taking Angelic Micro should be stopped immediately.
Special monitoring of women with an increase in triglyceride concentration is necessary. In such cases, the use of HRT can cause a further increase in the concentration of triglycerides in the blood, which increases the risk of acute pancreatitis.
Although HRT can affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen for patients with diabetes mellitus during HRT. However, women with diabetes should be monitored during HRT.
Some patients may develop undesirable manifestations of estrogen stimulation, for example, pathological uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for the study of the endometrium in order to exclude diseases of an organic nature.
Under the influence of estrogen, uterine fibroids can increase in size. In this case, treatment should be discontinued.
It is recommended to stop treatment with the development of a relapse of endometriosis against HRT.
If there is a suspicion of prolactinoma, treatment should be ruled out before treatment. If prolactinoma is detected, the patient should be under close medical supervision (including periodic assessment of prolactin concentration).
In some cases, chloasma can be observed, especially in women with a history of pregnant chloasma. During therapy with Angelic Micro, women with a tendency to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.
The following conditions / diseases can occur or worsen against the background of HRT, and women with these conditions / diseases during HRT should be under the supervision of a doctor: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus, lesser chorea.
In women with hereditary forms of exogenous angioedema
Called estrogens can cause or worsen symptoms of AHE.
Preclinical Safety Data
Preclinical data obtained in the course of standard studies to detect toxicity with multiple doses of the drug, as well as genotoxicity, carcinogenic potential and toxicity to the reproductive system, do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of some hormone-dependent tissues and tumors.
Medical Examination and Counseling
Before starting or resuming taking the drug, Angelik Micro should thoroughly familiarize yourself 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 1 time in 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.
Influence on the results of laboratory indicators.
Reception of sex hormones can affect the biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentration of transport proteins, such as globulin, sex hormone binding and lipid / lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis.
Angelique Micro does not adversely affect glucose tolerance.