Angelic Micro, 28 pcs.

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

Effects of estradiol

The decline in ovarian function, accompanied by decreased estrogen and progesterone production, leads to 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 greatest affinity (binding force) to estrogen receptors. Target organs for estrogen include, but are not limited to, the uterus, hypothalamus, pituitary gland, vagina, mammary glands, and bone (osteoclasts).

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

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

Monotherapy with estrogens has a dose-dependent stimulatory effect on endometrial mitosis and proliferation and thus increases the incidence of endometrial hyperplasia and thus the risk of endometrial cancer. To avoid the development of endometrial hyperplasia, a combination with irogestagens is necessary.

Effects of drospirenone

Drospirenone has very similar pharmacodynamic effects to natural progesterone.

Progestagen activity

Drospirenone is a powerful progestagen with central inhibitory effects on the hypothalamic-pituitary-gonadal system. In women of reproductive age drospirenone has a contraceptive effect; when administered as a monopreparation drospirenone suppresses ovulation. The threshold dose of drospirenone for ovulation suppression is 2 mg/day. The complete transformation of the endometrium which has been earlier exposed to estrogen occurs after taking a dose of 4 or 6 mg/day for 10 days (= 40-60 mg per cycle).

Continuous hormonal replacement therapy with Angelik Micro allows to avoid regular “cancellation” bleedings which are observed at cyclic or phasic ZGT. During the first months of treatment bleeding and “majestic” discharge are quite common, but with time their frequency decreases.

Antimineralocorticoid activity

Drospirenone has the ability to competitive antagonism with aldosterone. Women who received drospirenone in a clinical trial in addition to estradiol were less likely to experience peripheral edema than those who took estradiol alone.

Antiandrogenic activity

Like natural progesterone, drospirenone has antiandrogenic properties.

Effect on carbohydrate metabolism

Drospirenone has neither glucocorticoid nor antiglucocorticoid activity and has no effect on glucose tolerance and insulin resistance. When using Angelik Micro drug glucose tolerance is not impaired.

Other properties

Observational studies suggest that the incidence of colorectal cancer decreases among postmenopausal women when using ZGT. The mechanism of action is still unclear.

Indications

– Hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with a failed uterus.

Active ingredient

Composition

coating

How to take, the dosage

If a woman is not taking estrogen or is switching to Angelik Micro from another combination drug for continuous use, she can start treatment at any time.

Patients who are switching to Angelik Micro from a combination drug for a cyclic ZGT regimen should start after the end of their current cycle of therapy.

Each pack is designed to be taken for 28 days.

One tablet should be taken daily. After the end of the 28 pills in the current package, start the next day the pills in the new package of Angelik Micro (continuous ZGT), taking the first pellet on the same day of the week as the first pellet in the previous package.

The tablet should be swallowed whole with a small amount of liquid. The pills are taken regardless of meals. The time of day a woman takes the pills does not matter, but if she begins taking them at a certain time, she must continue to take them.

The forgotten pill must be taken as soon as possible. If more than 24 hours have elapsed since the usual time, the extra pill should not be taken. If several pills are missed, vaginal bleeding may occur.

Interaction

Long-term treatment with drugs that induce liver enzymes (e.g., some anticonvulsants and antimicrobials) can increase the clearance of sex hormones and decrease their clinical efficacy, which is manifested by irregular bleeding. A similar property of inducing liver enzymes has been found in the hydantoins, barbiturates, primidone, carbamazepine, and rifampicin; this feature has also been suggested in oxcarbazepine, topiramate, felbamate, and griseofulvin. Maximum enzyme induction is not usually seen before 2-3 weeks, but then it may persist for at least another 4 weeks after discontinuation of the drug.

In rare cases, a decrease in estradiol concentrations has been observed with concomitant administration of certain antibiotics (e.g., penicillin and tetracycline groups).

The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, it is unlikely that cytochrome P450 inhibitors affect the metabolism of drospirenone. However, CYP3A4 inhibitors (e.g., cimetidine, ketoconazole, etc.) can inhibit estradiol metabolism.

Interaction of the drug Angelik Micro with other medicinal products

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

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

An increase in serum potassium concentration when combined administration of Angelik Micro and nonsteroidal anti-inflammatory drugs (NSAIDs) or hypotensive drugs is unlikely. Co-administration of the above three types of drugs may lead to a slight increase in serum potassium concentration, which is more pronounced in women with diabetes mellitus.

Interaction with alcohol

Excessive consumption of alcohol during ZGT can lead to an increase in circulating estradiol concentrations.

Special Instructions

Anjelik Micro is not used for contraceptive purposes.

If pregnancy is suspected, the pills should be withheld until pregnancy can be excluded (see section “Administration during pregnancy and breastfeeding”).

In the presence or worsening of any of the following conditions/diseases or risk factors, before starting or continuing Angelik Micro, the individual risk-benefit ratio of the treatment should be assessed, taking into account the possible need for withdrawal.

When prescribing HRT to women with multiple risk factors for thrombosis or with a high degree of severity of one of the risk factors, the possible synergistic effect of the risk factors and the prescribed treatment on thrombosis should be considered. In such cases, the cumulative effect of available risk factors is increased. Anjelik Micro is contraindicated if there is a high risk.

Venous thromboembolism

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

High-risk factors for VTE include individual and family history (the presence of VTE in immediate family members at a relatively young age may indicate a genetic predisposition) and obesity with a body mass index greater than 30 kg/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, “large” elective and post-traumatic surgeries, or extensive trauma. In case of prolonged immobilization or planned surgical intervention the drug should be discontinued 4-6 weeks prior to surgery, resumption is possible only after full restoration of the woman’s motor activity.

The treatment should be stopped immediately if symptoms of thrombotic disorders appear or if there is suspicion of their occurrence.

The individual risk-benefit ratio of women using MHT with anticoagulants should be assessed.

Arterial thromboembolism

In randomized controlled trials, there has been no evidence of cardiovascular benefit with long-term use of conjugated equine estrogen (HEE) and medroxyprogesterone acetate (MPA). Large-scale clinical trials of the combination of CLE and MPA have found a possible increased risk of coronary heart disease (CHD) in the first year of use, followed by a lack of benefit. One large clinical trial using only CLE found a potential reduction in CHD among women aged 50-59 years, with no overall benefit in the total study population. As a secondary finding, two large-scale clinical trials using CLE both as monotherapy and in combination with IPA found a 30-40% increased risk of stroke. Therefore, it is not known whether this increased risk extends to MHT preparations containing other types of estrogens and irogestagens or to nsperoral routes of administration.

Endometrial cancer

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

Breast cancer

An increase in the relative risk of breast cancer has been found in women who have used ZGT for several years, according to clinical and observational studies. This may be due to earlier diagnosis, to accelerated growth of an existing tumor on MHT, or a combination of both. Relative risk increases with increasing duration of therapy but may be absent or reduced with estrogen therapy alone. This increase is comparable to an increase in breast cancer risk in women with delayed natural menopause, and with obesity and alcohol abuse. The increased risk gradually declines to normal levels over a period of years after discontinuation of MHT.

The assumptions for increased risk of breast cancer are based on more than 50 epidemiological studies (risk ranges from 1 to 2).

Two large-scale randomized trials with CLE as monotherapy or in combination with MPL yielded estimated risk scores of 0.77 (95% confidence interval: 0.59 to 1.01) or 1.24 (95% confidence interval: 1.01 to 1.54) after approximately 6 years of MHT. It is not known whether this increased risk also extends to other MHT drugs. MHT increases mammographic breast density, which in some cases may have a negative impact on radiological detection of breast cancer.

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

Ovarian cancer

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

Hepatic tumor

Per the use of sex hormones, which include MHT agents, has rarely resulted in benign, and even more rarely, malignant liver tumors. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If there is upper abdominal pain, an enlarged liver, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Biliary stone disease

Oestrogens are known to increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times when treated with estrogens.

Dementia

There is limited evidence from clinical studies of a possible increased risk of dementia in women who begin taking CLE-containing medications at age 65 or older. As has been observed in studies, the risk may be reduced if the CLE-containing MHT medication is started early in menopause.

Other conditions/diseases

Treatment should be stopped immediately if migraine-like pain or frequent and unusually severe headaches first occur, or if other symptoms – possible precursors of cerebral thrombotic stroke – occur.

The relationship between MHT and the development of clinically significant arterial hypertension has not been established. Small increases in blood pressure have been described in women taking MHT, and clinically significant increases are rare. However, in individual cases, if persistent clinically significant arterial hypertension develops against the background of ZGT, discontinuation of ZGT may be considered.

Potassium excretion may decrease in renal insufficiency. Taking drospirenone does not affect plasma potassium concentrations in patients with mild to moderate renal insufficiency. The risk of hyperkalemia cannot theoretically be excluded only in the group of patients whose plasma potassium concentration before treatment was determined to be at the upper limit of normal, and who additionally take potassium-saving drugs.

In mild liver function disorders, including various forms of hyperbilirubinemia such as Dubin-Johnson syndrome or Rotor syndrome, monitoring by a physician is necessary, as well as periodic liver function tests.

If liver function worsens, Angelik Micro should be discontinued.

If there is a recurrence of cholestatic jaundice or cholestatic pruritus observed for the first time during pregnancy or prior treatment with sex hormones, Angelik Micro should be stopped immediately.

Women should be particularly monitored if triglyceride concentrations are elevated. In such cases, use of ZGT may cause a further increase in triglyceride concentrations in the blood, which increases the risk of acute pancreatitis.

While MHT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change a diabetic patient’s regimen while on MHT. Nevertheless, women with diabetes should be monitored while on MHT.

Some patients may develop adverse effects of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding after treatment is an indication for endometrial exploration to rule out organic disease.

Estrogens may cause uterine myomas to increase in size. In this case the treatment should be stopped.

To discontinue treatment, discontinuation is recommended if endometriosis relapses on ZHT.

If prolactinoma is suspected, this disease should be ruled out 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 be observed, especially in women with a history of pregnancy chloasma. During therapy with Angelik Micro, women who are prone to chloasma should avoid prolonged sun exposure or ultraviolet radiation.

The following conditions/diseases can occur or worsen on MHT, and women with these conditions/diseases should be under medical supervision while on MHT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus; small chorea.

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

Preclinical safety data

Preclinical data from standard multiple-dose toxicity studies, as well as genotoxicity, carcinogenic potential, and reproductive toxicity, do not indicate any particular risk to humans. However, we should keep in mind that sex hormones can promote the growth of some hormone-dependent tissues and tumors.

Medical examination and counseling

Before starting or restarting Angelik Micro, you should review the patient’s medical history in detail and perform a general medical and gynecologic exam. The frequency and nature of these examinations should be based on current standards of medical practice with due consideration of the individual characteristics of each patient (but at least once every 6 months) and should include measurement of blood pressure, assessment of the condition of the breast, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

Impact on laboratory results.

The administration of sex hormones may affect biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of transport proteins such as sex hormone-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, coagulation and fibrinolysis.

Angelik Micro has no negative effect on glucose tolerance.

Influence on the ability to drive and operate vehicles

No effect has been detected.

Contraindications

The use of Angelik Micro is contraindicated in the presence of any of the following conditions/diseases. If any of these conditions/diseases occur while taking Angelik Micro, the drug should be stopped immediately.

Pregnancy or breast-feeding (see section “Administration during pregnancy and breast-feeding”).

– pregnancy or breastfeeding (see “Administration during pregnancy and breastfeeding”);

– vaginal bleeding of unspecified etiology;

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

– a confirmed or suspected diagnosis of hormone-dependent precancer or hormone-dependent malignancy;

– current or history of liver tumors (benign or malignant);

– severe liver disease;

– current or history of severe renal disease or acute renal failure (until normal renal function);

– acute arterial thrombosis or thromboembolism (e.g., myocardial infarction, stroke), angina pectoris;

– aggravated deep vein thrombosis, venous thromboembolism (including thromboembolism).

– current or past history of venous thromboembolism (including pulmonary embolism);

– current or past history of high risk of venous and arterial thrombosis (see “Special Precautions”).

– 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;

– porphyria;

– marked hypertriglyceridemia;

– hypersensitivity to components of Angelik Micro;

– childhood and adolescence under 18 years of age;

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

With caution: Angelik Micro should be administered with caution in the following conditions: congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during previous pregnancy, endometriosis, uterine myoma, diabetes (see Special Instructions).

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

Side effects

The most common adverse drug reactions (ADRs) observed with Angelik Micro were breast tenderness, bleeding from the reproductive tract, and abdominal pain (less than 2% of patients).

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

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

The NERs described in clinical trials with Angelik Micro are shown in the table below. The following terms are used to define frequency: very frequent (> 1/10), frequent (> 1/100 to < 1/10), infrequent (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000).

In clinical trials, adverse events were coded using the MedDRA dictionary. Different MedDRA terms reflecting the same medical phenomenon were grouped into one adverse event to avoid duplication or confusion in describing the true effect.

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

** The relationship with use of the drug was obtained from post-marketing observational studies; frequency data were obtained from clinical trials with Angelik Micro.

For venous and arterial thromboembolic complications, breast cancer, and migraine, see Contraindications and Special Indications.

In one placebo-controlled study, adverse reactions were reported with a frequency of > 2%: headache (6% of patients taking Angelik Micro and 5% of patients receiving placebo), nausea (3.3% and 1.1%, respectively), diarrhea (2.2% and 0.6%, respectively), candidal vulvovaginitis (5.5% and 0.6%, respectively), peripheral edema (2.2% and 1.1%, respectively).

Unwanted reactions that occur sporadically, or symptoms that develop very long after initiation of therapy and that are considered to be related to the use of drugs from the group of combined products for continuous hormone replacement therapy, are listed below:

– liver tumors (benign and malignant);

– hormone-dependent malignancies or hormone-dependent precancerous conditions (if the patient is known to have such conditions/diseases, this is a contraindication to the use of Angelik Micro)

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– cholelithiasis;

– dementia;

– endometrial cancer;

– arterial hypertension;

– liver function disorders;

– hypertriglyceridemia;

– changes in glucose tolerance or insulin resistance;

– increase in the size of a uterine myoma;

– reactivation of endometriosis;

– prolactinoma;

– chloasma;

– jaundice and/or itching associated with cholestasis;

– occurrence or worsening of conditions/diseases for which the relationship to use of ZGT is not clearly proven: Epilepsy; benign breast disease; bronchial asthma; porphyria; systemic lupus erythematosus; otosclerosis; minor chorea;

– In women with hereditary angioedema, exogenous estrogens may contribute to exacerbation of symptoms;

Hypersensitivity (including symptoms such as rashes and urticaria).

For more information about serious adverse events associated with hormone replacement therapy, see “Special Precautions.

Overdose

Acute toxicity studies have shown no risk of acute side effects when the drug is accidentally taken in amounts many times greater than the daily therapeutic dose.

In clinical trials, the use of drospirenone up to 100 mg or combined estrogen/gestagen preparations containing 4 mg estradiol was well tolerated.

Symptoms that may be noted in overdose: nausea, vomiting, vaginal bleeding.

There is no specific antidote, treatment is symptomatic.

Similarities