Angelique, 28 pcs.

Pharmacodynamics

An anti-climacteric drug.

Anzhelik® contains estrogen, estradiol, which is identical to natural 17β-estradiol. Angelik® also contains the spironolactone derivative drospirenone which has gestagenic, antigonadotropic and antiandrogenic as well as anti-mineralocorticoid effects.

. Angelik® is a combination drug for hormone replacement therapy (HRT) for menopausal disorders in the postmenopausal period (natural menopause, hypogonadism, castration or premature ovarian exhaustion), including vasomotor symptoms (such as hot flashes, increased sweating), sleep disorders, decreased mood, irritability, atrophic changes of the urogenital tract in women with a failed uterus. Continuous hormone replacement therapy with Anjelik® avoids regular withdrawal bleeding, which is observed with cyclic or phasic ZGT.

Estradiol replenishes estrogen deficiency in women after menopause and provides effective treatment of psycho-emotional and vegetative menopausal symptoms (such as hot flashes, increased sweating, sleep disorders, increased nervous excitability, irritability, palpitations, cardialgia, dizziness, headache, libido reduction, muscle and joint pains); Involution of the skin and mucous membranes, especially the genitourinary system (urinary incontinence, dryness and irritation of the vaginal mucosa, painful intercourse).

Estradiol prevents loss of bone mass caused by estrogen deficiency, which is mainly related to suppression of osteoclast function and a shift of bone remodeling process towards bone formation. Long-term use of MHT has been shown to reduce the risk of periprosthetic bone fractures in postmenopausal women. When MHT is withdrawn, the rate of bone mass decline is comparable to that of the immediate postmenopausal period. It has not been shown that MHT can restore bone mass to premenopausal levels.

HST also has beneficial effects on the collagen content of the skin, as well as its density, and can also slow the formation of lines and wrinkles. In addition, because of the anti-androgenic properties of drospirenone, Angelik® has a therapeutic effect on androgen-dependent conditions such as acne, seborrhea, androgenic alopecia.

Drospirenone has anti-mineralocorticoid activity and increases sodium and water excretion, which may prevent high blood pressure, weight gain, edema, breast pain, and other symptoms associated with fluid retention. After 12 weeks of Anjelik® use, a slight decrease of BP (systolic BP decreased by 2-4 mmHg on average, diastolic BP decreased by 1-3 mmHg) was observed. The effect on BP was more pronounced in women with arterial hypertension. After 12 months of using Angelik® the average body weight remained unchanged or decreased by 1.1-1.2 kg.

Drospirenone is devoid of any androgenic, estrogenic, glucocorticosteroid and antiglucocorticosteroid activity and has no effect on glucose tolerance and insulin resistance. This, in combination with anti-mineralocorticoid and anti-androgenic activity, provides drospirenone with a biochemical and pharmacological profile similar to that of natural progesterone.

The administration of Angelik® leads to a decrease in total and LDL cholesterol and a slight increase in triglyceride levels. Drospirenone reduces the increase in triglyceride concentration caused by estradiol.

The addition of drospirenone prevents the development of hyperplasia and endometrial cancer.

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

Pharmacokinetics

Estradiol

Estradiol absorption

After oral administration, estradiol is quickly and completely absorbed from the gastrointestinal tract. It undergoes a “first pass” effect with the formation of estrone, estriol and estrone sulfate. Bioavailability when ingested is about 5% and does not depend on food intake. The Cmax of estradiol in serum is approximately 22 pg/ml and is reached after 6-8 hours. The bioavailability of estradiol is not affected by food intake.

Distribution

Bound to albumin and sex steroid-binding globulin (SBSG). The free fraction of estradiol in serum is approximately 1-12% and GSSB bound 40-45%. The apparent Vd after a single IV administration is about 1 L/kg. After multiple administration, estradiol concentrations are approximately 2 times higher than after single administration, with Css ranging from 20 pg/ml to 43 pg/ml. After discontinuation, estradiol and estrone levels return to baseline values within approximately 5 days.

Metabolism

. Estradiol is metabolized mainly in the liver, partially – in the intestine, kidneys, skeletal muscles and in the target organs to form estrone, estriol, catecholestrogens, and sulfate and glucuronide conjugates of these compounds, which have significantly lower estrogenic activity compared to estradiol or are inactive at all.

The serum clearance of estradiol is about 30 ml/min/kg. Estradiol metabolites are excreted in the urine and bile. The T1/2 is approximately 24 hours.

Drospirenone

Intake

Drospirenone is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Bioavailability is 76-85% and does not depend on food intake. Food intake does not affect the bioavailability of drospirenone.

Distribution

After a single or multiple doses of 2 mg, serum Cmax is reached after 1 hour and is about 22 ng/ml. Thereafter, there is a biphasic decrease in the serum concentration of drospirenone with a final T1/2 of approximately 35-39 h. drospirenone binds to albumin and does not bind to HSPC and corticoid-binding globulin (CRB); about 3-5% is the free fraction. Due to the long T1/2 Css is reached after 10 days of daily administration of Angelik® and exceeds the concentration after a single dose by 2-3 times.

Metabolism

The main metabolites are the acidic form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate, which are formed without participation of cytochrome P450 isoenzymes.

The serum clearance of drospirenone is 1.2-1.5 ml/min/kg. Some part of the dose received is excreted unchanged. Most of the dose is excreted by the kidneys and through the intestine as metabolites at a ratio of 1.2:1.4; T1/2 is about 40 hours.

Indications

Hormone therapy, Prevention of postmenopausal osteoporosis, Tachycardia, Hot flashes, Breast hypersensitivity

Hormone replacement therapy for menopausal disorders in postmenopause.

Prevention of postmenopausal osteoporosis.

Active ingredient

Drospirenone, Estradiol

Composition

Active substances:

Estradiol (in hemihydrate form) 1 mg;

drospirenone 2 mg.

Auxiliary substances:

Lactose monohydrate – 48.2 mg,

Corn starch – 14.4 mg,

corn starch pregelatinized – 9.6 mg,

povidone K25 – 4 mg,

magnesium stearate – 0.8 mg,

hypromellose – 1.0112 mg,

macrogol 6000 – 0.2024 mg,

talc – 0.2024 mg,

titanium dioxide – 0.5438 mg,

red iron oxide dye – 0.0402 mg.

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How to take, the dosage

If a woman is not taking estrogen or is switching to Angelix® from another combination drug for continuous use, she can start treatment at any time. Patients who are switching to Angelik® from a combination drug for cyclic ZHT should start after a bleeding withdrawal ends.

Each package is designed for a 28-day regimen.

The drug should be taken 1 tablet daily. When the 28 pills in the current package are finished, start a new package of Angelik® the next day, taking the first tablet on the same day of the week as the first tablet from the previous package.

The tablet is swallowed whole with a small amount of liquid.

The time of day that a woman takes the pills is not important, but if she starts taking the pills at a specific time, she must keep taking them.

If you miss a pill, take it as soon as possible. If more than 24 hours have elapsed since the usual time, the extra tablet 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 effectiveness.

This property of inducing liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin and is also suspected in oxcarbazepine, topiramate, felbamate and griseofulvin.

The maximum induction of enzymes is usually not observed until 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 levels has been observed with concomitant administration of certain antibiotics (e.g., penicillins and tetracyclines).

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) can inhibit estradiol metabolism.

Based on in vitro interaction studies as well as in vivo studies in female volunteers taking omeprazole, simvastatin and midazolam as markers, it can be concluded that the effect of drospirenone at 3 mg dose on metabolism of other drug substances is unlikely.

The use of Angelique in women receiving antihypertensive therapy (e.g., ACE inhibitors, angiotensin II receptor antagonists, hydrochlorothiazide) may slightly increase the antihypertensive effect.

An increase in serum potassium levels when combined administration of Angelik and NSAIDs or antihypertensive drugs is unlikely. Co-administration of the above three types of drugs may result in a slight increase in serum potassium levels, which is more pronounced in women with type 1 and type 2 diabetes mellitus.

The excessive consumption of alcohol during MHT can lead to increased levels of circulating estradiol.

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Special Instructions

The drug Anjelik® is not used for the purpose of contraception.

If contraception is necessary, non-hormonal methods (with the exception of calendar and temperature methods) should be used. If pregnancy is suspected, the pills should be suspended until pregnancy can be ruled out.

In the presence or worsening of any of the following conditions or risk factors, the individual risk-benefit ratio of treatment should be evaluated before starting or continuing Angelik®.

When prescribing HRT to women who have multiple risk factors for thrombosis or a high degree of severity of one of the risk factors, the possibility of a mutual increase in the effect of risk factors and the prescribed treatment on the development of thrombosis should be considered. In such cases, the cumulative effect of available risk factors is increased. Anjelik® 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) with CGT, i.e. deep vein thrombosis or pulmonary embolism. Therefore, the risk-benefit ratio of Anjelik® prescribing to women with risk factors for VTE should be carefully weighed and discussed with the patient.

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 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 massive trauma. Depending on the cause or duration of immobilization, the appropriateness of temporarily discontinuing Angelix® should be considered.

Stop treatment immediately if symptoms of thrombotic disorders occur or are suspected.

Arterial thromboembolism

In randomized controlled trials, there was no evidence of beneficial cardiovascular effects with long-term use of conjugated equine estrogens (HEE) and medroxyprogesterone acetate (MPA). In large-scale clinical trials of this compound, a possible increase in the risk of CHD during the first year of use, followed by a lack of a positive effect, has been identified. One large clinical trial using CLE alone found a potential reduction in CHD among women aged 50-59 years, with no overall beneficial effect in the total study population. As a secondary finding, two large-scale clinical trials using CLE as monotherapy or in combination with MPA 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 progestagens or to non-oral routes of administration.

Endometrial cancer

Long-term estrogen monotherapy increases the risk of endometrial hyperplasia or carcinoma. Studies have confirmed that the addition of gestagens reduces the risk of hyperplasia and endometrial cancer.

Breast cancer

In clinical trials and observational studies, an increase in the relative risk of breast cancer has been found in women who have used ZHT for several years. This may be due to earlier diagnosis, accelerated growth of an existing tumor with MHT, or a combination of both.

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 later onset of natural menopause and with obesity and alcohol abuse. The increased risk gradually declines to normal levels over several (but mostly five) 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 alone or in constant combination with IPA yielded estimated risk scores of 0.77 (95% confidence interval: 0.59-1.01) or 1.24 (95% confidence interval: 1.01-1.54) after approximately 6 years of MHT. It is not known whether this increased risk also extends to other MHT products.

MGT increases mammographic breast density, which in some cases may have a negative impact on the radiological detection of breast cancer.

Hepatic tumors

In the background of using sex steroids, which include MHT, benign and even rarer malignant liver tumors have been observed in rare cases. 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. Some women are predisposed to develop gallstone disease when treated with estrogen.

Dementia

There is limited evidence from clinical studies of a possible increased risk of dementia in women who begin taking products containing BLE at age 65 or older. As observed in the studies, the risk may be reduced if the CLE-containing MHT medication is started early in menopause. It is not known whether this applies to other MHT drugs.

Other conditions

Treatment should be stopped immediately if migraine-like 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 BP have been described in women taking MHT, and clinically significant increases are rare. However, in some cases, if persistent clinically significant arterial hypertension develops on ZGT, discontinuation of ZGT may be considered. In women with elevated BP, a slight decrease in BP during Angelik® administration is possible. No significant BP changes are expected in women with normal BP.

Potassium excretion may decrease in renal insufficiency. Drospirenone administration does not affect serum potassium concentration in patients with mild to moderate renal insufficiency. The risk of hyperkalemia cannot theoretically be excluded only in the group of patients whose serum potassium concentration before treatment was determined by IGN and who additionally take potassium-saving drugs.

In non-serious 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® 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 steroid hormones, Angelik® should be stopped immediately.

Women with elevated triglyceride concentrations require special monitoring. In such cases, use of MHT may cause a further increase in triglyceride blood concentrations, 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’s treatment 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, under the influence of ZGT. 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 drug concentrations).

In some cases, chloasma may be observed, especially in women with a history of pregnancy chloasma. Women with a history of chloasma should avoid prolonged sun exposure or ultraviolet radiation during therapy with Angelik®.

The following conditions may occur or worsen on MHT, and women with these conditions should be under medical supervision during 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.

Preliminary information

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

In women with mild to moderate hepatic impairment, drospirenone is well tolerated.

In women with mild to moderate renal impairment, a slight delay in drospirenone excretion was observed that was not clinically significant.

Preclinical safety data Preclinical data from standard multiple-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies do not indicate any particular risk to humans. However, it should be remembered that sex steroids can promote the growth of some hormone-dependent tissues and tumors.

Medical examination

Before starting or resuming Angelix® medication, the patient’s medical history should be reviewed in detail and a physical and gynecologic examination should be performed. The frequency and nature of these examinations should be based on current medical practice, with due consideration of each patient’s individual characteristics (but at least once every 6 months) and should include measurement of BP, assessment of breast, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

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

Influence on laboratory results

. Administration of sex steroids may affect biochemical parameters of liver, thyroid, adrenal, and renal function, plasma levels of transport proteins such as sex hormone-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism, coagulation, and fibrinolysis parameters. Angelik® has no negative effect on glucose tolerance.

Effect on the ability to drive vehicles and other mechanisms requiring increased concentration

No effect has been found.

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Contraindications

Angelik® should not be started if any of the following conditions occur; if any of these conditions occur while taking Angelik®, the drug should be stopped immediately:

• high sensitivity to the components of Angelic®;
• vaginal bleeding of unclear etiology;
• confirmed or suspected breast cancer or a history of breast cancer;
• Confirmed or suspected diagnosis of hormone-dependent precancerous disease or hormone-dependent malignancy;
• Benign or malignant liver tumors (including a history ofsevere liver disease;
• Severe current or past renal disease or acute renal failure (pending normalization of renal function);
• acute arterial thrombosis or thromboembolism (includingч. acute arterial thrombosis or thromboembolism (including those leading to myocardial infarction, stroke);
• deep vein thrombosis, current or history of venous thromboembolism;
• having a high risk of venous and arterial thrombosis;
• pulmonary thromboembolism;
• severe hypertriglyceridemia;
• pregnancy and lactation;
• children and adolescents under 18 years of age;
• congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Angelic® should be prescribed with caution in the following conditions: arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during previous pregnancy, endometriosis, uterine myoma, diabetes.

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: smoking, hypercholesterolemia, obesity, systemic lupus erythematosus, dementia, gallbladder disease, retinal vascular thrombosis, moderate hypertriglyceridemia, edema in chronic heart failure, severe hypocalcemia, endometriosis, bronchial asthma epilepsy, migraine, porphyria, hepatic hemangiomas, hyperkalemia, conditions predisposing to hyperkalemia, taking drugs that cause hyperkalemia (potassium-saving diuretics, potassium preparations, ACE inhibitors, angiotensin II receptor antagonists and heparin).

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Side effects

The most common adverse drug reactions observed with Angelik® are breast pain, bleeding from the reproductive tract, gastrointestinal pain, and abdominal pain. These reactions develop in ≥ 6% of women using Angelik®.

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 adverse drug reactions described in clinical trials with Angelik® are presented in decreasing order of severity. The frequency of adverse events was classified as follows:

• very frequently (≥1/10);
• frequently (≥1/10, < 1/10);
• infrequently (≥1/1000, < 1/100);
• infrequently ( < 1/10,000).

Mental disorders: often – emotional lability.

CNS disorders: often – migraine.

Cardiovascular system disorders: infrequent – venous and arterial thromboembolic complications (peripheral deep vein occlusion, thrombosis and embolism/occlusive pulmonary vessels, thrombosis, embolism and myocardial infarction/cerebral infarction and stroke, except hemorrhagic).

Digestive system disorders: often – gastrointestinal pain, abdominal pain.

Perior genital system: very common – pain in the mammary glands (including breast discomfort), bleeding from the genital tract; frequent – cervical polyp; infrequent – breast cancer*.

* – Interrelationship data were obtained from post-marketing observational studies; incidence data were obtained from clinical trials with Angelik®.

For additional information on venous and arterial thromboembolic complications, breast cancer, and migraine, see “Contraindications. “Contraindications” and “Special Indications.”

Unwanted reactions that occur sporadically, or whose symptoms develop over a very long period of time after starting therapy and that are thought to be associated with the use of drugs from the group of combined agents for continuous MHT Liver tumors (benign and malignant); hormone-dependent malignancies or hormone-dependent precancerous conditions (if the patient is known to have these conditions, this is a contraindication to the use of Angelik®); cholelithiasis; dementia; endometrial cancer; arterial hypertension; hepatic dysfunction; hypertriglyceridemia; changes in glucose tolerance or effects on peripheral tissue insulin resistance; increased uterine myoma size; endometriosis reactivation; prolactinoma; chloasma; jaundice and/or itching associated with cholestasis.

The occurrence or worsening of conditions for which the relationship to the use of MHT 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 reactions (including symptoms such as rash and urticaria) have also been reported.

For additional serious adverse events associated with hormone replacement therapy, see “Special Precautions. “Special Indications.”

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 seen in overdose: nausea, vomiting, vaginal bleeding.

Treatment: there is no specific antidote, if necessary, symptomatic therapy is carried out.

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Pregnancy use

ZGT is contraindicated in pregnancy and while breast-feeding.

If pregnancy is detected while taking Angelik® , the drug should be stopped immediately.

A small amount of sex hormones may be excreted with the mother’s milk.

Similarities

Angelique Micro