Angeliq^® Micro (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Contact Information

Bayer AG (Germany)

ATC Code

G03FA17 (Drospirenone and estrogens)

Active Substances

Estradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Dosage Form

Angeliq® Micro

Film-coated tablets, 0.25 mg+0.5 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex, with the embossing “EL” in a regular hexagon on one side.

Excipients: lactose monohydrate – 50.45 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone – 4 mg, magnesium stearate – 0.8 mg.

Shell composition yellow lacquer – 2 mg: hypromellose (5 cP) – 1.0112 mg, macrogol 6000 – 0.2024 mg, talc – 0.2024 mg, titanium dioxide – 0.464 mg, yellow iron oxide dye – 0.12 mg.

28 pcs. – blisters (1) with a pocket for carrying the blister – cardboard packs with first opening control.
28 pcs. – blisters (3) with a pocket for carrying the blister – cardboard packs with first opening control.

Clinical-Pharmacological Group

Anticlimacteric combined drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined antimenopausal agent (estrogen + progestogen)

Pharmacological Action

The drug Angeliq^® Micro contains 17β-Estradiol, chemically and biologically identical to endogenous human estradiol, and a synthetic progestogen, Drospirenone. 17β-Estradiol provides estrogen replacement in the female body during and after menopause. The addition of drospirenone provides control over bleeding and prevents the development of estrogen-induced endometrial hyperplasia.

Effects of estradiol

The decline of ovarian function, accompanied by a decrease in the production of estrogens and progestogens in the body, leads to the development of menopausal syndrome, 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. The target organs for estrogens are, in particular, the uterus, hypothalamus, pituitary gland, vagina, mammary glands, and bones (namely, osteoclast cells).

Other effects of estrogens include: a decrease in the concentration of insulin and glucose in the blood, receptor-mediated vasoactive effects, and receptor-independent effects on the 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 a more favorable effect on lipid metabolism in the liver.

Treatment with Angeliq^® Micro for 2 years led to an increase in bone mineral density of approximately 3-5%, while with placebo, bone mineral density decreased by about 0.5%. A statistically significant difference was found in bone mineral density in the pelvic bones in patients in the active treatment groups (with and without osteopenia), compared with placebo. An increase in bone mineral density in the whole body and in the lumbar spine was also noted in patients from the active treatment group.

Long-term HRT reduces the risk of peripheral fractures in postmenopausal women without osteoporosis.

HRT also has a positive effect on the collagen content in the skin, skin density, and may delay the process of wrinkle formation.

Estrogen monotherapy has a dose-dependent stimulating effect on mitoses and endometrial proliferation and thus increases the incidence of endometrial hyperplasia and, consequently, the risk of endometrial cancer. To avoid the development of endometrial hyperplasia, combination with progestogens is necessary.

Effects of drospirenone

Drospirenone exerts pharmacodynamic effects very similar to natural progesterone.

Progestogenic activity

Drospirenone is a potent progestogen with a central inhibitory effect on the “hypothalamic-pituitary-ovarian axis”. In women of reproductive age, Drospirenone has a contraceptive effect; when drospirenone is administered as a monotherapy, ovulation is suppressed. The threshold dose of drospirenone for ovulation suppression is 2 mg/day. Complete transformation of the previously estrogen-exposed endometrium occurs after administration at a dose of 4-6 mg/day for 10 days (40-60 mg per cycle).

Continuous hormone replacement therapy with Angeliq^® Micro avoids regular “withdrawal” bleeding, which is observed with cyclic or phasic HRT. During the first months of treatment, bleeding and “spotting” are quite common, but their frequency decreases over time.

The combination of active substances of Angeliq^® Micro effectively prevents the development of estrogen-induced endometrial hyperplasia. After 12 months of therapy with Angeliq^® Micro, 71-77% of women had endometrial atrophy.

Antimineralocorticoid activity

Drospirenone has the ability for competitive antagonism with aldosterone. The hypotensive effect is most pronounced in women with elevated blood pressure with an increase in the dose of drospirenone. After 8 weeks of therapy with Angeliq^® Micro, patients with elevated blood pressure showed a noticeable decrease in systolic/diastolic blood pressure (a decrease of 12 and 9 mm Hg compared to baseline, compared to placebo – by 3/4 mm Hg; when assessing 24-hour ambulatory blood pressure compared to baseline, a decrease of 5/3 mm Hg was noted, compared to placebo – by 3/2 mm Hg). The effect of the drug becomes noticeable after 2 weeks, while the maximum effect is achieved within 6 weeks after the start of therapy.

Corresponding changes in blood pressure are not expected in women with normal blood pressure.

Women who, as part of a clinical study, received Drospirenone in addition to estradiol, reported peripheral edema less often than those taking only Estradiol.

Antiandrogenic activity

Like natural progesterone, Drospirenone has antiandrogenic properties.

Effect on carbohydrate metabolism

Drospirenone has neither glucocorticoid nor antiglucocorticoid activity and does not affect glucose tolerance and insulin resistance. When using Angeliq^® Micro, glucose tolerance is not impaired.

Other properties

Angeliq^® Micro has a positive effect on health status and quality of life. According to the Women’s Health Questionnaire, the beneficial effect of Angeliq^® Micro significantly exceeded the effect compared to estradiol monotherapy (absolute score). This high score is mainly explained by the improvement in somatic symptoms, reduction in the severity of anxiety/fears, as well as cognitive impairment.

Observational studies and the Women’s Health Initiative (WHI) study of conjugated equine estrogens (CEE) together with medroxyprogesterone acetate (MPA) indicate a reduction in the incidence of colon cancer in postmenopausal women taking HRT. In the WHI study with estrogen monotherapy using CEE, this risk reduction was not observed. It is unknown whether the findings also apply to other HRT drugs.

Pharmacokinetics

Estradiol

Absorption

After oral administration, Estradiol is rapidly and completely absorbed. During absorption and the “first pass” through the liver, Estradiol is largely metabolized to form estrone, estriol, and estrone sulfate. After oral administration, the bioavailability of estradiol is about 5%. The C_max of estradiol in plasma, which is approximately 16 pg/ml, is usually reached 2-8 hours after taking the tablet. Food intake does not affect the bioavailability of estradiol.

Distribution

When taking Angeliq^® Micro orally, a gradual change in the concentration of estradiol in the blood plasma is observed over 24 hours. Due to the circulation of estrogen sulfates and glucuronides in a wide range on the one hand and enterohepatic recirculation on the other, the T_1/2 of estradiol is a complex parameter that depends on all these processes and is in the range of 13-20 hours after oral administration.

Estradiol binds nonspecifically to serum albumin and specifically to sex hormone-binding globulin (SHBG). The free fraction of estradiol is approximately 1-2%, and the fraction of the substance bound to SHBG is within 40-45%. After oral administration, Estradiol causes the formation of SHBG, which affects the distribution of serum proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound and unbound fractions, indicating the nonlinearity of estradiol pharmacokinetics after taking Angeliq^® Micro. The apparent V_d of estradiol after a single intravenous administration is about 1 L/kg.

Steady-state concentration. With daily use of Angeliq^® Micro, the C_ss of estradiol in blood plasma is reached in approximately 5 days. The concentration of estradiol in plasma increases approximately 2-fold. On average, the concentration of estradiol in blood plasma ranges from 12 pg/ml (minimum level) to 29 pg/ml (maximum level).

Metabolism

Estradiol is metabolized mainly in the liver, and also partially in the intestine, kidneys, skeletal muscles, and target organs. These processes are accompanied by the formation of estrone, estriol, catecholestrogens, as well as sulfate and glucuronide conjugates of these compounds, each of which has significantly less estrogenic activity or no estrogenic activity at all. The concentration of estrone in plasma is 6 times higher than that of estradiol. The concentration in blood plasma of estrone conjugates is 26 times higher than the corresponding concentrations of free estrone.

Excretion

The clearance of estradiol from plasma is about 30 ml/min/kg. Estradiol metabolites are excreted by the kidneys and through the intestine with a T_1/2 of approximately 24 hours.

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed. As indicated in the table below, the C_max of the substance in blood plasma is reached approximately 1 hour after single and multiple administration of Angeliq^® Micro. The pharmacokinetic characteristics of drospirenone are dose-dependent in the range of 0.25-4 mg. Bioavailability is 76-85% and is independent of food intake (compared to taking on an empty stomach).

SD – single dose, SS – steady state

Distribution

The C_max of drospirenone in plasma, which is about 3.35 ng/ml, is reached approximately 1 hour after single and multiple administration of drospirenone at a dose of 0.25 mg. After this, a biphasic decrease in the concentration of drospirenone in plasma is observed with a terminal T_1/2 of about 35-39 hours.

Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). About 3-5% of the total concentration of drospirenone in plasma is not bound to protein.

Steady-state concentration. C_ss is reached after approximately 5 days of daily intake of Angeliq^® Micro. Due to the long T_1/2 of drospirenone, the C_ss is 2-3 times higher than the concentration after a single dose.

Metabolism

After oral administration, Drospirenone is largely metabolized. The main metabolites in plasma are the acid form of drospirenone and 4,5-dihydrodrospirenone-3-sulfate. Both metabolites are formed without the involvement of the cytochrome P450 system. According to in vitro data, Drospirenone is minimally metabolized with the participation of the CYP3A4 isoenzyme.

Excretion

The clearance of drospirenone from plasma is 1.2-1.5 ml/min/kg. Some of the administered dose is excreted unchanged. Most is excreted by the kidneys and through the intestine as metabolites in a ratio of 1.2:1.4, with a T_1/2 of about 40 hours.

Pharmacokinetics in special patient groups

Liver function impairment. The pharmacokinetics of a single oral dose of 3 mg drospirenone in combination with 1 mg estradiol was evaluated in 10 female patients with moderate liver function impairment (Child-Pugh class B) and in 10 healthy participants matched for age, body weight, and smoking history. The mean plasma concentration-time profiles for drospirenone were comparable between both groups of women in the absorption/distribution phase with similar C_max and T_max values, leading to the conclusion that liver function impairment does not affect the extent of absorption. The mean terminal T_1/2 was longer by approximately 1.8 times, and systemic exposure increased 2-fold, corresponding to an approximately 50% reduction in apparent oral clearance (CL/f) in volunteers with moderate liver function impairment compared to participants with normal liver function. The observed decrease in drospirenone clearance in volunteers with moderate liver function impairment compared to volunteers with normal liver function did not result in a significant difference in plasma potassium concentration between the two groups of volunteers. Even with a history of diabetes mellitus and concomitant therapy with spironolactone (two factors predisposing patients to hyperkalemia), an increase in serum potassium concentrations above the upper limit of normal was not observed. Based on this, it can be concluded that Drospirenone is well tolerated by patients with mild to moderate liver function impairment (Child-Pugh class B).

Renal impairment. The effect of renal impairment on the pharmacokinetics of drospirenone (3 mg daily intake for 14 days) was evaluated in patients with normal renal function and in patients with mild and moderate renal impairment. At steady state, plasma concentrations of drospirenone in the group of patients with mild renal impairment (CrCl 50-80 ml/min) were comparable to those in the group of patients with normal renal function (CrCl>80 ml/min). Plasma concentrations of drospirenone were on average 37% higher in the group of participants with moderate renal impairment (CrCl 30-50 ml/min) compared to participants with normal renal function. The results of linear regression analysis of drospirenone AUC (0-24 h) values with respect to CrCl revealed a 3.5% increase against a background of a 10 ml/min decrease in CrCl. The small increase is not considered clinically significant.

Ethnicity. The influence of ethnicity on the pharmacokinetics of drospirenone (1-6 mg) and ethinylestradiol (0.02 mg) was evaluated in young and healthy patients from Europe and Japan after single and multiple daily oral administration. Based on the assessment, it was concluded that ethnic differences between women from Europe and Japan do not have a clinically significant effect on the pharmacokinetics of drospirenone and ethinylestradiol.

Indications

• Hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus.

ICD codes

Dosage Regimen

If a woman has not taken estrogens or is switching to Angeliq^® Micro from another combined preparation for continuous use, she can start treatment at any time.

Patients who are switching to Angeliq^® Micro from a combined preparation for a cyclic HRT regimen should start taking it after the end of the current therapy cycle.

Each package is designed for a 28-day intake.

1 tablet should be taken daily. After finishing the 28 tablets from the current package, the next day they start taking tablets from a new package of Angeliq^® 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 with a small amount of liquid. The tablets are taken regardless of meals. The time of day when a woman takes the drug does not matter, but if she started taking the tablets at a specific time, she should adhere to this time in the future. A forgotten tablet must be taken as soon as possible. If more than 24 hours have passed since the usual time of administration, an additional tablet should not be taken. If several tablets are missed, vaginal bleeding may develop.

Use in specific patient groups

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Elderly patients there are no data on the need for dose adjustment in women under 65 years of age.

In women with mild to moderate liver function impairment Drospirenone is well tolerated.

The drug Angeliq^® Micro is contraindicated in women with current or history of liver tumors, and with severe liver function impairment (see section “Contraindications”). Women with impaired liver function require careful monitoring, and if markers of worsening liver function are detected, HRT should be discontinued (see section “Special Precautions”).

In women with mild to moderate renal impairment, a small increase in drospirenone exposure was observed; however, it is not expected to be of clinical significance.

The drug is contraindicated for use in women with severe renal impairment (see section “Contraindications”).

Adverse Reactions

The most frequently observed adverse reactions with Angeliq^® Micro were breast tenderness, genital bleeding, abdominal pain (in 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 (AR) include arterial and venous thromboembolic complications and breast cancer.

ARs described in clinical studies with Angeliq^® Micro are presented in the table. Definition of AR frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000).

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

*The concept “venous and arterial thromboembolic complications” includes the following medical terms: peripheral deep vein occlusion, thrombosis and embolism/occlusion of pulmonary vessels, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke, excluding hemorrhagic.
** Data on the relationship with the drug use were obtained from post-marketing surveillance; frequency data are from clinical studies with Angeliq^® Micro.

Also see sections “Contraindications” and “Special Precautions” regarding venous and arterial thromboembolic complications, breast cancer, and migraine.

In one placebo-controlled study, ARs reported with a frequency of ≥2% were: headache (6% of patients taking Angeliq^® Micro and 5% of patients receiving placebo), nausea (3.3% and 1.1%, respectively), diarrhea (2.2% and 0.6%, respectively), vulvovaginal candidiasis (5.5% and 0.6%, respectively), peripheral edema (2.2% and 1.1%, respectively).

ARs that occur in isolated cases, or symptoms that develop after a very long time after the start of therapy and are considered associated with the use of drugs from the group of continuous combined HRT agents are listed below.

Neoplasms

• Liver tumors (benign and malignant);
• Hormone-dependent malignant tumors or hormone-dependent precancerous conditions (if it is known that the patient has such conditions, this is a contraindication to the use of Angeliq^® Micro);
• Epidemiological studies of HRT using estrogen alone or estrogen-progestin combination have been associated with a small increased risk of ovarian cancer. The risk may be more pronounced with long-term use (several years) (see also section “Special Precautions”).

Other conditions

• Cholelithiasis;
• Dementia;
• Endometrial cancer;
• Hypertension;
• Liver function disorders;
• Hypertriglyceridemia;
• Changes in glucose tolerance or insulin resistance;
• Increase in the size of uterine fibroids;
• Reactivation of endometriosis;
• Prolactinoma;
• Chloasma;
• Jaundice and/or pruritus related to cholestasis;
• Onset or worsening of conditions for which the relationship with HRT use is not definitively proven: epilepsy; benign breast diseases; bronchial asthma; porphyria; systemic lupus erythematosus; otosclerosis, Sydenham’s chorea;
• In women with hereditary angioedema, exogenous estrogens may exacerbate symptoms;
• Hypersensitivity (including symptoms such as rash and urticaria).

For additional information on serious ARs associated with hormone replacement therapy, see section “Special Precautions”.

Contraindications

The use of Angeliq^® Micro is contraindicated in the presence of any of the conditions/diseases listed below. If any of these conditions/diseases occur during the use of Angeliq^® Micro, the drug should be discontinued immediately.

• Pregnancy;
• Breastfeeding period;
• Vaginal bleeding of unknown etiology;
• Confirmed or suspected diagnosis of breast cancer or history of breast cancer;
• Confirmed or suspected diagnosis of hormone-dependent precancerous condition or hormone-dependent malignant tumor;
• Current or history of liver tumors (benign or malignant);
• Severe liver diseases;
• Current or history of severe kidney diseases or acute renal failure (until kidney function parameters normalize);
• Acute arterial thrombosis or thromboembolism (e.g., myocardial infarction, stroke), angina pectoris;
• Acute deep vein thrombosis, current or history of venous thromboembolism (including pulmonary embolism);
• Presence of high risk of venous and arterial thrombosis;
• Identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Adrenal insufficiency;
• Untreated endometrial hyperplasia;
• Porphyria;
• Severe hypertriglyceridemia;
• Hypersensitivity to the components of Angeliq^® Micro;
• Childhood and adolescence under 18 years of age;
• Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

Angeliq^® Micro should be prescribed with caution for the following diseases: congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during a previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus, arterial hypertension (see “Special Precautions”, “Drug Interactions”).

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: presence of risk factors for thrombosis or thromboembolism and estrogen-dependent tumors in the family history (first-degree relatives with thromboembolic complications at a young age or breast cancer), history of endometrial hyperplasia, 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, liver hemangiomas, hyperkalemia, conditions predisposing to the development of hyperkalemia, use of drugs that cause hyperkalemia – potassium-sparing diuretics, potassium preparations, ACE inhibitors, angiotensin II receptor antagonists and heparin.

Use in Pregnancy and Lactation

HRT is contraindicated during pregnancy or breastfeeding. If pregnancy is detected during the use of Angeliq^® Micro, the drug should be discontinued immediately.

A small amount of sex hormones may be excreted in breast milk.

Use in Hepatic Impairment

The drug is contraindicated for use in women with severe liver function impairment, current or history of liver tumors (benign or malignant).

Use in Renal Impairment

The drug is contraindicated for use in women with severe renal impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

There are no data on the need for dose adjustment in women under 65 years of age.

Special Precautions

Angeliq^® Micro is not used for contraception.

If pregnancy is suspected, tablet intake should be suspended until pregnancy is ruled out (see section “Pregnancy and Lactation”).

In the presence or worsening of any of the conditions/diseases or risk factors listed below, the individual risk-benefit ratio of treatment should be assessed before starting or continuing Angeliq^® Micro, taking into account the possible need for its discontinuation.

When prescribing HRT to women with multiple risk factors for thrombosis or a high degree of severity of one risk factor, the possibility of a mutual enhancement of the effect of risk factors and the prescribed treatment on the development of thrombosis should be considered. In such cases, the total value of the existing risk factors increases. In the presence of 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, during HRT. Therefore, when prescribing Angeliq^® Micro to women with VTE risk factors, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

High-risk factors for VTE include individual and family history (presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and obesity with BMI greater than 30 kg/m². 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 during prolonged immobilization, after surgery, major trauma, surgery on the lower extremities or in the pelvic area, neurosurgical operations. In case of prolonged immobilization or planned surgery, HRT should be discontinued 4-6 weeks before surgery; resumption of use is possible only after the woman has fully regained mobility.

Treatment should be discontinued immediately if symptoms of thrombotic disorders appear or are suspected.

The individual risk-benefit ratio of treatment should be assessed in women using HRT drugs concomitantly with anticoagulants.

Arterial thromboembolism

In randomized controlled trials with long-term use of CEE and MPA, no evidence of a positive effect on the cardiovascular system was obtained. In large-scale clinical studies of the CEE and MPA combination, a possible increase in the risk of CHD was detected in the first year of use, with no positive effect thereafter. In one large clinical study using CEE alone, a potential reduction in the number of CHD cases among women aged 50-59 years was found, with no overall positive effect in the aggregate study population. As a secondary outcome, two large-scale clinical studies using CEE both as monotherapy and in combination with MPA revealed a 30-40% increased risk of stroke. Therefore, it is unknown whether this increased risk applies to HRT drugs containing other types of estrogens and progestogens or to non-oral routes of administration.

Endometrial cancer

Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. Studies suggest that the proper addition of progestogens to the dosing regimen eliminates this increased risk. The addition of drospirenone prevents estrogen-induced development of endometrial hyperplasia. In the presence of a history of endometrial hyperplasia, estrogens alone or in combination with progestogens should be used with caution.

Breast cancer

According to clinical and observational studies, an increased relative risk of developing breast cancer was found in women receiving HRT for several years. This may be due to earlier diagnosis, acceleration of the growth of an existing tumor during HRT, or a combination of both factors.

The relative risk increases with increasing duration of therapy, but may be absent or reduced with estrogen-only therapy. This increase is comparable to the increased risk of breast cancer in women with later natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to the usual level within a few years after discontinuation of HRT.

Assumptions regarding the increased risk of breast cancer are based on the results of more than 50 epidemiological studies (risk varies from 1 to 2).

In two large-scale randomized studies with CEE alone or in continuous combination with MPA, estimated risk rates of 0.77 (95% CI: 0.59-1.01) or 1.24 (95% CI: 1.01-1.54) were obtained after approximately 6 years of HRT use. It is unknown whether this increased risk also applies to other HRT drugs.

HRT increases the mammographic density of the breast, which in some cases may negatively affect the radiological detection of breast cancer.

When prescribing Angeliq^® Micro to women with risk factors for estrogen-dependent tumors (e.g., first-degree relatives with breast cancer), the risk-benefit ratio of treatment must be carefully weighed and discussed with the patient.

Ovarian cancer

Ovarian cancer is less common in the population than breast cancer.

A meta-analysis of 52 epidemiological studies indicates a slight increase in the relative risk of developing ovarian cancer in women receiving HRT compared to women who never received such treatment (prospective studies: RR 1.20, 95% CI 1.15-1.26; all studies: RR 1.14, 95% CI 1.10-1.19). In women continuing to receive HRT, the risk of developing ovarian cancer was somewhat further increased (RR 1.43, 95% CI 1.31-1.56).

Other studies, including the WHI study, suggest that the use of combined HRT drugs may be associated with a similar or slightly lower risk, but the risk may be more significant with long-term use (over several years).

Liver tumors

During the use of sex hormones, which include HRT drugs, benign, and even more rarely, malignant liver tumors have been observed in rare cases. In isolated cases, these tumors have led to life-threatening intra-abdominal bleeding. In case of pain in the upper abdomen, enlarged liver or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Cholelithiasis

Estrogens are known to increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2-4 times with estrogen treatment.

Dementia

There are limited clinical trial data on a possible increased risk of dementia in women starting drugs containing CEE at the age of 65 and older. As observed in studies, the risk may be reduced if HRT drugs containing CEE are started in early menopause.

Other conditions/diseases

Treatment should be discontinued immediately if migraine-like or frequent and unusually severe headache occurs for the first time, as well as if other symptoms – possible precursors of thrombotic stroke – appear.

The relationship between HRT and the development of clinically significant hypertension has not been established. A small increase in BP has been described in women taking HRT; clinically significant increases are rare. However, in individual cases, if persistent clinically significant hypertension develops during HRT, discontinuation of HRT may be considered. In women with elevated BP, some decrease in BP may occur during the use of Angeliq^® Micro. In women with normal BP, no significant changes in BP occur.

In renal failure, the ability to excrete potassium may be reduced. The use of drospirenone does not affect plasma potassium concentration in patients with mild and moderate forms of renal failure. The risk of developing hyperkalemia can theoretically not be excluded only in the group of patients whose plasma potassium concentration before treatment was at the upper limit of normal, and who are additionally taking potassium-sparing drugs.

In non-severe liver function disorders, 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 parameters worsen, Angeliq^® Micro should be discontinued.

In case of recurrence of cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or previous treatment with sex hormones, the use of Angeliq^® Micro must be discontinued immediately.

Special monitoring is required for women with elevated triglyceride concentrations. In such cases, the use of HRT may cause a further increase in blood triglyceride concentrations, 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 for patients with diabetes mellitus during HRT. Nevertheless, women with diabetes mellitus should be under medical supervision during HRT.

In some patients, undesirable manifestations of estrogen stimulation may develop, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial examination to rule out organic disease.

Under the influence of estrogens, uterine fibroids may increase in size. In this case, treatment should be discontinued.

It is recommended to discontinue treatment if a recurrence of endometriosis develops during HRT.

If prolactinoma is suspected, this condition should be ruled out before starting treatment. If prolactinoma is detected, the patient should be under close medical supervision (including periodic assessment of prolactin concentration).

In some cases, chloasma may be observed, especially in women with a history of chloasma during pregnancy. During therapy with Angeliq^® Micro, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following conditions/diseases may occur or worsen during HRT, and women with these conditions/diseases receiving HRT should be under medical supervision: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus; Sydenham’s chorea.

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

Preclinical safety data

Preclinical data from standard studies on toxicity after repeated administration of the drug, as well as genotoxicity, carcinogenic potential, and reproductive toxicity, do not indicate a specific risk for humans. However, it should be remembered that sex hormones may promote the growth of some hormone-dependent tissues and tumors.

Medical examination and counseling

Before starting or resuming Angeliq^® Micro, the patient’s medical history should be reviewed in detail, and a general medical and gynecological examination should be performed. The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient (but not less than once every 6 months) and should include blood pressure measurement, assessment of the condition of the breasts, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

Effect on ability to drive vehicles and machinery

Studies on the effect of Angeliq^® Micro on the ability to drive a car and use machinery have not been conducted. No effect of the drug on the ability to drive a car and use machinery was noted.

Overdose

Acute toxicity studies have not revealed a risk of acute adverse effects following accidental ingestion of the drug in an amount significantly exceeding the daily therapeutic dose.

In clinical studies, the use of drospirenone up to 100 mg or combined estrogen/progestogen drugs containing 4 mg of estradiol was well tolerated.

Symptoms that may be observed with overdose: nausea, vomiting, vaginal bleeding.

Treatment: there is no specific antidote; treatment is symptomatic.

Drug Interactions

The physician prescribing HRT should always be informed about any medications the patient is already taking (for example, antihypertensive drugs). Any other physician or dentist prescribing any other medications for the woman should also be informed that she is taking Angeliq^® Micro. If a woman has any doubts regarding any medication used, she should consult a doctor.

Effect of other drugs on Angeliq^® Micro

Interactions may occur with drugs that induce microsomal enzymes, resulting in increased clearance of sex hormones, which can lead to uterine bleeding and/or reduced therapeutic effect. Enzyme induction can be observed as early as a few days after starting treatment. Maximum enzyme induction is usually observed within a few weeks. After discontinuation of the drug, enzyme induction may persist for approximately 4 weeks.

Drugs that increase the clearance of sex hormones (reducing the effectiveness of sex hormones through enzyme induction): phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort.

Drugs with variable effects on the clearance of sex hormones when co-administered with sex hormones, many non-nucleoside reverse transcriptase inhibitors (drugs for the treatment of HIV and viral hepatitis C) can lead to either an increase or a decrease in the concentration of estrogen, progestin, or both. These changes may in some cases be clinically significant.

Drugs that reduce the clearance of sex hormones (enzyme inhibitors) strong and moderate CYP3A4 inhibitors, for example, azole antifungals (fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase the plasma concentration of estrogens or progestin, either individually or together. Substances that undergo significant conjugation (for example, paracetamol) may increase the bioavailability of estradiol by inhibiting the conjugation system during absorption.

In a multiple-dose study of the combination of drospirenone (3 mg/day) and estradiol (1.5 mg/day), concurrent administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC (0-24 h) of drospirenone by 2.30 times (90% CI: 2.08, 2.54). No changes in estradiol concentration were observed, but the AUC (0-24 h) of its less active metabolite estrone increased by 1.39 times (90% CI: 1.27, 1.52).

Interaction with alcohol

Alcohol abuse while taking HRT drugs may lead to an increase in circulating estradiol concentration.

Effect of Angeliq^® Micro on other drugs

Based on in vivo interaction studies in volunteers taking omeprazole, simvastatin, or midazolam as markers, it can be concluded that clinically significant interaction of drospirenone at a dose of 3 mg with other drugs metabolized via the cytochrome P450 system is unlikely.

Pharmacodynamic interaction with antihypertensive drugs and NSAIDs

The use of Angeliq^® Micro in women receiving antihypertensive therapy (for example, ACE inhibitors, angiotensin II receptor antagonists, hydrochlorothiazide) may slightly increase the antihypertensive effect.

If a woman has high blood pressure, Angeliq^® Micro may lower blood pressure. The physician should be informed if the woman is taking any antihypertensive drugs.

An increase in serum potassium concentration with the combined use of Angeliq^® Micro and NSAIDs or antihypertensive drugs is unlikely. Concurrent use of all three of the aforementioned types of drugs may lead to a slight increase in serum potassium concentration, more pronounced in women with diabetes mellitus.

Other forms of interaction

Effect on laboratory tests. The use of sex hormones may affect the accuracy of laboratory test results, including biochemical parameters of the liver, thyroid, adrenal glands, plasma protein concentration (for example, sex hormone-binding globulin) and lipid/lipoprotein fractions, and coagulation and fibrinolysis parameters. Fluctuations in these parameters usually remain within the reference ranges. Glucose tolerance was not impaired with the use of Angeliq^® Micro_^.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.