Angeliq^® (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®

Film-coated tablets, 2 mg+1 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of a grayish-pink color, round, biconvex, with the embossing “DL” in a regular hexagon on one side.

Excipients: lactose monohydrate – 48.2 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone K25 – 4 mg, magnesium stearate – 0.8 mg, hypromellose, viscosity 5 cP – 1.0112 mg, macrogol 6000 – 0.2024 mg, talc – 0.2024 mg, titanium dioxide – 0.5438 mg, iron oxide red dye – 0.0402 mg.

28 pcs. – blisters (1) with a carrying pouch – cardboard packs with first-opening control.
28 pcs. – blisters (3) with a carrying pouch – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Anticlimacteric combined drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined antimenopausal agent (estrogen + gestagen)

Pharmacological Action

The drug Angeliq^® 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, determines the climacteric syndrome, characterized by vasomotor and organic symptoms. To eliminate these disorders, hormone replacement therapy (HRT) is prescribed.

Of all natural estrogens, Estradiol is the most active and has the greatest 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).

Among other effects of estrogens, a decrease in the concentration of insulin and glucose in the blood, local vasoactive effects mediated by receptors, as well as receptor-independent effects on vascular smooth muscle cells should be noted. 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.

After one year of therapy with a drug containing Estradiol and Drospirenone, the mean changes in HDL cholesterol (HDL-C) concentrations were insignificant. When taking a drug containing, in addition to 1 mg estradiol, 2 mg drospirenone, the HDL-C concentration decreased by 1.6%, and the plasma LDL cholesterol (LDL-C) concentration decreased by an average of 14% compared to a decrease of 9% after one year of monotherapy with 1 mg estradiol.

Combined preparations with drospirenone likely reduce the increase in triglyceride (TG) concentration induced by monotherapy with 1 mg estradiol. After one year of treatment with 1 mg estradiol, TG concentrations in patients on average exceeded the baseline level by approximately 18%, compared to an average increase of 5% when using the combination with 2 mg drospirenone. Therapy with Angeliq^® 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 of patients in the active treatment groups (with and without osteopenia) compared to 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 proliferation of the endometrium and thus increases the frequency of endometrial hyperplasia. To avoid the development of endometrial hyperplasia, it is necessary to combine estrogen with any progestogen.

Effects of drospirenone

Drospirenone exerts pharmacodynamic effects similar to natural progesterone.

Progestogenic activity

Drospirenone is a potent progestogen with a central inhibitory effect on the “hypothalamus-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-primed endometrium occurs after taking a dose of 4-6 mg/day for 10 days (40-60 mg per cycle).

Continuous hormone replacement therapy with Angeliq^® avoids regular “withdrawal” bleeding observed with cyclic or sequential HRT. During the first months of treatment, bleeding and “spotting” are quite common, but their frequency decreases over time. While taking Angeliq^®, the percentage of amenorrhea cases rapidly increases to 81% by the 6th cycle, then to 86% by the 12th cycle, and to 91% by the 24th cycle.

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

Antimineralocorticoid activity

Drospirenone has the ability for competitive antagonism with aldosterone. The antihypertensive effect is most pronounced in women with elevated blood pressure with increasing doses of drospirenone. After 8 weeks of therapy with Angeliq^®, 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 readings compared to baseline, a decrease of 5/3 mm Hg was noted, compared to placebo – by 3/2 mm Hg). The drug’s effect 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.

In clinical studies of the drug containing a combination of estradiol with drospirenone, the average body weight of patients decreased by 1.1-1.2 kg over 12 months of treatment, whereas in patients receiving estradiol monotherapy, an increase in body weight of 0.5 kg was noted.

Women who received Drospirenone in addition to estradiol in a clinical study reported peripheral edema less frequently than women taking Estradiol alone.

In patients with angina pectoris, after 6 weeks of therapy with Angeliq^® (containing 1 mg estradiol and 2 mg drospirenone), adaptation of the coronary flow reserve in response to stress improves (relative change +14% compared to -15% in the placebo group).

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^®, glucose tolerance is not impaired.

Other properties

Angeliq^® has a positive effect on health status and quality of life. According to the Women’s Health Questionnaire, the beneficial effect of Angeliq^® 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 these 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 significantly metabolized, which reduces the absolute bioavailability of the estrogen after oral administration to approximately 5% of the administered dose. C_max (about 16 or 22 pg/ml) was reached 2-8 hours after a single oral dose of 0.5 mg or 1 mg estradiol, respectively. Food intake does not affect the bioavailability of estradiol (compared to taking on an empty stomach).

Distribution

When taking Angeliq^® orally, a gradual change in estradiol concentration in the blood plasma is observed over 24 hours. Due to the circulation of estrogen sulfates and glucuronides over 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 non-specifically to serum albumin and specifically to sex hormone-binding globulin (SHBG). The free fraction of estradiol is 1-2%, and the fraction of the substance bound to SHBG is within 40-45%. After oral administration, Estradiol induces 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^®. The apparent V_d of estradiol after a single intravenous administration is about 1 L/kg.

Steady-state concentration. With daily oral administration of Angeliq^®, the C_ss of estradiol is reached after 5 days. The plasma concentration of estradiol increases approximately 2-fold. With a 24-hour dosing interval, the mean steady-state plasma concentrations of estradiol range from 20-43 pg/ml after taking a drug containing 1 mg estradiol.

Metabolism

Estradiol is rapidly metabolized, with a large number of other metabolites and conjugates formed in addition to estrone and estrone sulfate. Estrone and estriol are known as pharmacologically active metabolites of estradiol. Only estrone was determined in significant concentrations in blood plasma. The estrone content in plasma is approximately 6 times higher than the concentration of estradiol. The concentrations of estrone conjugates in blood plasma are approximately 26 times higher than the corresponding concentrations of free estrone.

Excretion

The plasma clearance of estradiol 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, C_max of the substance in blood plasma is reached approximately 1 hour after single and multiple administration of Angeliq^®. The pharmacokinetic characteristics of drospirenone are dose-dependent within the range of 0.25-4 mg. The bioavailability is 76-85% and is independent of food intake (compared to taking on an empty stomach).

C_max – maximum concentration
SD – single dose
SS – steady state

Distribution

After oral administration, the plasma concentration of drospirenone decreases in two phases with a mean terminal T_1/2 of about 35-39 hours. Drospirenone binds to serum albumin, does not bind to sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). Only 3-5% of the total drospirenone concentration is present in plasma as free hormone. The mean apparent V_d of drospirenone is 3.7-4.2 L/kg.

Steady-state concentration. The maximum steady-state plasma concentrations of drospirenone, achieved during multiple daily administration of Angeliq^®, are indicated in the table above. C_ss is reached approximately after 10 days of daily administration of Angeliq^®. 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 extensively metabolized. The main metabolites in plasma are the acid form of drospirenone, formed as a result of lactone ring opening, and 4,5-dihydrodrospirenone-3-sulfate, formed during reduction and sulfation. Drospirenone undergoes oxidative metabolism in the presence of the CYP3A4 isoenzyme.

Excretion

The total plasma clearance of drospirenone is 1.2-1.5 ml/min/kg. Only very small amounts of drospirenone are excreted unchanged. Drospirenone metabolites are excreted by the kidneys and through the intestine in a ratio of about 1.4:1.2. The T_1/2 of metabolites by the kidneys and through the intestine is about 40 hours.

Pharmacokinetics in special patient groups

Hepatic 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 hepatic 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 hepatic impairment does not affect the extent of absorption. The mean terminal phase T_1/2 was longer by approximately 1.8 times, and systemic exposure increased by 2 times, corresponding to an approximately 50% reduction in apparent oral clearance (CL/f) in volunteers with moderate hepatic impairment compared to participants with normal liver function. The observed decrease in drospirenone clearance in volunteers with moderate hepatic impairment compared to volunteers with normal liver function did not result in a significant difference in plasma potassium concentrations 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 hepatic 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 (HRT) for disorders due to estrogen deficiency in postmenopausal women with an intact uterus, not earlier than 12 months after the last menstruation;
• Prevention of osteoporosis in postmenopausal women at high risk of fractures, in case of intolerance or contraindications to the use of other drugs for the prevention of osteoporosis.

ICD codes

Dosage Regimen

If a woman is not taking estrogens or is switching to Angeliq^® from another continuous combined drug, she can start treatment at any time.

Patients switching to Angeliq^® from a cyclical combined HRT drug should start taking it after the end of the current therapy cycle.

Each package is designed for a 28-day course.

One tablet should be taken daily. After finishing the 28 tablets from the current package, a new package of Angeliq^® (continuous HRT) should be started the next day, taking the first tablet on the same day of the week as the first tablet from the previous package.

The tablet should be swallowed whole with a small amount of liquid. The time of day when a woman takes the drug does not matter; however, if she started taking the tablets at a specific time, she should continue to adhere to that time. A forgotten tablet should 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

Children and adolescents

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 elderly patients.

Patients with impaired liver function

Drospirenone is well tolerated in women with mild to moderate liver function impairment. Angeliq^® 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”).

Patients with impaired renal function

A slight delay in the excretion of drospirenone was observed in women with mild to moderate renal impairment, which was not clinically significant.

Adverse Reactions

The most frequently observed adverse drug reactions (ADRs) with the use of Angeliq^® were breast tenderness, genital bleeding, gastrointestinal pain, and abdominal pain. These reactions occur in ≥6% of women taking Angeliq^®.

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.

ADRs described in clinical studies with Angeliq^® are presented in the table in order of decreasing severity. The following concepts are used to determine frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (from ≥1/10000 to <1/1000).

*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 use of the drug were obtained from post-registration observations; frequency data were obtained from clinical studies with Angeliq^®.

For additional information on venous and arterial thromboembolic complications, breast cancer, and migraine, also see the sections “Contraindications” and “Special Precautions”.

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

Tumors

• 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^®);
• In epidemiological studies, HRT with estrogen alone or estrogen-progestin combination has been associated with a small increase in the 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;
• Arterial hypertension;
• Liver function disorders;
• Hypertriglyceridemia;
• Changes in glucose tolerance or effects on peripheral tissue insulin resistance;
• Increase in the size of uterine fibroids;
• Reactivation of endometriosis;
• Prolactinoma;
• Chloasma;
• Jaundice and/or pruritus associated with cholestasis;
• Occurrence 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; chorea minor;
• In women with hereditary angioedema, exogenous estrogens may exacerbate symptoms;
• Hypersensitivity (including symptoms such as rash and urticaria).

If a woman believes that she has developed any side effects while taking Angeliq^®, even those not included in this list, she should inform her doctor.

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

Contraindications

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

• Pregnancy;
• Breastfeeding period;
• Vaginal bleeding of unspecified 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;
• Acute arterial thrombosis or thromboembolism, including those leading to myocardial infarction, stroke;
• Acute deep vein thrombosis, current or history of venous thromboembolism (including pulmonary embolism);
• Presence of high risk of venous and arterial thrombosis;
• Identified hereditary or acquired predisposition to arterial or venous thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); conditions preceding thrombosis (transient ischemic attacks, angina pectoris);
• Untreated endometrial hyperplasia;
• Severe hypertriglyceridemia;
• Porphyria;
• Hypersensitivity to the components of Angeliq^®;
• Childhood and adolescence under 18 years of age;
• Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

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

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 the development of 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 diseases, 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^®, the drug should be discontinued immediately.

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

Use in Hepatic Impairment

The use of the drug is contraindicated in benign or malignant liver tumors (including history), severe liver diseases.

Angeliq^® should be prescribed with caution in congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus. If liver function parameters worsen, HRT should be discontinued.

Use in Renal Impairment

The use of the drug is contraindicated in current or history of severe kidney diseases, acute renal failure.

Pediatric Use

The use of the drug is contraindicated in childhood and adolescence under 18 years of age.

Geriatric Use

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

There is evidence of an increased risk of developing dementia in women starting combined or single-drug HRT at over 65 years of age.

Special Precautions

Angeliq^® is not used for contraception.

HRT drugs should be prescribed only for the treatment of symptoms due to estrogen deficiency in postmenopause that affect the quality of life. HRT should be continued only as long as the benefit outweighs the risk of using the drug.

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

If any of the following conditions or risk factors are present or worsening, the individual risk-benefit ratio of treatment should be assessed before starting or continuing Angeliq^®.

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 taken into account. In such cases, the total value of the existing risk factors increases. If the risk is high, Angeliq^® 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) during HRT, i.e., deep vein thrombosis or pulmonary embolism. Therefore, when prescribing Angeliq^® to women with VTE risk factors, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

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 severe obesity. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial.

Risk factors for VTE also include the use of estrogens, thrombophilic diseases/conditions, systemic lupus erythematosus, and cancer.

The individual risk-benefit ratio of HRT drugs should be assessed in patients taking anticoagulant drugs on a permanent basis.

The risk of VTE may temporarily increase with prolonged immobilization, after surgery, extensive trauma, surgery on the lower extremities or in the pelvic area, and 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 restored mobility.

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

Arterial thromboembolism

Controlled randomized studies of the use of combined or estrogen-only HRT drugs have not found evidence of their protective effect against myocardial infarction, regardless of the presence or absence of a history of coronary artery disease. The relative risk of developing coronary artery disease is slightly increased with the use of combined HRT drugs, and the risk increases with age. The use of combined HRT drugs increases the risk of stroke by 1.5 times.

Endometrial cancer

Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. Studies have confirmed that the addition of progestogens prevents the increased risk of hyperplasia and endometrial cancer. The addition of drospirenone prevents the development of endometrial hyperplasia caused by estrogens. If there is a history of endometrial hyperplasia, estrogens alone or in combination with progestogens should be used with caution.

Breast cancer

According to clinical trials and observational studies, an increased relative risk of developing breast cancer was found in women using 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 the 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 natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to the usual level within several (mostly five) years after stopping 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 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.

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 who continued to receive hormone replacement therapy, the risk of developing ovarian cancer was even somewhat increased (RR 1.43, 95% CI 1.31-1.56).

Other studies, including the WHI study, indicate 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 some instances, these tumors have led to life-threatening intra-abdominal bleeding. In the case of upper abdominal pain, enlarged liver, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered during differential diagnosis.

Cholelithiasis

Estrogens are known to increase the lithogenicity of bile. Some women are predisposed to developing gallstones during treatment with estrogens.

Dementia

The use of HRT drugs does not improve cognitive function. There is evidence of an increased risk of developing dementia in women starting combined or estrogen-only HRT after the age of 65.

Other Conditions

Treatment should be stopped immediately if migraine-like or frequent and unusually severe headaches occur 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 arterial hypertension has not been established. A small increase in blood pressure has been described in women taking HRT; clinically significant increases are rare. However, in individual cases where persistent, clinically significant arterial hypertension develops during HRT, discontinuation of HRT may be considered. In women with elevated blood pressure, some reduction in blood pressure may occur while taking Angeliq^®. In women with normal blood pressure, no significant changes in blood pressure occur.

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

In non-severe liver dysfunction, 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^® should be discontinued.

If cholestatic jaundice or cholestatic pruritus recurs, which occurred for the first time during pregnancy or previous treatment with sex hormones, Angeliq^® should be stopped immediately.

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

Some patients may develop undesirable manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial investigation 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 endometriosis recurs 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^®, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following conditions may occur or worsen during HRT, and women with these conditions should be under medical supervision during HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; 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 obtained from standard studies on repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity do not indicate a specific 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 Angeliq^®, 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 organs, and pelvic organs, including cytological examination of the cervical epithelium.

If prolactinoma is present, periodic determination of prolactin concentration is required.

Effect on Ability to Drive and Use Machines

Angeliq^® does not affect the ability to drive vehicles and use machinery.

Overdose

Acute toxicity studies have not revealed a risk of acute adverse effects following accidental ingestion of the drug in quantities 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 occur with overdose: nausea, vomiting, vaginal bleeding.

Treatment There is no specific antidote; treatment is symptomatic.

In case of overdose, a doctor should be consulted.

Drug Interactions

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

Effect of Other Drugs on Angeliq^®®

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 just 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 drugs 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 decrease 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 (e.g., 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), concomitant administration for 10 days with the strong CYP3A4 inhibitor ketoconazole increased the AUC (0-24 h) of drospirenone by 2.30-fold (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-fold (90% CI: 1.27, 1.52).

Interaction with Alcohol

Alcohol abuse during the use of HRT drugs may lead to an increase in the concentration of circulating estradiol.

Effect of Angeliq^® 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^® in women receiving antihypertensive therapy (e.g., ACE inhibitors, angiotensin II receptor antagonists, hydrochlorothiazide) may slightly increase the antihypertensive effect.

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

An increase in serum potassium concentration with the combined use of Angeliq^® and NSAIDs or antihypertensive drugs is unlikely. Concomitant 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.

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, adrenals, plasma protein concentrations (e.g., 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 during the use of Angeliq^®®_.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date.

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.