Instructions for Angelique film-coated tablets No. 28
Composition
active ingredients: estradiol, drospirenone;
1 tablet contains estradiol (as estradiol hemihydrate) 1.0 mg and drospirenone 2.0 mg;
Excipients: lactose monohydrate, corn starch, pregelatinized starch, povidone 25,000, magnesium stearate, hydroxypropylmethylcellulose, macrogol 6,000, talc, titanium dioxide (E 171), red iron oxide (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, moderately red tablets, coated, embossed with "DL" in a regular hexagon on one side.
Pharmacotherapeutic group
Hormones of the sex glands. Estrogen-gestagen combinations.
ATX code G03F A17.
Pharmacological properties
Pharmacodynamics.
Estradiol.
Angelique contains synthetic 17β-estradiol, which is chemically and biologically identical to estradiol produced in the human body. It compensates for the decrease in estrogen production in menopausal women and alleviates postmenopausal symptoms. Estrogens prevent bone loss after menopause or oophorectomy.
Drospirenone.
Drospirenone is a synthetic progestogen.
Since estrogens promote endometrial growth, estrogen monotherapy increases the risk of endometrial hyperplasia and cancer. The use of additional progestogen reduces, but does not completely eliminate, the estrogen-induced risk of endometrial hyperplasia in women with an intact uterus.
Drospirenone exhibits antagonistic activity against aldosterone. Therefore, an increase in sodium and water excretion and a decrease in potassium excretion may be observed.
In preclinical studies, drospirenone did not show estrogenic, glucocorticoid, or antiglucocorticoid activity.
Data obtained during clinical trials.
Reducing symptoms of estrogen deficiency and improving the bleeding profile.
A reduction in menopausal symptoms was achieved within the first few weeks of treatment. Amenorrhea was observed in 73% of women during 10–12 months of treatment. Menstrual-like bleeding and/or spotting occurred in 59% of women during the first three months of therapy and in 27% of women during 10–12 months of treatment.
Osteoporosis prevention.
Estrogen deficiency during menopause is associated with an increased rate of bone remodeling and a decrease in bone mass. The effect of estrogens on bone mineral density is dose-dependent. Effective protection is provided throughout the treatment period. After discontinuation of hormone replacement therapy (HRT), bone loss occurs at the same rate as in untreated women.
The results of the WHI trial and meta-analyses of other studies suggest that the use of HRT, either alone or in combination with a progestogen, in predominantly healthy women reduces the risk of hip, spine and other fractures associated with osteoporosis. HRT may also prevent fractures in women with low bone density and/or osteoporosis, but the evidence to support this is limited.
After 2 years of treatment with Angeliq, the increase in bone mineral density of the hip was 3.96 ± 3.15% (mean ± standard deviation) in patients with osteoporosis and 2.78 ± 1.89% (mean ± standard deviation) in those without osteoporosis. The number of women who maintained or increased bone mineral density of the hip during treatment was 94.4% among patients with osteoporosis and 96.4% among patients without osteoporosis.
The effect of the drug Angeliq on the mineral density of the lumbar spine was also established. The increase in density after 2 years of therapy was 5.61 ± 3.34% (mean ± standard deviation) in women with osteoporosis and 4.92 ± 3.02% (mean ± standard deviation) in women without osteoporosis. During treatment, preservation or increase in the mineral density of the lumbar spine was observed in 100% of women with osteoporosis and in 96.4% of women without osteoporosis.
Antimineralocorticoid activity.
Drospirenone has a competitive antagonistic effect on aldosterone, which may lead to a decrease in blood pressure in women with hypertension. In a double-blind, placebo-controlled study in postmenopausal women with hypertension who received Angeliq (n = 123) for 8 weeks, a significant decrease in systolic/diastolic blood pressure was observed (office cuff measurements compared to baseline: -12/-9 mmHg, including placebo effect: -3/-4 mmHg; 24-hour ambulatory blood pressure measurements compared to baseline: -5/-3 mmHg, including placebo effect: -3/-2 mmHg).
Angeliq is not used to treat hypertension. Women with hypertension should be treated according to hypertension treatment protocols.
Pharmacokinetics.
Absorption. After oral administration, drospirenone is rapidly and almost completely absorbed. The maximum concentration of the substance in the blood serum is reached approximately 1 hour after a single oral administration of the drug Angeliq and is 21.9 ng/ml. With repeated administration, the maximum equilibrium concentration of 35.9 ng/ml is observed approximately after 10 days. Bioavailability is 76-85% and does not depend on whether the drug is taken with food or on an empty stomach.
Distribution: After oral administration, the serum concentration of drospirenone decreases in two phases with a mean terminal half-life of approximately 35–39 hours. Drospirenone binds to serum albumin but not to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 3–5% of the total drospirenone concentration is present in serum as free steroid. The mean apparent volume of distribution of drospirenone is 3.7–4.2 l/kg.
Metabolism: After oral administration, drospirenone is extensively metabolized. The main metabolites in plasma are the acid form of drospirenone, which is obtained by opening the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, which is formed by reduction followed by sulfation. These two main metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalyzed by cytochrome P450 3A4.
Excretion. The plasma clearance of drospirenone is 1.2–1.5 ml/min/kg with individual deviations of this indicator at the level of about 25%. Only very small amounts of drospirenone are excreted unchanged. The metabolites of drospirenone are excreted with feces and urine in a ratio of approximately 1.2:1.4. The half-life of metabolites with urine and feces is approximately 40 hours.
Steady-state concentration and linearity. Steady-state concentration is reached after approximately 10 days of daily oral administration of Angeliq. As a result of the relationship between terminal half-life and dosing interval, the serum concentration of drospirenone increased approximately 2–3-fold. At steady state, the mean serum concentration of drospirenone varies in the range of 14 to 36 ng/ml after administration of Angeliq. The pharmacokinetic properties of drospirenone are dose-proportional over the 1–4 mg dose range.
Estradiol.
Absorption. After oral administration, estradiol is rapidly and completely absorbed. During absorption and first pass through the liver, estradiol is extensively metabolized, which reduces the absolute bioavailability of estrogen after oral administration to approximately 5% of the dose received. The maximum concentration, approximately 22 pg/ml, was reached approximately 6–8 hours after a single oral administration of the drug Angeliq. The bioavailability of estradiol is not affected by food intake compared to administration in the fasting state.
Distribution. After oral administration of Angeliq, only gradual changes in serum estradiol concentrations are observed during the 24-hour interval between doses of the drug. Due to the large volume of circulating estrogen sulfates and glucuronides on the one hand and enterohepatic recirculation on the other, the terminal half-life of estradiol is a composite parameter that depends on all of these processes and lasts approximately 13–20 hours after oral administration.
Estradiol binds nonspecifically to serum albumin and specifically to sex steroid binding globulin (SSGB). Only 1–2% of estradiol circulates as free steroid, 40–45% is bound to SSGB. The apparent volume of distribution of estradiol after a single intravenous dose is approximately 1 L/kg.
Metabolism. Estradiol is rapidly metabolized, with the formation of a large number of other metabolites and conjugates in addition to estrone and estrone sulfate. Estrone and estriol are known as pharmacologically active metabolites of estradiol. Only estrone has been detected in significant plasma concentrations. The serum concentration of estrone is approximately 6 times that of estradiol. The serum concentrations of estrone conjugates are approximately 26 times higher than the corresponding concentrations of free estrone.
Equilibrium concentration. After daily oral administration of the drug Angeliq, the equilibrium concentration of estradiol is reached after approximately five days. The concentration of estradiol in serum increases approximately 2-fold. When administered orally, estradiol induces the formation of GSH, which affects the distribution in the part of serum proteins, resulting in an increase in the GSH-bound fraction and a decrease in the albumin-bound and unbound fractions, which indicates the nonlinear nature of the pharmacokinetics of estradiol after taking the drug Angeliq. With a 24-hour dosing interval, the average equilibrium concentration of estradiol in serum varies within 20–43 pg/ml after taking the drug Angeliq. The pharmacokinetic properties of estradiol are directly proportional to the dose when using the drug in doses of 1 and 2 mg.
Special categories of patients.
Liver failure.
The pharmacokinetic properties of a single oral dose of 3 mg drospirenone in combination with 1 mg estradiol were evaluated in 10 patients with moderate hepatic impairment (Child-Pugh class B) and 10 healthy women matched for age, weight, and smoking history. The mean serum concentration/time profiles for drospirenone were similar in both groups of women during the absorption/distribution phases with similar Cmax and tmax values, suggesting that hepatic impairment does not affect the rate of absorption. In patients with moderate hepatic impairment, the mean terminal half-life was approximately 1.8 times longer and the apparent total oral clearance (CL/f) was approximately 50% lower than in healthy women without hepatic impairment.
Kidney failure.
The effect of renal insufficiency on the pharmacokinetics of drospirenone (3 mg daily for 14 days) was studied in patients with normal renal function and with mild to moderate renal insufficiency. When steady-state drospirenone therapy was achieved, similar serum drospirenone concentrations were observed in women with mild renal insufficiency (creatinine clearance 50–80 ml/min) and in women without renal impairment (creatinine clearance > 80 ml/min). In women with moderate renal insufficiency (creatinine clearance 30–50 ml/min), serum drospirenone concentrations were on average 37% higher than in women with normal renal function. Linear regression analysis of drospirenone AUC (0-24 hours) versus creatinine clearance revealed a 3.5% increase with a 10 mL/min decrease in creatinine clearance. The small increase is not clinically significant.
Preclinical safety data.
Animal studies with estradiol and drospirenone have shown the expected estrogenic and progestogenic effects. There are no preclinical data to supplement the information already provided in other sections of this leaflet for the medicinal product Angeliq.
Indication
Hormone replacement therapy (HRT) for symptoms of estrogen deficiency in postmenopausal women more than 1 year after menopause.
Prevention of osteoporosis in postmenopausal women who are at increased risk of bone fractures and who are intolerant to other drugs used to prevent osteoporosis or for whom such drugs are contraindicated (see section "Special warnings and precautions for use").
Experience with the drug in women over 65 years of age is limited.
Contraindication
Genital bleeding of unknown etiology.
Breast cancer, suspected breast cancer, or a history of the condition.
Estrogen-dependent malignant tumors or suspicion of them (for example, endometrial cancer).
Untreated endometrial hyperplasia.
Venous thromboembolism or history of the specified pathology (deep vein thrombosis, pulmonary embolism).
Arterial thromboembolism in the acute stage or recently suffered (e.g. angina pectoris, myocardial infarction, stroke).
High risk of venous or arterial thrombosis.
Acute liver disease or history of liver disease – until liver function tests return to normal.
Severe liver disease.
Current or history of liver tumors (benign or malignant).
Tendency to develop thrombosis (e.g. protein C deficiency, protein S or antithrombin deficiency, see section "Special warnings and precautions for use").
Renal impairment or acute renal failure.
Adrenal insufficiency.
Anaphylactic reactions, angioedema, hypersensitivity to the active substances or to any of the excipients of the drug are known.
Porphyria.
Severe hypertriglyceridemia.
Interaction with other medicinal products and other types of interactions
Note: The information for the concomitant medicinal product should be consulted for potential interactions.
The effect of other medicines on the drug Angeliq.
The metabolism of estrogens and progestogens may be enhanced by the concomitant use of enzyme inducers, especially cytochrome 450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz); felbamate, griseofulvin, oxcarbazepine, topiramate and medicinal products containing St. John's wort extract (Hypericum Perforatum).
Clinically, increased metabolism of estrogens and progestogens may lead to reduced efficacy and altered uterine bleeding profile.
Enzyme induction may be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.
Substances with variable effects on sex hormone clearance
When used concomitantly with HRT, most HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may cause increases or decreases in estrogen and progestin concentrations. These changes may be clinically significant in some cases.
Therefore, the prescribing information for the concomitant HIV/HCV drug should be consulted to identify potential interactions.
Substances that reduce the clearance of sex hormones (enzyme inhibitors)
Strong or moderate CYP3 A4 inhibitors, such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice, may increase plasma concentrations of estrogens and progestins. In a multiple-dose study of a combination of drospirenone (3 mg/day) and estradiol (1.5 g/day), co-administration of the strong CYP3 A4 inhibitor ketoconazole for 10 days resulted in a 2.30-fold increase in drospirenone AUC (0-24 h) (90% CI: 2.08, 2.54). No changes were observed in estradiol parameters, and the AUC (0–24 h) of its less potent metabolite estrone increased 1.39-fold (90% CI: 1.27; 1.52).
The effect of the drug Angeliq on other drugs
In vitro, drospirenone is capable of weakly or moderately inhibiting the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.
Based on the results of an in vivo interaction study conducted in healthy female volunteers receiving drospirenone at fixed doses of 3 mg per day using omeprazole, simvastatin or midazolam as marker substrates, clinically significant interactions of drospirenone with other medicinal products metabolised by cytochrome P450 are considered unlikely.
It is unlikely that the combined use of the drug Angeliq and NSAIDs (non-steroidal anti-inflammatory drugs) or angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists increases the concentration of potassium in the blood serum. However, the simultaneous use of these three types of drugs may cause a small increase in the concentration of potassium in the blood serum, which is more pronounced in women with diabetes. In women with arterial hypertension during therapy with the drug Angeliq, an additional decrease in blood pressure may be observed (see section "Special instructions").
Alcohol abuse during HRT can lead to increased levels of circulating estrogen in the blood.
Other types of interaction
In clinical trials in patients treated for hepatitis C with medicinal products containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using ethinylestradiol-containing medicinal products, such as combined hormonal contraceptives (CHCs).
The rate of ALT elevations in women taking estrogens other than ethinyl estradiol, such as estradiol, was similar to that in women not taking any estrogens. However, due to the limited number of women taking estrogens other than ethinyl estradiol, caution should be exercised when co-administering ombitasvir/paritaprevir/ritonavir with or without dasabuvir, and glecaprevir/pibrentasvir (see section 4.4).
Laboratory studies.
The use of sex hormones may affect the results of certain laboratory tests, including biochemical indicators of liver function, thyroid, adrenal, renal, protein (transporter) levels, such as sex hormone binding globulin, lipids/lipoprotein fractions, coagulation and fibrinolysis parameters. As a rule, changes remain within the normal range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone, which is due to its moderate antimineralocorticoid activity.
Application features
In the treatment of postmenopausal disorders, HRT should only be initiated if symptoms are life-threatening. In all cases, a careful benefit-risk assessment should be performed at least annually and HRT should only be continued if the benefits outweigh the risks.
Data on the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit/risk ratio may be more favourable in these women than in older women.
Medical examination/follow-up.
Before initiating or reinstituting HRT, a careful personal and family medical history should be taken, a physical examination (including pelvic and breast examination), taking into account the contraindications (see section 4.3) and precautions (see section 4.8), and such examinations should be repeated periodically. The frequency and nature of the examinations should be based on current medical practice and should be individualised for each patient. Women should be advised of any changes in their breasts that they should report to their doctor or nurse. Examinations, including appropriate imaging techniques such as mammography, should be carried out in accordance with current screening practices, adapted to the individual clinical needs of the woman.
Diseases requiring supervision.
If any of the following diseases are present at the moment, have occurred in the anamnesis and/or have been observed to worsen during pregnancy or previous hormonal therapy, the patient should be under close supervision. It should be borne in mind that such diseases may recur or their course may worsen during therapy with the drug Angeliq. In particular, this refers to:
leiomyoma (uterine fibroids) or endometriosis;
the presence of risk factors for the development of thromboembolic complications (see below);
the presence of risk factors for the development of estrogen-dependent tumors, for example, 1st degree hereditary predisposition to breast cancer;
arterial hypertension;
liver disease (e.g., hepatoadenoma);
diabetes mellitus with or without vascular lesions;
gallstone disease;
migraine or (severe) headache;
systemic lupus erythematosus (SLE);
history of endometrial hyperplasia (see below);
epilepsy;
asthma;
otosclerosis.
Reasons for immediate discontinuation of therapy
The use of HRT should be discontinued immediately if any of the contraindications are identified, as well as in the presence of the following conditions and diseases:
jaundice or impaired liver function;
significant increase in blood pressure;
first appearance of migraine-like headache;
pregnancy;
cholestatic pruritus that occurred for the first time either during pregnancy or after the use of sex steroids;
symptoms of thrombosis or suspicion of thrombosis.
Gallbladder disease.
Estrogens increase the lithogenicity of bile. Some women are prone to developing gallbladder disease during estrogen therapy.
Endometrial hyperplasia and carcinoma.
In women with an intact uterus, prolonged monotherapy with estrogens increases the risk of developing endometrial hyperplasia or carcinoma. The observed increased risk of endometrial cancer in patients taking estrogens as monotherapy, depending on the duration of treatment and estrogen dose, is 2-12 times higher than in women who did not receive estrogens (see section "Adverse reactions"). After stopping treatment, the increased risk may persist for at least 10 years.
Including progestogens in the treatment regimen cyclically for at least 12 days per month (28-day cycle) or continuous combined estrogen-progestogen therapy prevents the increased risks associated with the use of estrogen-only hormone replacement therapy in women with an intact uterus.
Menstrual-like bleeding and spotting may occur during the first months of treatment. If such phenomena occur some time after the start of treatment or continue after discontinuation of therapy, their causes should be identified, for which an endometrial biopsy may be performed to exclude malignant neoplasms of the endometrium.
Breast cancer.
There is evidence of an increased risk of breast cancer in women taking combined estrogen-progestogen therapy or, possibly, estrogen-only HRT; this risk depends on the duration of HRT.
Combined estrogen-progestogen therapy
Results from the randomised, placebo-controlled Women's Health Initiative study (WHI) and a meta-analysis of prospective epidemiological studies have shown an increased risk of breast cancer in women taking combined oestrogen-progestagen HRT. This risk appeared to occur after approximately 3 (1-4) years of treatment (see section 4.8).
The WHI trial did not find an increased risk of breast cancer with estrogen-only HRT in women who had undergone hysterectomy. Observational studies have in most cases shown a slightly increased risk of breast cancer being diagnosed with estrogen-only HRT, but the risk was lower than the risk in women using combined estrogen-progestagen therapy (see section 4.8).
A large meta-analysis has shown that the increased risk decreases with time after cessation of therapy and that the time it takes to return to age-related baseline levels depends on the duration of HRT use. If HRT has been used for more than 5 years, the risk may persist for 10 years or longer.
HRT, especially combined estrogen-progestogen therapy, increases image density during mammographic examinations, which may negatively affect the radiological diagnosis of breast cancer.
Venous thromboembolism
HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The risk of these events is higher during the first year of HRT than in subsequent years (see section 4.8).
Generally recognized risk factors for VTE include estrogen use, older age, major surgery, obesity or family history of the condition (BMI > 30 kg/m2), pregnancy/postpartum period, SLE, and cancer. There is currently no consensus on the role of varicose veins in the development of VTE.
Patients with a known predisposition to thrombosis are at increased risk of VTE and HRT may further increase this risk. Therefore, HRT is contraindicated in this group of patients (see section 4.3).
As in all postoperative patients, prophylactic measures should be taken to prevent VTE after surgery. If prolonged immobilization is required after elective surgery, it is recommended to temporarily stop HRT 4–6 weeks before surgery. Treatment should not be restarted until the woman has fully recovered from her physical activity.
Women with no personal history of VTE but a first-degree relative with a history of thrombotic episodes at a young age may be offered screening, but with careful discussion of the limitations of the data that will be obtained (only a subset of thrombophilic disorders may be detected by screening). If a specific variant of thrombotic predisposition is identified that is also observed in other family members, or if the disorder is severe (e.g., antithrombin, protein S, protein C deficiency, or multiple disorders), HRT is contraindicated.
In women already receiving continuous anticoagulant therapy, the benefit/risk ratio of HRT use should be carefully weighed.
If venous thromboembolism develops after initiation of therapy, the drug should be discontinued. Patients should be advised to seek medical attention immediately if potential symptoms of thromboembolism occur (e.g., painful swelling of a leg, sudden chest pain, shortness of breath).
Coronary heart disease (CHD).
Randomised controlled trials have shown no protective effect on myocardial infarction in women with or without coronary heart disease who use combined oestrogen-progestagen HRT or oestrogen-only HRT. The relative risk of coronary heart disease is slightly increased with combined oestrogen-progestagen HRT. Since the baseline absolute risk of coronary heart disease is largely age-dependent, the number of additional cases of coronary heart disease attributable to oestrogens and progestagens is very small in healthy women approaching menopause but will increase with age.
Ischemic stroke.
Combined oestrogen-progestagen therapy and oestrogen-only therapy are associated with an up to 1.5-fold increased risk of ischaemic stroke. The relative risk does not change with age or with time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women using HRT will increase with age (see section 4.8).
Ovarian cancer.
Ovarian cancer is much less common than breast cancer.
Epidemiological data from a large meta-analysis suggest a slightly increased risk of ovarian cancer in women using estrogen-only or combined estrogen-progestogen HRT, which becomes more pronounced within 5 years of use and decreases for some time after discontinuation.
The results of some studies, including the WHI study, indicate that the use of combined HRT may be associated with a similar or slightly lower risk (see section “Adverse reactions”).
Liver tumors.
In isolated cases, benign (rarely malignant) liver tumors have been observed after the use of hormonal drugs (e.g. for HRT). Sometimes these tumors led to the development of life-threatening intra-abdominal bleeding.
In clinical trials in patients treated for hepatitis C with the medicinal product containing ombitasvir/paritaprevir/ritonavir with or without the addition of dasabuvir, ALT elevations greater than 5 times the ULN were observed significantly more frequently in women using ethinylestradiol-containing medicinal products such as COCs. In addition, ALT elevations were observed in women using ethinylestradiol-containing medicinal products during treatment with glecaprevir/pibrentasvir.
The rate of ALT elevations in women taking estrogens other than ethinyl estradiol, such as estradiol, was similar to that in women not taking any estrogens. However, due to the limited number of women taking estrogens other than ethinyl estradiol, caution should be exercised when co-administering ombitasvir/paritaprevir/ritonavir with or without dasabuvir, and glecaprevir/pibrentasvir (see section 4.5).
Other states.
Estrogens can cause fluid retention, so patients with impaired cardiac or renal function require close monitoring.
Women with moderately elevated triglyceride levels require special monitoring. In such cases, the use of HRT may cause a further increase in triglyceride levels, which carries a risk of developing pancreatitis.
Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.
Estrogens increase thyroxine-binding globulin (TBG), which leads to an increase in total circulating thyroid hormone levels. This is measured by protein-bound iodine, T4 (measured by column assay or radioimmunoassay), or T3 (measured by radioimmunoassay). T3 uptake is reduced, indicating increased TGB. Free T3 and T4 concentrations are not affected. Other serum binding proteins, corticosteroid-binding globulin and sex hormone-binding globulin, may be increased, leading to increased circulating corticosteroid and sex hormone concentrations, respectively. Free or biologically active hormone concentrations are not affected. Concentrations of other plasma proteins (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin) may increase.
HRT does not improve cognitive function. There is limited evidence that long-term use of combined HRT or estrogen monotherapy increases the risk of dementia when treatment is initiated in women over 65 years of age.
The progesterone component of Angeliq is an aldosterone antagonist with a slight potassium-sparing effect. In most cases, an increase in serum potassium is unlikely. However, in a clinical study in some patients with mild to moderate renal insufficiency, concomitant use of potassium-sparing drugs (e.g. ACE inhibitors, angiotensin II receptor antagonists or NSAIDs) resulted in a slight increase in serum potassium while taking drospirenone. Therefore, during the first month of treatment, and especially during concomitant therapy with potassium-sparing drugs, it is recommended to check serum potassium concentrations in patients with renal insufficiency whose serum potassium levels were at the upper limit of normal before starting treatment (see section "Interaction with other medicinal products and other forms of interaction").
In women with high blood pressure, a decrease in blood pressure may be observed during treatment with Angeliq, due to the antagonistic activity of drospirenone against aldosterone (see section "Pharmacodynamics"). Angeliq is not used to treat arterial hypertension. Women suffering from arterial hypertension should be treated according to the appropriate therapy protocol.
In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. When taking HRT, women prone to chloasma should avoid exposure to the sun or ultraviolet radiation.
Each Angeliq tablet contains 46 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Mild hepatic dysfunction, including hyperbilirubinemia (e.g., Dubin-Johnson, Rotor syndrome), requires close monitoring; periodic monitoring of liver function tests is also necessary.
