Instructions for use ANGELIQ® (ANGELIQ)
Angelique should be prescribed with caution in case of arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itching during previous pregnancy, endometriosis, uterine fibroids, diabetes mellitus.
If any of these conditions are present or worsening, before starting or continuing HRT, the ratio of individual risk to benefit of treatment should be assessed.
Before starting or resuming HRT, a woman is recommended to undergo a thorough general and gynecological examination (including examination of the mammary glands and cytological examination of cervical mucus) and exclude pregnancy. In addition, disorders of the blood coagulation system should be excluded. Control examinations should be carried out periodically.
A number of controlled randomized and epidemiological studies have revealed an increased relative risk of developing venous thromboembolism
(VTE) against the background of HRT. When prescribing HRT to women with risk factors for VTE (deep vein thrombosis or pulmonary embolism), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient. Risk factors for developing VTE include a history of VTE (including familial 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. The risk of VTE may temporarily increase with prolonged immobilization, extensive surgery, or trauma. Depending on the cause or duration of immobilization, the question of the advisability of temporarily stopping HRT should be decided.
Treatment should be stopped immediately if symptoms of thrombosis appear or are suspected.
Randomized controlled trials of long-term use of combined conjugated estrogens and medroxyprogesterone acetate did not provide evidence of a beneficial effect on the cardiovascular system. An increased risk of stroke was also found. To date, no long-term randomized controlled trials have been conducted with other HRT drugs to identify beneficial effects on cardiovascular morbidity and mortality. It is therefore unknown whether this increased risk applies to HRT products containing other types of estrogens and progestogens.
Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma.
. Studies have confirmed that the addition of gestagens reduces the risk of endometrial hyperplasia and cancer.
breast cancer has been found in clinical trials and observational studies.
in women using HRT for several years. This may be due to earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with the duration of treatment (by 2.3% per year of use). This is comparable to the increase in the risk of breast cancer in women with each year of delay in the onset of natural menopause (by 2.8% per year of delay). The increased risk gradually decreases to normal levels during the first 5 years after stopping HRT. Breast cancer found in women taking HRT is usually more localized than in women not taking it.
HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.
During the use of sex steroids, which also include drugs for HRT, benign and even more rarely malignant liver tumors
, which in some cases led to life-threatening intra-abdominal bleeding. If there is pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding, the differential diagnosis should take into account the possibility of a liver tumor.
It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to developing gallstones when treated with estrogen.
You should immediately stop using the drug if you experience migraine-like or frequent and unusually severe headaches for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain.
The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT (a clinically significant increase is rare). In some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered.
With renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect serum potassium concentrations in patients with mild to moderate renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in those patients whose serum potassium concentration before treatment was determined at the upper limit of normal and who are additionally taking potassium-sparing drugs.
For mild liver dysfunction, including various forms of hyperbilirubinemia (including Dubin-Johnson syndrome or Rotor syndrome), medical supervision is necessary, as well as periodic liver function tests. If liver function tests worsen, HRT should be discontinued.
If cholestatic jaundice or cholestatic pruritus recurs, which was observed for the first time during pregnancy or during previous treatment with sex steroid hormones, HRT should be stopped immediately.
Special monitoring is required for women with moderately elevated triglyceride levels. In such cases, the use of HRT may cause a further increase in blood triglyceride levels, which increases the risk of acute pancreatitis.
Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to adjust the dosage regimen in patients with diabetes mellitus. Nevertheless, this category of patients should be monitored during HRT.
Some patients under the influence of HRT may develop undesirable manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for endometrial examination.
If treatment for irregular menstrual cycles does not produce results, an examination should be performed to exclude an organic disease.
Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped.
It is recommended to discontinue treatment if endometriosis relapses during HRT.
If prolactinoma is suspected, this disease should be excluded before starting treatment.
In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During HRT, women with a tendency to develop chloasma should avoid prolonged exposure to the sun or UV radiation.
Epilepsy, benign tumor of the mammary gland, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, minor chorea may first appear or worsen during HRT. Although a direct relationship with HRT has not been proven, patients with these diseases (or with a predisposition to them) should be under medical supervision when undergoing HRT.
Taking sex steroids can affect biochemical indicators of liver, thyroid, adrenal and kidney function, plasma levels of transport proteins such as SHBG, lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Angelique does not have a negative effect on glucose tolerance.
Excessive alcohol consumption during HRT may increase circulating estradiol levels.
Pharmacological properties of the drug Angeliq
The drug Angelique contains 17β-estradiol, which is identical in its chemical and biological properties to estradiol produced in the human body, and a synthetic progestogen, drospirenone. 17β-Estradiol provides hormone replacement therapy during and after the menopausal period. The additional inclusion of drospirenone helps regulate bleeding and prevents the development of endometrial hyperplasia caused by estrogen. Effect of estradiol. Inhibition of ovarian function, accompanied by a decrease in the production of estrogens and progestogens in the body, predetermines menopausal syndrome, characterized by vasomotor and organic symptoms. To eliminate these disorders, hormone replacement therapy (HRT) is prescribed. Estradiol is the most effective of all physiological estrogens and has the greatest affinity for estrogen receptors. The target organs affected by estrogen include the uterus, hypothalamus, pituitary gland, vagina, mammary glands, bones (namely osteoclast cells). Other effects of estrogen include decreased blood insulin and glucose concentrations, local receptor-mediated vasoactive effects, and receptor-independent effects on vascular muscle. Estrogen receptors have been identified in the heart and coronary arteries. Oral administration of natural estrogens has a beneficial effect in some cases of hypercholesterolemia, maximizing the metabolic effect of the liver on lipids. After one year of treatment with Angeliq, the mean changes in HDL cholesterol concentrations were insignificant. With simultaneous use of 1 mg of drospirenone, a slight increase in these indicators by 1.1% was determined; when using 2 and 3 mg of drospirenone, this figure decreased by 1.6 and 3.4%, respectively. Serum LDL-C concentrations decreased by an average of 11 (1 mg drospirenone), 14 (2 mg drospirenone), and 13% (3 mg drospirenone) compared with a 9% decrease after one year of 1 mg estradiol monotherapy. It is likely that combination drugs with drospirenone attenuate the increase in TG concentrations caused by monotherapy with 1 mg estradiol. After one year of treatment with 1 mg estradiol, TG concentrations in patients averaged approximately 18% higher than baseline, compared with an average increase of 9 (1 mg drospirenone), 5 (2 mg drospirenone), and 4% with the combination of 1 mg estradiol and drospirenone. . Therapy with Angeliq for 2 years leads to an increase in bone mineral density throughout the body, in the lumbar spine and pelvic bones by approximately 3-5%. Long-term HRT reduces the risk of peripheral bone fractures in postmenopausal women. HRT also has a positive effect on the collagen content of the skin, skin density and can delay the formation of wrinkles. Estrogen monotherapy, depending on the dose, stimulates mitotic activity and proliferation of the endometrium, which leads to an increase in the number of cases of endometrial hyperplasia and an increased risk of developing endometrial carcinoma. To prevent endometrial hyperplasia, it is necessary to combine estrogen with any progestogen. Effect of drospirenone. The pharmacodynamic properties of drospirenone are similar to those of natural progesterone. Progestogenic effect Drospirenone is a strong progestogen that has a central inhibitory effect on the hypothalamic-pituitary-gonad system. In women of childbearing age, drospirenone provides a contraceptive effect; monotherapy with drospirenone inhibits the ovulation process. The minimum dose of drospirenone required to inhibit ovulation is 2 mg/day. Complete transformation of the endometrium under the influence of estrogen is achieved at doses of 4–6 mg/day for 10 days (40–60 mg per cycle). Angelique is a combination drug for continuous HRT, which allows you to avoid regular withdrawal bleeding observed with cyclic or phase HRT. Bleeding and spotting are quite common in the first months of treatment, but over time their number decreases. While taking Angelique (2 mg drospirenone), the incidence of amenorrhea quickly increased to 81% in the 6th cycle, then to 86% in the 12th cycle and to 91% in the 24th cycle. After 12 months of treatment with Angeliq, 72–82% of women reported endometrial atrophy. The combination of components of the drug Angeliq effectively prevents the development of endometrial hyperplasia caused by estrogen. In clinical studies, no endometrial hyperplasia was detected in women receiving different doses of the active substance of the drug. Antimineralocorticoid activity Drospirenone has a competing antagonistic effect with aldosterone. The antihypertensive effect is most pronounced in women with hypertension with increasing doses of drospirenone. After 12 weeks of therapy with 1 mg estradiol/3 mg drospirenone, mean blood pressure decreased (systolic/diastolic by 14-8 mm Hg, compared with placebo - 6-3 mm Hg). No corresponding changes in blood pressure are expected in women with normal blood pressure. When using the drug Angeliq, the average body weight decreased during 12 months of treatment by 1.1–1.2 kg (2 mg of drospirenone daily), while in patients receiving estradiol monotherapy, an increase in body weight of 0.5 kg was noted. During a clinical study, women receiving drospirenone in combination with estradiol had a lower incidence of peripheral edema compared to patients receiving estradiol monotherapy. Antiandrogenic activity Like natural progesterones, drospirenone has antiandrogenic properties. Effect on carbohydrate metabolism Drospirenone does not have glucocorticoid or antiglucocorticoid activity and does not affect glucose tolerance and insulin resistance. When using Angelique, glucose tolerance does not change. Other properties Angelique has a positive effect on health and quality of life. According to the survey, the beneficial effects of the drug Angeliq significantly exceeded the effect compared with estradiol monotherapy. This high rate is mainly due to an improvement in somatic symptoms, a decrease in the severity of anxiety/fear, and cognitive impairment. According to numerous studies, the use of a combination of conjugated equine estrogens with medroxyprogesterone acetate suggests that the incidence of colon cancer in women receiving HRT is reduced. With monotherapy with conjugated equine estrogens, no reduction in the risk of developing this pathology was observed. Drospirenone Following oral administration, drospirenone is rapidly and almost completely absorbed. As indicated in the table below, maximum serum concentrations are achieved approximately 1 hour after single and multiple oral administration of Angeliq. The pharmacokinetic characteristics of drospirenone depend on the dose received, ranging from 1 to 4 mg. Bioavailability is 76–85% and is independent of food intake.
Pharmacokinetic parameter | Angelique 1 mg (drospirenone) | Angelique 2 mg* (drospirenone) | Angelique 3 mg* (drospirenone) |
| Maximum concentration, single dose (ng/ml) | 11,6 | 21,9 | 32,2 |
| Maximum concentration, equilibrium concentration, (ng/ml) | 17,6 | 35,9 | 54,1 |
| Area under the curve (AUC, 0–24 h), single dose, (ng/ml) | 82,1 | 161 | 240 |
| Area under the curve (AUC, 0–24 h), equilibrium concentration, (ng/ml) | 194 | 408 | 623 |
*Data for Angelique 2 mg and Angelique 3 mg were calculated by interpolating the studied doses of 1 mg drospirenone + 1 mg estradiol and 4 mg drospirenone + 1 mg estradiol.
After oral administration, the serum concentration of drospirenone decreases over two phases with a mean terminal half-life of approximately 35–39 hours. Drospirenone binds to serum albumin, but does not bind to sex steroid binding globulin (SHBG) and corticoid binding globulin (GSK, CBG). Only 3–5% of the total concentration of drospirenone is present in the blood serum as a free steroid. The average apparent volume of distribution of drospirenone is 3.7–4.2 L/kg. After oral administration, drospirenone is significantly metabolized. The main metabolites in plasma are the acid form of drospirenone, obtained due to the opening of the lactone ring, as well as 4,5 dihydro-drospirenone - 3-sulfate. Both metabolites are formed without the participation of the P450-dependent system. in vitro studies , drospirenone is slightly metabolized by cytochrome P450 3A4. The total clearance of drospirenone from serum is 1.2–1.5 ml/min/kg. Only very small amounts of drospirenone are excreted unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of about 1.2:1.4. The half-life of metabolites in urine and feces is up to 40 hours. The table above shows the maximum equilibrium concentrations (AUC) of drospirenone in the blood serum achieved during treatment. AUC is achieved after approximately 10 days of daily use of Angeliq. Estradiol After oral administration, estradiol is rapidly and completely absorbed. During absorption and first passage through the liver, estradiol is significantly metabolized, which reduces the absolute bioavailability of estrogen after oral administration to approximately 5% of the received dose. The maximum concentration, about 22 pg/ml, was achieved 6–8 hours after a single oral dose of Angeliq. The bioavailability of estradiol is not affected by food intake. When taking Angeliq orally during the 24-hour interval between doses of the drug, only a gradual change in the concentration of estradiol in the serum is noted. 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 lasts about 13–20 hours after oral administration. Estradiol binds nonspecifically to serum albumin and specifically to sex steroid binding globulin (SHBG). Only 1–2% of estradiol circulates as a free steroid, 40–45% is associated with SHBG. Orally administered estradiol induces the formation of SHBG, which affects the distribution of serum proteins. As a result, the part of estradiol bound to SHBG increases, and the part bound to albumin and free decreases, indicating the non-linear nature of the pharmacokinetics of estradiol after oral administration of the drug Angeliq. The apparent volume of distribution of estradiol after a single intravenous injection is about 1 l/kg. Estradiol is rapidly metabolized, and in addition to estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are known as pharmacologically active metabolites of estradiol. Only estrone was detected in significant concentrations in blood plasma. The serum estrone content is approximately 6 times higher than the estradiol concentration. Serum concentrations of estrone conjugates are approximately 26 times higher than the corresponding concentrations of free estrone. Metabolic clearance is about 30 ml/min/kg. Estradiol metabolites are excreted in urine and bile with a half-life of approximately 1 day. After daily oral administration of the drug Angeliq, the equilibrium concentration of estradiol is achieved after 5 days. The concentration of estradiol in serum accumulates approximately 2 times. At a 24-hour dosing interval, serum AUC of estradiol ranges from 20–43 mg/ml after taking Angeliq.
Indications for use of the drug Angeliq
HRT for the treatment of menopausal syndrome in postmenopausal women, including vasomotor symptoms (hot flashes and bouts of sweating), sleep disturbances, depressive mood changes, nervousness and atrophic changes in the urogenital tract caused by insufficient production of endogenous estrogen due to natural menopause, hypogonadism, sterilization or primary ovarian dysfunction in women with a non-removed uterus. Prevention of postmenopausal osteoporosis.
Contraindications to the use of the drug Angeliq
HRT should not be used for any of the following conditions. If any of these conditions occur during HRT, the drug should be stopped immediately. Vaginal bleeding of unknown etiology. Diagnosed or suspected breast cancer. Diagnosed precancerous conditions or malignant tumors dependent on sex steroids, or suspicion of their presence. Current or history of liver tumors (benign or malignant). Severe liver diseases. Current or past history of severe kidney disease until normalization of renal function tests. Arterial thromboembolism in the acute stage (for example, myocardial infarction, stroke). Exacerbation of deep vein thrombosis, current thromboembolic disorders or information about these diseases in the anamnesis. Severe form of hypertriglyceridemia. During pregnancy and breastfeeding. Hypersensitivity to the active substances or to any of the auxiliary components of the drug.
Side effects of the drug Angeliq
Below is the frequency distribution of various side effects when taking Angeliq. These rates are based on the incidence of adverse reactions recorded during four phase III clinical trials (1532 at-risk women). It is considered that an association between these reactions and the use of Angeliq (drospirenone content: 1.2 or 3 mg) is at least probable. At the beginning of therapy (the first few months), spotting may be noted. These phenomena are usually temporary and their frequency decreases as treatment continues. One of the common symptoms (noted in approximately every fifth woman) is pain in the mammary gland. Frequency: common (≥1/100, ≤1/10) From the body as a whole: abdominal pain or bloating, asthenia, pain in the extremities. From the digestive system : nausea. From the nervous system: headache, mood swings, hot flashes, nervousness. From the skin and subcutaneous tissues: benign neoplasms in the mammary glands, enlargement of the mammary glands. From the urogenital system : increase in uterine fibroids, cervical neoplasms, leukorrhea. Frequency: uncommon (≥1/1000, ≤1/100). From the body as a whole: pain in the back or pelvic area, chills, malaise, changes in laboratory parameters. From the cardiovascular system: migraine, hypertension, chest pain, palpitations, varicose veins, vein thrombosis, superficial thrombophlebitis, vasodilation. From the digestive system: gastrointestinal disorders, increased appetite, increased functional activity of the liver. Metabolism: generalized or local edema, weight gain, hyperlipidemia. From the musculoskeletal system: muscle cramps, arthralgia. From the nervous system: insomnia, dizziness, decreased libido, decreased ability to concentrate, paresthesia, increased sweating, anxiety, dry mouth, vertigo. From the respiratory system: shortness of breath. Skin and subcutaneous tissue disorders: alopecia, skin or hair diseases, hirsutism, breast carcinoma, breast engorgement. From the sensory organs: taste disturbance. From the urogenital system: vulvovaginitis, diseases of the endometrium and cervix, bleeding, dysmenorrhea, ovarian cyst, urinary tract infections or urinary incontinence. Extremely rarely, erythema nodosum, exudative erythema multiforme, chloasma and hemorrhagic dermatitis were detected in women receiving HRT.
