ANJYeLIK
Active material: Drospirenone, Estradiol
When ATH: G03FA17
CCF: Protivoklimakterichesky drug
ICD-10 codes (testimony): M81.0, M81.1, N95.1, N95.3
When CSF: 15.11.04.01
Manufacturer: BAYER SCHERING PHARMA AG (Germany)
Pharmaceutical form, composition and packaging
Pills, coated moderate Red (dark pink) colors, round, lenticular, Embossed “DL” in the right tones on one side.
| 1 tab. | |
| Estradiol (in the form of hemihydrate) | 1 mg |
| Drospirenone | 2 mg |
Excipients: corn starch, modified corn starch (Starch 1500), lactose monohydrate, magnesium stearate, polyvidone (povidone) 25 000.
The composition of the shell: gipromelloza (hydroxypropyl), iron oxide red (E172), polyethylene glycol 6000, talc, Titanium dioxide (E171), Purified water.
28 PC. – blisters (1) – packs cardboard.
Pharmacological action
Combined product for continuous hormone replacement therapy (AFE), to avoid regular bleeding cancellation.
Contains estrogen – 17b-эстрадиол, identical to the endogenous, and drospirenone, with gestagennym, antigonadotropnym and antiandrogennym, as well as antimineralokortikoidnym action.
Estradiol fills deficit of estrogen in the female body after menopause and provides effective treatment of psycho-emotional and vegetative climacteric symptoms (such as hot flashes, increased perspiration, sleep disorders, increased nervous irritability, irritability, palpitations, kardialgija, dizziness, headache, decreased libido, muscle and joint pain); reduces the involution of skin and mucous membranes, especially genito-urinary system (ie. has a positive effect on incontinence, dryness and irritation of mucous membrane vagina, pain during intercourse).
Estradiol prevents bone loss, caused by estrogen deficiency, what, mainly, due to the Suppression function of osteoclasts and bone remodeling process shift toward bone formation. It has been proved, that long term use of HRT reduces the risk of fractures of the peripheral bones in women after menopause. If you cancel HRT rate of decline of bone mass comparable to the, characteristic of the period immediately after the menopause. Not shown, that HRT can restore bone mass to the level of pre-.
HRT also has a beneficial effect on the collagen content in the skin, as well as its density, and may also slow down the formation of wrinkles.
Drospirenone, Thanks to antiandrogennym properties, provides therapeutic effect on androgenozawisimae diseases, such as acne, seborrhea, Androgenetic alopecia.
Drospirenone has antimineralokortikoidnoj activity, increases the excretion of sodium and water, that could prevent the ad, weight gain, the appearance of edema, Breast pain and other symptoms, associated with water retention. After 12 weeks of preparation Angélique® noted a slight decrease in HELL (systolic on average 2-4 mmHg., diastolic-on 1-3 mmHg.). In other works garden has decreased 9 mm Hg. Article. and Dad on 5.7 mm Hg. Article. In women with normotenziej HELL nobody changed. Their influence on HELL was more pronounced in women with arterial hypertension. Through 12 months of application of Angélique® average body weight remained constant or declined 1.1-1.2 kg.
Drospirenone is deprived of any androgen, estrogenic, and glukokortikoidna activity antiglûkokortikoidnoj, does not affect glucose tolerance and insulin resistance, that, combined with antimineralokortikoidnym and antiandrogennym effect provides drospirenonu biochemical and pharmacological profile, similar to natural progesterone.
Welcome Angelique® leads to lower levels of total cholesterol (Hs) and HS-LDL, as well as a slight increase triglyceride levels.
The inclusion of the drug drospirenona prevents the development of hyperplasia and endometrial cancer.
Observational studies suggest, among postmenopausal women with use of HRT reduced the incidence of colon cancer. The mechanism of action is unclear to date.
Angélique® has a positive impact on the well-being and quality of life, mainly in terms of reduction of somatic symptoms, a sense of anxiety/fear, improve ability to cognition (cognitive function).
Pharmacokinetics
Estradiol
Absorption
After taking the drug inside estradiol rapidly and completely absorbed from the digestive tract. Treated effect “first pass” with the formation of estrone, estriol and estrone sulphate. Oral bioavailability is about 5% and independent of food intake. Cmax estradiol in serum is approximately 22 PG/ml achieved through 6-8 no.
Distribution
Binds to albumin and globulin, binding sex steroids (GTN). The free fraction of estradiol in serum is approximately 1-12%, and the associated GSPS 40-45%. Vd After a single on/in the introduction is about 1 l / kg.
After repeated use estradiol concentration approximately 2 times higher, than after a single dose, wherein Css It varies between 20 PG/ml to 43 pg / ml. After discontinuation of estrone and estradiol levels return to baseline values within approximately 5 d.
Metabolism
Estradiol predominantly metabolized in the liver, partially – in the gut, kidney, skeletal muscle and in organah-misheniah with formation of estrone, estriol, kateholèstrogenov, as well as sulphate and glucuronid conjugates of these compounds, which have significantly less estrogenic activity when compared with estradiol or generally inactive.
Deduction
Clearance of estradiol of the serum – about 30 ml / min / kg. Estradiol metabolites are excreted in the urine and jelchew. T1/2 approximately 24 no.
Drospirenone
Absorption
After intake of drospirenone rapidly and completely absorbed from the digestive tract. Bioavailability is 76-85% and independent of food intake.
Distribution
After receiving a single or multiple dose 2 mg Cmax in serum obtained through 1 and h is about 22 ng / ml. After the two-phase drospirenona decreased concentration in serum with an end T1/2 about 35-39 no. Drospirenone contact albuminom and not associated with GSPS and kortikoid-binding globulin (KSG); about 3-5% – free fraction.
Css achieved through 10 days daily dose Angélique® and higher than the concentration after a single admission 2-3 times.
Metabolism
The main metabolites are acidic form drospirenona and 4.5-dihydro-drospirenone-3-sulfate, which are formed without the participation of a system isoenzymes of cytochrome P450.
Deduction
Drospirenona clearance from serum is 1.2-1.5 ml / min / kg. Report mostly in the form of metabolites in urine and feces in the ratio 1.2:1.4; T1/2 about 40 no.
Testimony
is hormone replacement therapy in women with intaktna uterus with climacteric disorders in postmenopauzne period, including vasomotor symptoms (such as hot flashes, increased perspiration), sleep disorders, depression, irritability, Involutional changes skin and urinary tract;
— postmenopauznogo prevention of osteoporosis.
Dosage regimen
If a woman does not take estrogen or goes to Angélique® with another drug combination for continuous reception, then she can start treatment at any time. Patients, moving on Angélique® with combined drug for cyclic HRT, should start after the end of withdrawal bleeding.
The drug should be taken daily 1 tab. After the end of the reception 28 current packaging of tablets the next day start new packaging Angélique®, taking the first pill on the same day of the week, as the first pill from a previous package.
Swallow whole tablets, drinking a small amount of liquid.
Times of Day, when a woman takes the drug, irrelevant, However, when she started taking the tablets at a specific time, it must adhere to this time and more.
In case of skipping the admission missed tablet should be taken as soon as possible. If, however, after the usual time of taking more than 24 no, more tablet should not be. When skipping a few tablets may develop vaginal bleeding.
Side effect
On the part of the reproductive system: sometimes – Advanced uterine bleeding and mazhushchie krovanistye allocation (usually stop during therapy), the changing nature of vaginal discharge, increasing the size of the fibroids, state, like premenstrual syndrome; soreness, voltage and / or breast enlargement, benign mammary glands; rarely – changes in libido.
From the digestive system: perhaps – dyspepsia, flatulence, nausea, vomiting, abdominal pain, recurrence of cholestatic jaundice.
CNS: perhaps – headache, migraine, dizziness, mood lability, anxiety, increased nervous irritability, fatigue, insomnia; rarely – visual impairment.
Cardio-vascular system: rarely – cardiopalmus, swelling, increased blood pressure, phlebeurysm, superficial thrombophlebitis, venoznыy thrombosis and tromboэmbolyya.
Dermatological reactions: perhaps – skin rash, itching, chloasma, uzlovataya эritema, erythema multiforme.
Other: rarely – muscle cramps, weight change, intolerance to contact lenses, allergic reactions.
Contraindications
is vaginal bleeding unclear etiology;
— confirmed or alleged breast cancer;
— confirmed or suspected a premalignant disease or gormonozavisimoe hormone-dependent malignant tumor;
— benign or malignant liver tumors (incl. history);
- Severe liver disease;
— severe kidney disease before normalization of laboratory parameters (incl. history);
— acute arterial thrombosis or pulmonary (including myocardial infarction, stroke);
-deep vein thrombosis in acute phase;
- Thromboembolism (incl. history);
— expressed hypertriglyceridemia;
- Pregnancy;
- Lactation;
- Hypersensitivity to the drug.
When developing against the background of any of the above conditions of HRT should immediately discontinue use of the drug.
Pregnancy and lactation
The drug is contraindicated in pregnancy and lactation.
Large-scale epidemiological studies the use of steroid hormones for contraception or HRT showed no increase in the risk of birth defects in children, born to women, those who took hormones before pregnancy, and teratogenic effects of hormones in their casual reception in the early stages of pregnancy.
The drug should not be used for contraception. If necessary, you should use non-hormonal methods of contraception (except for calendar and temperature methods). When pregnancy is suspected, the drug should be suspended until the, Pregnancy is not to be ruled out.
Small amounts of sex hormones may be released from the mother's milk.
Cautions
The caution should appoint Angelique® with hypertension, congenital hyperbilirubinemia (Gilbert syndrome, Dubin-Johnson and Rotor), holetsaticescoy jaundice or holestatičeskom irritation with previous pregnancy, endometriosis, uterine myoma, diabetes.
In the presence of or diminished flow of any of the States, before you begin or continue HRT, You should weigh the individual risks and benefits of treatment.
Before starting or resuming HRT woman recommended to undergo a thorough General and gynaecological examination (including the study of mammary glands and cytological examination of cervical mucus), exclude pregnancy. Besides, to exclude violations of blood coagulation. Periodically carry out test survey.
In a number of randomized and controlled epidemiological studies revealed an increased relative risk of Venous thromboembolism (VTЭ) HRT. When prescribing HRT for women with risk factors for VTE (deep vein thrombosis or pulmonary embolism) You should carefully consider and discuss with the patient the correlation of risks and benefits of treatment. Risk factors for VTE include a VTE in history (incl. family of VTE among close relatives in a relatively young age may indicate genetic predisposition) and severe obesity. The risk of VTE also increases with age. The question of the possible role of varicose veins in VTE remains controversial. The risk of VTE may temporarily rise in prolonged immobilization, extensive surgery, injuries. Depending on the cause or duration of immobilization should decide whether a temporary cessation of HRT.
Should immediately discontinue treatment if symptoms of thrombosis or in case of their occurrence.
During the randomized controlled trials of long-term use of combined conjugated estrogen and medroxyprogesterone acetate has not received evidence of positive effects on the cardiovascular system. There was also found an increased risk of stroke. So far, with other drugs for long-term hormone replacement therapy was conducted randomized controlled trials to identify a positive effect on morbidity and mortality, relating to the cardiovascular system. Therefore, it is not known, Does this increased risk of drugs for HRT, containing other types of estrogens and progestogens.
During long monotherapies estrogenami increases the risk of hyperplasia or endometrial Carcinoma. Studies have confirmed, that the addition of progestogen reduces the risk of endometrial hyperplasia and cancer.
According to clinical trials and results of observational studies was found increased risk of Breast Cancer female, using HRT for several years. This may be due to earlier diagnosis, biological effects of HRT, or a combination of both factors. Relative risk increases with duration of treatment (on 2.3% for the year use). This compares with an increase in the risk of breast cancer in women with every year of delay the onset of natural menopause (on 2.8% for the year delay). Increased risk of gradually drops to normal levels during the first 5 years after stopping HRT. Mammary cancer, identified women, taking HRT, is usually more localized, than in women, its not taking.
HRT increases breast density breast, In some cases, it may adversely affect the radiological detection of breast cancer.
Against the background of sex steroids, which include means for HRT, in rare cases, the observed benign and malignant liver tumors even less, that in some cases led to life-threatening vnutribrûšnomu representing the bleeding. When the pain in the upper abdomen, increase of liver or signs of intra-abdominal bleeding with differential diagnosis should take into account the probability of liver tumors.
Known, Estrogens increase bile lithogenicity. Some women are predisposed to the development of gallstone disease during treatment with estrogen.
Immediately discontinue use of the drug when first encountered migrenepodobnykh or frequent and extraordinarily strong headaches, as well as other symptoms - possible precursors of thrombotic stroke brain.
The relationship between HRT and the development of clinically expressed hypertension not installed. Women, taking HRT, Describes a small ad (clinically significant increase is rare). In some cases, when the development against the backdrop of the admission of HRT clinically relevant resistant hypertension may be considered canceling HRT.
Renal failure may decrease the ability to the development of potassium. Accepting drospirenona does not affect the concentration of potassium in serum in patients with renal insufficiency, mild. Risk of giperkaliemii theoretically cannot be excluded only from those patients, whose serum potassium concentration prior to treatment consistent with VGN and which additionally take kalisberegate preparations.
For non-severe hepatic dysfunction, in t. no. various forms of hyperbilirubinemia (Dubin-Johnson Syndrome or rotor syndrome) necessary medical supervision, as well as periodic liver function tests. If deterioration in liver function HRT should be abolished.
At relapse cholestatic jaundice or cholestatic pruritus, seen for the first time during pregnancy or if the previous treatment of sex steroid hormones, you must immediately stop HRT.
Need special monitoring in women with moderately elevated levels of triglycerides. In such cases, the use of HRT may cause a further increase in the level of triglycerides in the blood, thereby increasing the risk of acute pancreatitis.
Although HT can influence on peripheral insulin resistance and glucose tolerance, need to adjust the dosage in patients with diabetes mellitus usually does not occur. Nonetheless, This category of patients while conducting HRT should be supervised.
Some patients under the influence of HRT may develop undesirable manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for the study of the endometrium.
If the treatment of irregular menstrual cycles fails, should undertake a survey to exclude organic disease of character.
Under the influence of estrogen uterine fibroids may increase in size. In this case, treatment should be discontinued.
It is recommended to discontinue treatment with the development of recurrent endometriosis HRT.
If you suspect the presence of prolactinoma before treatment to exclude this disease.
In some cases, it may be observed chloasma, especially in women with a history of chloasma pregnant. During the HRT woman with a tendency to rise to Chloasma should avoid prolonged exposure to sunlight or UV-irradiation.
Epilepsy, a benign tumor of the breast, bronchial asthma, migraine, porphyria, otosclerosis, SLE, Chorea minor may occur or worsen for the first time against the backdrop of HRT. Although a direct relationship with HRT is not proven, patients with these diseases (or predisposition thereto) When undertaking HRT should be under the supervision of a physician.
Acceptance of sex steroids may influence biochemical parameters of liver function, Thyroid, adrenal glands and kidneys, on plasma levels of transport proteins, such as SHBG, lipid/lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis. Angélique® will not have a negative impact on tolerance to glukoze.
Excessive consumption of alcohol during HRT may lead to an increase in circulating levels of estradiol.
Overdose
In the study of acute toxicity risk acute side effects if accidentally taken drugs inside in the number, many times greater than the daily therapeutic dose, not identified.
Symptoms: nausea, vomiting, vaginal bleeding.
Treatment: No specific antidote, if necessary, symptomatic therapy.
Drug Interactions
With prolonged simultaneous use with drugs, inducing hepatic microsomal enzymes (eg, some anticonvulsants and antimicrobials), may increase clearance of sex hormones and decrease their clinical efficacy. This interaction is set to hydantoins, ʙarʙituratov, prymydona, carbamazepine and rifampicin, as well as okskarbazepina have expected, topiramate, felbamata and griseofulvin. Maximum induction of enzymes normally not earlier than 2-3 weeks after the start of the reception and may persist for, at least, 4 weeks after stopping treatment.
In rare cases, against the backdrop of the combined use of some antibiotics (the Group of penicillin and tetracycline) there was a reduction in estradiol levels.
Substances, highly exposed conjugation (eg, paracetamol), may increase the bioavailability of estradiol as a result of competitive inhibition of the conjugation system during absorption.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 5 years.
