Angelica Micro Film-coated Tablets N28
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Active ingredients
Drospirenone + Estradiol
Release form
Pills
Composition
Estradiol (in the form of hemihydrate) micronized 0.5 mg; drospirenone (micronized) 0.25 mg; Auxiliary substances: lactose monohydrate — 50.45 mg, corn starch — 14.4 mg, pregelatinized corn starch — 9.6 mg, povidone — 4 mg, magnesium stearate — 0.8 mg. ; Film coating composition: yellow varnish - 2 mg or (alternatively): hypromellose (5 cP) - 1.0112 mg, macrogol-6000 - 0.2024 mg, talc - 0.2024 mg, titanium dioxide - 0.464 mg, iron dye yellow oxide - 0.12 mg.
Pharmacological effect
Pharmacological action - estrogen-progestin, anti-menopausal.
Pharmacokinetics
Estradiol ;; Absorption ;; After oral administration, estradiol is rapidly and completely absorbed. During absorption and first passage through the liver, estradiol is largely metabolized, for example, to estrone, estriol, and estrone sulfate. After oral administration, the bioavailability of estradiol is about 5%. Cmax estradiol in plasma of approximately 16 pg / ml is usually achieved 28 hours after taking the tablet. Eating does not affect the bioavailability of estradiol. ;; Distribution ;; After ingestion of the drug Angelica; Micro, there is a gradual change in the concentration of estradiol in the blood plasma within 24 hours. Due to the circulation of estrogen sulfates and glucuronides in a wide range on the one hand, and enteric-hepatic recirculation on the other, T1 / 2 estradiol is a complex parameter that depends on all these processes, and is in the range of 13-20 hours after ingestion. ;; Estradiol binds nonspecificly to serum albumin and specifically with SHBG. The free fraction of estradiol in plasma is about 1–2%, and the fraction of the substance bound by SHBG is in the range of 40–45%. After ingestion, estradiol causes the formation of SHBG, which affects the distribution of whey proteins, causing an increase in the SHBG-bound fraction and a decrease in albumin-bound and unbound fractions, indicating the non-linearity of estradiol pharmacokinetics after taking Angelica; Micro. The apparent Vd of estradiol after a single IV injection is about 1 l / kg. ;; Metabolism ;; Estradiol is metabolized mainly in the liver, and also partially in the intestine, kidneys, skeletal muscles and target organs.These processes are accompanied by the formation of estrone, estriol, catechol estrogen, as well as the sulfate and glucuronide conjugates of these compounds, each of which has significantly less estrogenic activity or no estrogenic activity at all. The concentration of estrone in plasma is 6 times higher than estradiol. The plasma concentration of estrone conjugates is 26 times higher than the corresponding concentrations of free estrone. ;; Elimination ;; The clearance of estradiol from plasma is about 30 ml / min / kg. Estradiol metabolites are excreted by the kidneys and through the intestines with a T1 / 2 of about 24 hours ;; Css ;; With daily use of the drug Angelica; Micro Css estradiol in plasma is reached in approximately 5 days. The concentration of estradiol in plasma increases by approximately 2 times. On average, plasma estradiol concentration ranges from 12 pg / ml (minimum level) to 29 pg / ml (maximum level). ;; Drospirenone ;; Absorption ;; After ingestion, Drospirenone is rapidly and almost completely absorbed. As indicated in the following table 1, Cmax substances in the blood plasma are reached approximately 1 hour after a single and repeated administration of the drug Angelica; Micro. The pharmacokinetic characteristics of drospirenone depend on the dose received in the range of 0.25–4 mg. Bioavailability is 76–85% and does not depend on food intake (when compared with taking on an empty stomach) .; Distribution ;; Cmax of drospirenone in plasma, amounting to about 3.35 ng / ml, is reached approximately 1 hour after a single and repeated administration 0.25 mg Drospirenone. After that, a two-phase decrease in plasma concentration of drospirenone is observed with a final T1 / 2 of about 35–39 hours. Drospirenone binds to serum albumin and does not bind to SHBG and corticoid-binding globulin. About 3-5% of the total concentration of drospirenone in plasma is not associated with protein. ;; Metabolism ;; After ingestion, drospirenone is largely metabolized. The main metabolites in human plasma are the acid form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate. Both metabolites are formed without participation of the cytochrome P450 system. Based on in vitro data, drospirenone is slightly metabolized by the cytochrome P4503A4 system. ;; Elimination ;; clearance of drospirenone from plasma is 1.2–1.5 ml / min / kg. Some of the dose received is excreted unchanged.Most of the dose is excreted by the kidneys and through the intestine in the form of metabolites in the ratio of 1.2: 1.4 with T1 / 2 about 40 hours ;; Css ;; Achieved after about 5 days of taking the drug Angelica; Micro. Due to the long-term T1 / 2 of drospirenone, Css is 2-3 times higher than the concentration after a single dose. ;; Use in some groups of patients ;; Liver dysfunction. The pharmacokinetics of a single oral dose of 3 mg of drospirenone in combination with 1 mg of estradiol was evaluated in 10 patients with moderate hepatic impairment (class B according to Child-Pugh classification) and in 10 healthy participants selected by age, body weight and history of smoking. Plasma concentration-time median profiles for drospirenone were comparable between both groups of women in the absorption / distribution phase with similar Cmax and Tmax, which suggests that abnormal liver function does not affect the degree of absorption. The average T1 / 2 in the final phase was about 1.8 times longer, and the systemic effect increased by 2 times, which corresponds to approximately 50% decrease in apparent oral clearance (CL / f) in volunteers with moderate severity of liver dysfunction compared to participants with normal liver function. The observed decrease in the clearance of drospirenone in volunteers with impaired liver function of moderate severity compared with volunteers with normal liver function did not cause a significant difference in plasma potassium concentrations between the two groups of volunteers. Even in the presence of diabetes mellitus in history and concomitant therapy with spironolactone (two factors contributing to the patient's susceptibility to the development of hyperkalemia), an increase in serum potassium concentrations above the upper limit of acceptable values was not observed. Based on this, we can conclude that drospirenone is well tolerated by patients with impaired liver function from mild to moderate severity (Child-Pugh class B).;; Renal dysfunction. The effect of renal failure on the pharmacokinetics of drospirenone (3 mg daily intake for 14 days) was evaluated in patients with normal renal function and patients with impaired renal function of mild to moderate severity.When pCss was reached, plasma drospirenone in the group of patients with mild renal dysfunction (C creatinine - 50–80 ml / min) was comparable to those in the group of patients with normal kidney function (Cl creatinine -> 80 ml / min). Plasma concentrations of drospirenone were on average 37% higher in the group of participants with moderate severity of renal dysfunction (Cl creatinine - 30–50 ml / min) compared with participants with normal renal function. The results of a linear regression analysis of AUC of drospirenone (0–24 h) with respect to Cl creatinine revealed a 3.5% increase against the background of a decrease in Cl creatinine by 10 ml / min. A slight increase is not considered clinically significant. ;; Ethnicity. The effect of ethnicity on the pharmacokinetics of drospirenone (1–6 mg) and ethinyl estradiol (0.02 mg) was evaluated in young and healthy patients from Europe and Japan after single and multiple daily oral administration. Based on the results of the assessment, it was concluded that the ethnic differences between women in Europe and Japan do not have a clinically significant effect on the pharmacokinetics of drospirenone and ethinyl estradiol.
Indications
- hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with a untreated uterus.
Contraindications
Angelic Micro Micro is contraindicated in the presence of any of the following conditions / diseases. If any of these conditions / diseases occur while taking Angelique Micro, then you should immediately discontinue use of the drug. - pregnancy or breastfeeding period (see the section "Use during pregnancy and during breastfeeding") ;; - bleeding of unspecified etiology ;; - a confirmed or suspected diagnosis of breast cancer or a history of breast cancer ;; - a confirmed or suspected diagnosis of a hormone-dependent precancerous disease or hormone therapy of this malignant tumor ;; - liver tumors now or in history (benign or malignant) ;; - severe liver disease ;; - severe kidney disease now or in history or acute renal failure (until normalization of renal function) ;; - acute arterial thrombosis or thromboembolism (for example, myocardial infarction, stroke), angina pectoris ;; - deep vein thrombosis in the acute stage, venous thromboembolism (includingpulmonary artery thromboembolism) currently or in history ;; - high risk of venous and arterial thrombosis (see section "Specific instructions") ;; - identified susceptibility to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency , protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant) ;; - adrenal insufficiency ;; - untreated hyperplasia ;; - porphyria ;; - pronounced hyper triglyceridemia ;; - hypersensitivity to the components of Angelique Micro ;; - children and adolescents under 18 years old ;; - congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.; With caution: Angelica Micro should be administered with caution in the following diseases: congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itch during a previous pregnancy, endometriosis, uterine myoma, diabetes mellitus (see "Special instructions"); It should be taken into account that estrogens alone or in combination with gestagens should be used with caution in the following diseases and conditions: risk factors for thrombosis and thromboembolism in the family history (thromboembolic complications in close relatives at a young age) , the presence of risk factors for the emergence of estrogen-dependent tumors (for example, relatives of the 1st degree of relationship with breast cancer), endometrial hyperplasia in history, smoking, hypercholesterolemia, irenia, systemic lupus erythematosus, dementia, gallbladder disease, retinal vascular thrombosis, moderate hypertriglyceridemia, edema in chronic heart failure, severe hycycalcemia, endometriosis, bronchial asthma, epilepsy, migraine, liver hemangioma, hyperkalemia, conditions, predisposition, epilepsy, migraine, liver hemangioma, hyperkalemia, conditions, predisposition, epilepsy, headache drugs that cause hyperkalemia - potassium-saving diuretics, potassium preparations, ACE inhibitors, apyoteisin II receptor antagonists, and heparin.
Dosage and administration
If a woman does not take estrogen or goes to Angelique Micro from another combination drug for continuous use, she can start treatment at any time. Patients who switch to Angelic Micro from a combination drug for cyclic HRT should start taking after the end of the current cycle therapy.; Each package is designed for a 28-day intake.; One pill should be taken daily. After the end of taking 28 pills from the current package, the next day they start taking the pills from the new package of Angelic Micro Micro (continuous HRT), taking the first tablet on the same day of the week as the first tablet from the previous package.; The tablet is swallowed whole with small amount of fluid. The pills are taken regardless of the meal. The time of day when a woman takes the drug does not matter, however, if she started taking pills at any particular time, she should stick to that time and beyond.; The forgotten pill should be taken as soon as possible. If more than 24 hours have elapsed after the usual reception time, an additional pill should not be taken. If you skip a few pills, you may develop bleeding from the vagina.; Use in some groups of patients; In children; The drug is contraindicated for use in children and adolescents under 18.; In elderly; There is no data indicating the need for dose adjustment in elderly patients. Information on the use of the drug in women aged 65 years and older is presented in the section "Specific Instructions."; For liver dysfunction; Drospirenone is well tolerated in women with mild to moderate liver function. The drug is contraindicated for use in women with severe impaired liver function (see section "Contraindications"); In case of impaired renal function; In women with impaired renal function, mild and moderate severity, there was a slight increase in the exposure of drospirenone, but suggests I do that it will not have clinical significance. The drug is contraindicated in women with severely impaired renal function (see "Contraindications" section.).