2010/09/21

Angeliq

Composition, structure and packing

Coated tablets moderate red (dark pink) colored, round, biconvex, embossed "DL" in a regular hexagon on one side.

1 tab. estradiol (in the form gemigidrata) 1 mg drospirenone 2 mg.

Excipients: lactose monohydrate, corn starch, modified starch, talc, magnesium stearate, polyvidone 25000, hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide, iron oxide red.

Clinico-pharmacological group: Protivoklimakterichesky drug.

Pharmacological action

Combined preparation for continuous hormone replacement therapy (HRT), avoiding regular withdrawal bleeding. Contains estrogen - 17β-estradiol, identical to endogenous and drospirenone, which has gestagen, antigonadotropnym and antiandrogenic and antimineralokortikoidnym action. Estradiol restores estrogen deficiency in the female body after menopause and provide effective treatment for psycho-emotional and vegetative menopausal symptoms (such as hot flushes, increased sweating, sleep disturbances, increased nervousness, irritability, a feeling heart, false angina, dizziness, headache, decreased libido, muscle and joint pain), reduces involution of the skin and mucous membranes, especially of the genitourinary system (ie, has a positive effect on urinary incontinence, dryness and irritation of the mucous membrane of the vagina, pain during sexual intercourse). Estradiol prevents bone loss caused by estrogen deficiency, which is mainly due to the suppression of osteoclast function and bone remodeling process of a shift toward the formation of bone.

It was shown that prolonged use of HRT reduces the risk of peripheral bone fractures in women after menopause. If you cancel HRT rate of decline in bone mass compared with those typical for the period immediately after menopause. Not been proved that during HRT may be to restore bone mass to premenopausal levels. HRT also has beneficial effects on the content of collagen in the skin, as well as on its density, and also can slow the formation of wrinkles. Drospirenone, thanks to anti-androgenic properties, has a therapeutic effect on androgenozavisimye diseases such as acne, seborrhea, alopecia androgenetical.

Drospirenone has antimineralokortikoidnoy activity, increases the excretion of sodium and water, which can prevent increase of blood pressure, weight gain, leading to swelling, painful breasts and other symptoms associated with water retention. After 12 weeks of the drug Angelique noted a small reduction in blood pressure (systolic - an average of 2-4 mm Hg, diastolic - by 1-3 mm Hg). In other studies showed a decrease SBP by 9 mm Hg. Art. and DBP by 5.7 mm Hg. Art.

In women with normotension BP was not significantly changed. Impact on blood pressure was more pronounced in women with arterial hypertension. After 12 months of the drug Angelique average body weight remained unchanged or decreased by 1.1-1.2 kg. Drospirenone devoid of any androgenic, estrogenic, glucocorticoid and antiglyukokortikoidnoy activity has no effect on glucose tolerance and insulin resistance, which in combination with antimineralokortikoidnym and antiandrogenic effect of drospirenone provides biochemical and pharmacological profile similar to natural progesterone. Receiving Angelica leads to a reduction in total cholesterol (TC) and CS-LDL, as well as slightly higher levels of triglycerides. The inclusion of the drug drospirenone prevents the development of hyperplasia and endometrial cancer. Observational studies suggest that among postmenopausal women using HRT reduces the incidence of colon cancer.

The mechanism of action so far unclear. Angelique has a positive effect on mood and quality of life, mainly reflected in a reduction of somatic symptoms, anxiety / fear and improve the ability to cognition (cognitive function).

Pharmacokinetics

Estradiol

Absorption

After taking the drug inside estradiol is rapidly and completely absorbed from the gastrointestinal tract. Treated the effect of "first pass" with the formation of estrone, estriol and estrone sulfate. Oral bioavailability is about 5% and is independent of food intake. Cmax of estradiol in serum is approximately 22 pg / ml and is reached after 6-8 hours

Distribution

Bound to albumin and globulin binding sex steroids (GSPC). The free fraction of estradiol in the serum of approximately 1-12% and 40-45% related to the GSPC. Vd after a single in / introduction of about 1 l / kg. After repeated application of estradiol is about 2 times higher than after a single dose, while Css ranging from 20 pg / ml to 43 pg / ml. After the termination of the levels of estradiol and estrone returned to baseline values within approximately 5 days.

Metabolism

Estradiol is metabolized primarily in the liver, partly - in the intestine, kidney, skeletal muscle and in target-organs with the formation of estrone, estriol, kateholestrogenov, as well as sulfate and glyukuronidnyh conjugates of these compounds, which have much lower estrogenic activity than estradiol or generally inactive .

Withdrawal

Clearance of estradiol from serum - 30 ml / min / kg. Estradiol metabolites excreted in the urine and bile. T1 / 2 approximately 24 hours

Drospirenone

Absorption

After oral drospirenone is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is 76-85% and is independent of the meal.

Distribution

After a single or multiple receive a dose of 2 mg C max in serum obtained after 1 h and is about 22 ng / ml. Then there is a biphasic decline in serum concentrations of drospirenone with a finite T1 / 2 approximately 35-39 hours drospirenone binds to albumin and is not connected with the GSPC and corticoid-binding globulin (GSB), about 3-5% - the free fraction. Css achieved after 10 days of daily administration of the drug Angelique and exceeds the concentration after a single dose of 2-3.

Metabolism

The main metabolites are acidic form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate, which are formed without the involvement of isoenzymes of cytochrome P450.

Withdrawal Clearance drospirenone from serum is 1.2-1.5 ml / min / kg. Write mainly in the form of metabolites in urine and feces at a ratio of 1.2:1.4; T1 / 2 about 40 hours

Statement
hormone replacement therapy in women with intact uterus in menopausal disorders in postmenopauznom period, including vasomotor symptoms (such as hot flushes, increased sweating), sleep disorders, depression, irritability and involutional changes in the skin and urinary tract;
postmenopauznogo prevention of osteoporosis.

Dosage regimen

If a woman does not take estrogens or transferred to Angelique from another combined preparation for continuous reception, it can begin treatment at any time. Patients who go to Angelique with combined preparation for cyclical HRT should begin reception after the withdrawal bleeding. The drug should be taken daily for 1 tab.

After receiving 28 tablets of the current package on the next day start a new pack Angelique, taking the first pill on the same day of the week as the first pill from the previous packaging. Swallow the whole pill, washed down with a small amount of liquid. Time of day when a woman takes a drug, it does not matter, but if she started taking pills at any particular time, it must adhere to this time and beyond.

If you missed the missed tablet should be taken as soon as possible. If, after the usual time of reception has been more than 24 hours, an extra tablet should not be accepted. When there are missing a few pills may develop vaginal bleeding.

Side effect

On the part of the reproductive system: sometimes - breakthrough uterine bleeding and spotting (usually terminated in the course of therapy), changes in vaginal discharge, increasing the size of fibroids, a condition like syndrome premenstrual tension, soreness, tension and / or an increase in the mammary glands, benign breast; rare - altered libido.

On the part of the digestive system: - dyspepsia, flatulence, nausea, vomiting, abdominal pain, recurrent cholestatic jaundice.

From the side of the central nervous system: possible - headache, migraine, dizziness, mood lability, anxiety, increased nervous irritability, fatigue, insomnia, rarely - visual impairment.

Since the cardiovascular system: rarely - palpitations, edema, increased blood pressure, varicose veins, superficial thrombophlebitis, venous thrombosis and thromboembolism.

Dermatological reactions: possible - skin rash, itchy skin, chloasma, nodular erythema multiforme erythema.

Other: rarely - muscle cramps, changes in body weight, intolerance to contact lenses, allergic reactions.

Contraindications
vaginal bleeding of unknown etiology;
confirmed or presumed breast cancer;
confirmed or suspected hormone-dependent precancerous condition or hormone dependent malignant tumor;
benign or malignant liver tumors (including history);
severe liver disease;
severe kidney disease to the normalization of laboratory parameters (including history);
acute arterial thrombosis or thromboembolism (including myocardial infarction, stroke);
deep vein thrombosis in acute phase;
thromboembolism (including history);
hypertriglyceridemia;
Pregnancy
lactation
Hypersensitivity to the drug's components.

With the development against the background of HRT of any of the states should immediately stop using the product.

Beremennnost and lactation

The drug is contraindicated during pregnancy and lactation. Large-scale epidemiological studies of steroid hormones for contraception or HRT showed no increased risk of birth defects in children born to women who have taken such hormones before pregnancy, and teratogenic effects of hormones in their casual reception in the early stages of pregnancy.

The drug should not apply to contraception. If necessary, non-hormonal contraceptive methods should be used (except for calendar and temperature methods). If you suspect a pregnancy should stop taking the drug for as long as the pregnancy will not be excluded. A small amount of sex hormones may be released from the mother's milk.

Application for violations of liver function

Do not use this product in benign or malignant tumors of the liver (including history), severe liver disease.

Precautions should be appointed Angelique in congenital hyperbilirubinemia (Gilbert syndrome, Dubin-Johnson and Rotor), cholestatic jaundice or cholestatic itch. When deterioration in liver function HRT should be abolished.

Application for violations of renal function

Do not use this drug for severe kidney disease to the normalization of laboratory parameters (including history).

Cautions

Precautions should be appointed Angelique in arterial hypertension, congenital hyperbilirubinemia (Gilbert syndrome, Dubin-Johnson and Rotor), cholestatic jaundice or cholestatic itching in the previous pregnancy, endometriosis, uterine myoma, diabetes. In the presence or worsening of any of these states, before you start or continue HRT should evaluate the relationship of the individual risks and benefits of treatment.

Before starting or resuming HRT a woman should undergo a thorough general and gynecological examination (including the study of mammary glands and cytological examination of cervical mucus), exclude pregnancy. Furthermore, it should exclude violations of blood coagulation system.

Periodic monitoring surveys should be conducted. A number of controlled randomized and epidemiological studies found an increased relative risk of venous thromboembolism (VTE) in the presence of HRT. In the appointment of HRT for women with risk factors for VTE (deep vein thrombosis or pulmonary embolism) should be carefully weighed and discussed with the patient, the ratio of risks and benefits of treatment. Risk factors for VTE include the presence of VTE in medical history (including family VTE have close relatives in the 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 the development of VTE remains controversial. The risk of VTE may be temporarily increased with prolonged immobilization, extensive surgery, trauma.

Depending on the cause or duration of immobilization should decide whether a temporary cessation of HRT. It should immediately discontinue treatment if symptoms of thrombosis or suspected their appearance. In the randomized controlled studies of prolonged use of combined conjugated estrogens and medroxyprogesterone acetate were obtained evidence of positive effects on the cardiovascular system. Was also found increased risk of stroke. So far, with other drugs for HRT is not carried out long-term randomized controlled trials to identify a positive effect on morbidity and mortality related to cardio-vascular system. Therefore unknown whether this increased risk of drugs for HRT, containing other types of estrogens and progestagens.

During prolonged estrogen alone increases the risk of endometrial hyperplasia or carcinoma. Studies have confirmed that the addition of gestagens reduces the risk of hyperplasia and endometrial cancer. According to clinical studies and the results of observational studies have found increased risk of developing breast cancer among women using HRT for several years. This may be due to earlier diagnosis, biological effects of HRT or combination of both factors.

The relative risk increases with duration of treatment (at 2.3% per year of use). This compares with an increase risk of breast cancer in women each year delay in the onset of natural menopause (2.8% per year of delay). The increased risk gradually decreases to normal levels during the first 5 years after cessation of HRT. Breast cancer detected in women taking HRT, usually more localized than in women, not accept it. HRT increases mammographic breast density, which in some cases may have a negative impact on the radiological detection of breast cancer.

Against the background of sex steroids, which include funds for HRT, in rare cases, there are benign and even more rarely malignant liver tumors, which in some cases led to life-threatening intraperitoneal bleeding.

When pain in the upper abdomen, liver enlargement or signs of intraabdominal haemorrhage in the differential diagnosis should consider the probability of having liver tumors.

It is known that estrogens increase lithogenicity bile. Some women are predisposed to the development of gallstone disease during treatment with estrogens. It should immediately stop using the drug during the first occurred migrenepodobnyh or frequent and unusually severe headaches, as well as the appearance of other symptoms - possible precursors of thrombotic stroke brain. The relationship between HRT and the development of clinically severe arterial hypertension is not installed.

In women taking HRT, described a slight increase in blood pressure (clinically significant improvement is rare). In some cases, the development on the background of taking HRT resistant clinically significant arterial hypertension can be considered the abolition of HRT.

As a result of clinical trials (AA Kirichenko, O. Flegentova "Hypertension and cardiodynia climacteric" / / Attending vrach.2006. № 6 pp 1-3), the most preferred drug for use of HRT for women with arterial hypertension in postmenopausal women, Angeliq is a drug containing natural estradiol in a low dose (1 mg / day) and drospirenone (2 mg / day) - with progestin antimineralokortikoidnym effect that increases the excretion of sodium and water.

In applying the drug Angeliq patients were observed: decrease in severity of edema, weight loss and more pronounced antihypertensive effect.

It is noted that the effect of drospirenone antialdosteronovy is important in post-menopausal, not only for women with already developed hypertension, but also for those who had normal blood pressure. The drug prepyatstvtuet sodium and water retention is usually taking place in women with climacteric syndrome and the influence of aldosterone receptors in the brain (the central mechanism for the development of hypertension), thereby enabling to reduce the risk of developing the disease.

In renal failure may decrease the capacity for the removal of potassium. Receiving drospirenone has no effect on the concentration of potassium in the serum of patients with renal insufficiency mild to moderate severity. The risk of developing hyperkalemia is theoretically impossible to exclude only those patients whose concentration of potassium in serum before treatment corresponded to FHG, and which additionally take Potassium-sparing drugs.

In mild liver problems, including various forms of hyperbilirubinemia (including the syndrome Dubin-Johnson or Rotor syndrome) should be supervision of the doctor, as well as periodic liver function tests. When deterioration in liver function HRT should be abolished.

When relapse cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or pre-treatment of sex steroid hormones, you should immediately discontinue HRT. Should special surveillance for women with moderately elevated triglyceride levels. In such cases, the use of HRT may cause a further increase in the level of triglycerides in the blood, which increases the risk of acute pancreatitis. Although HRT may influence the peripheral insulin resistance and glucose tolerance, the need for correction of dosing regimen in patients with diabetes usually does not arise.

Nevertheless, this category of patients during HRT should be supervised. Some patients under the influence of HRT may develop undesirable manifestations of estrogen stimulation, such as 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 do not yield results, should undertake a survey to exclude organic disease 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 recurrence of endometriosis on the background of HT.

Suspicion of prolaktinomy before treatment should be eliminated this disease. In some cases, chloasma may occur, especially in pregnant women with a history of chloasma.

During HRT, women with a tendency to rise to chloasma should avoid prolonged exposure to sunlight or UV-irradiation. Epilepsy, benign tumor of the breast, bronchial asthma, migraine, porphyria, otosclerosis, SLE, chorea may first appear or worsen in the background of HRT. Although a direct relationship with HRT is not proven, patients with these diseases (or with a predisposition to it) when HRT should be under medical supervision.

Acceptance of sex steroids may affect the biochemical parameters of liver function, thyroid gland, adrenal glands and kidneys, and the content in the plasma transport proteins such as SHBG, lipid / lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis. Angelique does not have a negative impact on glucose tolerance. Excessive consumption of alcohol during HRT may increase the level of circulating estradiol.

Overdose

In the study of acute toxicity risk of acute side effects if accidentally taking the drug orally in quantities many times greater than the daily therapeutic dose, was not detected.

Symptoms: nausea, vomiting, vaginal bleeding.

Treatment: No specific antidote, if necessary, carry symptomatically.

Drug Interactions

With long-term simultaneous use of drugs, inducing microsomal liver enzymes (eg, certain anticonvulsants, and antimicrobial drugs) may increase clearance of sex hormones and reducing their clinical effectiveness.

Such interaction is set to hydantoin, barbiturates, primidona, carbamazepine and rifampicin, as well as expected with oxcarbazepine, topiramate, and griseofulvin felbamata.

Maximal enzyme induction is typically observed not earlier than 2-3 weeks after the beginning of the reception and can persist for at least 4 weeks after stopping treatment. In rare cases, against the background of a combined use of some antibiotics (penicillins and tetracyclines groups) observed reduction of estradiol.

Substances heavily exposed to conjugation (eg, acetaminophen) may increase the bioavailability of estradiol due to competitive inhibition of conjugation in the process of suction.

Terms and Conditions of storage

The drug should be stored out of reach of children at or above 25 ° C.

Shelf life - 5 years.