Expiration date: 11/2028

Structure and Composition: 

Film-coated tablets. 1 tablet contains:

1 mg of estradiol hemihydrate

2 mg drospirenone

Excipients: lactose monohydrate, corn starch, modified starch talc, magnesium stearate, polyvidone 25,000 hydroxypropylmethylcellulose polyethylene glycol 6000 titanium dioxide, iron oxide red

in blisters 28 pcs. a stack of cardboard packaging 1 or 3.

Description pharmaceutical form:

Round, biconvex, moderately red (dark pink) film-coated tablets, embossed with «DL» in a regular hexagon on one side.

Pharmacokinetics:

Estradiol: after ingestion rapidly and completely absorbed. During absorption and "first pass" through the liver estradiol partially metabolized. After oral bioavailability of about 5%, does not affect food intake on bioavailability of estradiol. Cmax in serum (approximately 22 pg / ml) is normally achieved after 6-8 hours after administration. Estradiol binds to albumin and binding globulin sex steroids (SHBG). Free fraction in serum estradiol is about 1-12% and the fraction of material associated GSM - in the range of 40-45%. The apparent volume of distribution of estradiol after single / in the introduction is about 1 l / kg. Is metabolized primarily in the liver, and partly in the intestine, kidney, skeletal muscle and target organs to form estrone, estriol, kateholestrogenov and glucuronide and sulphate conjugates thereof that have substantially less estrogenic activity or do not have estrogenic activity. Clearance of serum estradiol - 30 ml / min / kg. Estradiol metabolites are excreted in the urine and bile from T1 / 2 of approximately 24 h. The concentration of estradiol in the serum after multiple administration is approximately 2 times higher than after a single dose. The average concentration of estradiol in the blood serum ranges from 20 pg / ml (minimum) to 43 pg / ml (the highest level). After discontinuation of Angeliq  levels of estradiol and estrone returned to baseline values ??within approximately 5 days.

Drospirenone: after oral administration over a wide dose range drospirenone is rapidly and completely absorbed. Bioavailability after oral administration is 76-85%, it does not affect food intake on bioavailability. Cmax in serum (approximately 22 ng / ml) was achieved after about 1 hour after single and multiple administration of 2 mg drospirenone. Reduction of drospirenone in serum is biphasic with the final T1 / 2 approximately 35-39 h. Drospirenone is bound to serum albumin and does not bind to SHBG and corticoid binding globulin (CBG). About 3-5% of the total serum concentration of drospirenone is not associated with the protein. The major metabolites in human serum are the acid form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate. Both metabolites are formed without the participation of cytochrome P450. Clearance of serum drospirenone is 1.2-1.5 ml / min / kg. Some of the resulting dose is excreted unchanged, a large part - in the form of metabolites in the urine and faeces in a ratio of 1.2:. 1.4 and T1 / 2 of about 40 h equilibrium concentration is reached after about 10 days of daily administration of the drug Angelique. Due to the long T1 / 2 of drospirenone equilibrium concentration is 2-3 times higher than the concentration after a single dose.

Description of the pharmacological actions:

Angeliq is a continuous combined preparation for hormone replacement therapy (HRT), avoiding the regular withdrawal bleeding, which occur in cyclical phase or HRT.

17 contains estradiol & beta-that the chemical structure and biological properties identical to human endogenous estradiol, and a derivative of spironolactone - Drospirenone having progestational, antigonadotropnym and antiandrogenic and antimineralokortikoidnym action.

Estradiol restores deficit of estrogen in the female body after menopause and provide effective treatment for psycho-emotional and vegetative menopausal symptoms ( 'hot flashes', sweating, insomnia, increased nervous excitability, irritability, palpitations, false angina, dizziness, headache, decreased libido, muscle and joint pain), involution of the skin and mucous membranes, especially the mucous membranes of the genitourinary system (urinary incontinence, dryness and irritation of the vagina, pain during sexual intercourse).

Estradiol prevents bone loss caused by estrogen deficiency. This is mainly due to the suppression of bone remodeling toward bone formation of osteoclast function and process shift. It has been proven that long-term use of HRT reduces the risk of fractures of the peripheral bone in women after menopause. If you cancel HRT rate of decline in bone mass comparable to the characteristic of the period immediately after menopause.

HRT also has a beneficial effect on the collagen content of the skin, as well as its density, and can also slow down the formation of wrinkles.

In addition, due to the antiandrogenic properties of drospirenone, Angeliq has a therapeutic effect on androgen such diseases as acne, seborrhea, androgenetic alopecia.

Drospirenone has anti-mineralocorticoid activity, increases the excretion of sodium and water, which can prevent the increase in blood pressure, weight gain, edema, breast tenderness and other symptoms associated with fluid retention. After 12 weeks of use of the drug Angeliq has been a slight decrease in blood pressure (SBP - an average of 2-4 mm Hg, Dad -.. By 1-3 mm Hg..). Have an effect on blood pressure was more pronounced in women with borderline hypertension. After 12 months of preparation Angeliq average body weight remained unchanged or decreased by 1.1 -1.2 kg.

Drospirenone has no androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity has no effect on glucose tolerance and insulin resistance. This, in combination with antiandrogenic action and antimineralokortikoidnym, drospirenone provides biochemical and pharmacological profile similar to natural progesterone.

Admission Angeliq leads to a decrease in total cholesterol and LDL cholesterol. Drospirenone weakens growth triglycerides, called estradiol.

The addition of drospirenone prevents the development of endometrial hyperplasia and cancer.

Observational studies suggest that among postmenopausal women using HRT reduced incidence of colon cancer.

Testimony:

• HRT at climacteric disorders in postmenopausal, including vasomotor symptoms (such as hot flushes, sweating), sleep disturbance, depression, irritability, involutional changes in skin and urinary tract in women with a uterus unremoved
  
• prevention of postmenopausal osteoporosis.
  

Contraindications:

• hypersensitivity to the drug
  
• pregnancy
  
• breastfeeding
  
• vaginal bleeding of unknown origin
  
• confirmed or presumptive diagnosis of breast cancer
  
• confirmed or presumptive diagnosis of hormone-dependent precancerous disease or hormone-dependent cancer
  
• liver cancer now or in history (benign or malignant)
  
• severe liver disease
  
• severe kidney disease at present or in history (up to normalization of renal function)
  
• acute arterial thrombosis or thromboembolism, including leading to myocardial infarction, stroke
  
• deep vein thrombosis in the acute stage
  
• Venous thromboembolism present or in history
  
• severe hypertriglyceridemia.
  

Application of pregnancy and breastfeeding:

HRT is not appointed during pregnancy or breastfeeding.

Large-scale epidemiological studies of steroid hormones used for contraception or hormone replacement therapy, found no increased risk of birth defects in children born to women who took such hormones before pregnancy, and teratogenic effects of hormones in their casual reception in the early stages of pregnancy.

Small amounts of sex hormones can be released from the mother's milk.

Side effect:

In rare cases, the following side effects.

Reproductive system and breast: breakthrough uterine bleeding and spotting (usually terminated in the course of therapy), changes in vaginal discharge, an increase of fibroids size, condition, like premenstrual syndrome pain, stress and / or breast enlargement, benign tumors of the mammary glands .

From the gastrointestinal tract: indigestion, bloating, nausea, vomiting, abdominal pain, recurrent cholestatic jaundice.

Skin and subcutaneous tissue: skin rash, itchy skin, chloasma, erythema nodosum.

CNS: headache, migraine, dizziness, mood lability, anxiety, increased nervous irritability, fatigue, insomnia.

Other: rarely - palpitations, edema, increased blood pressure, varicose veins, superficial thrombophlebitis, venous thrombosis and thromboembolism, muscle cramps, changes in body weight, changes in libido, visual disturbances, intolerance to contact lenses, allergic reactions.

Drug Interactions:

Long-term treatment with drugs that induce liver enzymes (eg several anticonvulsants and antimicrobials) can increase the clearance of sex hormones and reduce their clinical efficacy. This property of inducing liver enzymes was found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, the presence of this feature is also supposed to have oxcarbazepine, topiramate, felbamate and griseofulvin. Maximal enzyme induction is generally not seen before 2-3 weeks, but then it can persist for at least 4 weeks after stopping treatment. In rare cases, during concomitant ingestion of certain antibiotics (such as penicillin and tetracycline groups) there was a decrease in estradiol levels. Substances largely exposed conjugation (such as acetaminophen) may increase the bioavailability of estradiol due to competitive inhibition of conjugation in the process of absorption. Excessive alcohol consumption during HRT may lead to an increase in circulating levels of estradiol.

Dosage and administration:

Inside. If a woman does not take estrogens or transferred to Angeliq from another combined preparation for continuous reception, it may start treatment at any time. Patients who switch to Angeliq with combined preparation for cyclical HRT should begin reception after the withdrawal bleeding. Each package is designed for a 28-day reception. Every day should take one tablet. After receiving 28 tablets from the current package, the next day, start a new pack Angeliq (continuous HRT), taking the first pill on the same day of the week as the first pill from the previous package. The tablet is swallowed whole with a little liquid. The time of day when a woman takes a drug, it does not matter, however, if she started to take the pills at any given time, it must adhere to this time and beyond. Forgotten tablet should be taken as soon as possible. If, however, after the usual time of reception has been more than 24 hours, an additional tablet should be taken. When skipping a few pills may develop vaginal bleeding.

Overdose:

Acute toxicity studies revealed no risk of acute side effects of taking the drug with random quantities many times greater than the daily therapeutic dose. Symptoms that may occur with overdose include nausea, vomiting, vaginal bleeding. No specific antidote, treatment is symptomatic.

Precautionary measures:

In the presence or worsening of any of the following conditions or risk factors before you begin or continue HRT should weigh the individual risks and benefits of treatment.

Venous thromboembolism. A number of controlled randomized and epidemiological studies found an increased relative risk of developing venous thromboembolism (VTE) HRT, ie deep vein thrombosis or pulmonary embolism. Therefore, the appointment of HRT for women with risk factors for VTE risk-benefit of treatment should be carefully weighed and discussed with the patient.

Risk factors for VTE include a personal and family history (VTE in the presence of the next of kin in a relatively early age may indicate genetic disposition) 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, "large" and the planned operations or massive trauma injury. Depending on the cause or duration of immobilization should decide whether a temporary cessation of HRT.

It should immediately discontinue treatment if symptoms of thrombotic disorders or suspected their appearance.

Cancer of the endometrium. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia and cancer.

Mammary cancer. According to the results of clinical trials and observational studies, may increase in women using HRT the risk of breast cancer for several years. This may be due to an earlier diagnosis, biological effects of HRT, or a combination of both factors. The relative risk increases with duration of treatment (2.3% per year of use). This compares with an increase in the risk of delaying the onset of natural menopause (2.8% per year delay) of breast cancer in women each year. The increased risk gradually decreases to normal levels during the first 5 years after stopping HRT. Breast cancer detected in women taking HRT, usually more localized than in women who did not take it. HRT increases mammographic breast density, which in some cases may adversely affect the radiological detection of breast cancer.

The tumor of the liver. Against the background of the use of sex steroids, which include means for HRT, in rare cases benign, and even more rarely - malignant tumors of the liver. In some cases, these tumors have led to life-threatening intra-abdominal haemorrhage. When the pain in the upper abdomen, enlarged liver or signs of intra-abdominal bleeding in the differential diagnosis should take into account the probability of having liver cancer.

Cholelithiasis. It is known that estrogens increase the lithogenic bile. Some women are predisposed to the development of gallstone disease during treatment with estrogens.

Other conditions. It should immediately discontinue treatment at the first appearance of migraine 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 significant hypertension has not been established. In women taking HRT, described a slight increase in blood pressure, a clinically significant increase is rare. However, in some cases, in the development against the backdrop of HRT reception clinically significant hypertension can be considered the abolition of HRT.

In renal failure can decrease potassium excretion capacity. Receiving drospirenone has no effect on serum potassium concentration in patients with mild to moderate renal insufficiency. The risk of hyperkalemia development theoretically can not be ruled only group of patients in whom potassium concentration in serum before treatment was determined at the upper limit of normal and which in addition are taking potassium-sparing drugs.

In non-severe hepatic dysfunction, including such forms of hyperbilirubinemia, as the syndrome Dubin - Johnson or Rotor syndrome, need medical supervision and periodic liver function tests. If deterioration in liver function HRT should be abolished.

When relapse cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or previous treatment sex steroid hormones, hormone replacement therapy should be discontinued immediately.

The need for special monitoring of 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, which increases the risk of acute pancreatitis.

Although HRT may influence the peripheral insulin resistance and glucose tolerance, need to change the treatment regimen of patients with diabetes during HRT is not usually arise. However, women suffering from diabetes, during HRT should be monitored.

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.

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 HRT.

If you suspect the presence of prolactinoma before treatment to exclude the disease.

In some cases, chloasma may occur, especially in women with a history of chloasma pregnant. During HRT women with a penchant for the emergence of chloasma should avoid exposure to the sun or UV radiation.

The following conditions may occur or be exacerbated by HRT. Although their relationship with HRT has not been proven, women with conditions such as epilepsy, benign breast tumors, asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, chorea during HRT should be under a doctor's supervision.

The drug does not affect the ability to drive and use machinery.

Special instructions:

Angeliq is not applicable for the purpose of contraception. non-hormonal methods (with the exception of the calendar and temperature methods) should be used if necessary contraception. If you suspect a pregnancy, you should stop taking as long as the pregnancy will not be excluded (see. "Pregnancy and breastfeeding").

Before starting or resuming HRT woman should undergo a thorough general medical and gynecological examination (including breast examination and cytological examination of cervical mucus), exclude pregnancy. In addition, to exclude blood coagulation disorders. Periodic follow-up examinations should be carried out.

Acceptance of sex steroids may influence biochemical parameters of liver, thyroid, adrenal and kidney, for the maintenance of the plasma transport proteins such as globulin, sex hormone binding and lipid / lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis. Angeliq has no negative effect on glucose tolerance.