Джес® Plus

General characteristics. Structure:

Active agents: дроспиренон (micronized) 3,000 mg; ethinylestradiol бетадекс the clathrate (micronized) in terms of Ethinylestradiol of 0,020 mg, calcium левомефолат (micronized) 0,451 mg;
Excipients: lactoses monohydrate of 45,329 mg, cellulose of microcrystallic 24,800 mg, croscarmellose sodium of 3,200 mg, hypro rod (5 Wednesday) of 1,600 mg, magnesium stearate of 1,600 mg; Cover
Varnish of pink 2,0000 mg or (alternatively): gipromelloza (5 Wednesday) of 1,0112 mg, macrogoal-6000 of 0,2024 mg, talc of 0,2024 mg, titanium dioxide of 0,5580 mg, dye ferrous oxide red
0,0260 mg;
Structure on one auxiliary vitamin tablet
Kernel
Active agent: calcium левомефолат (micronized) - 0,451 mg; Auxiliary    veshchestva:laktoza monohydrate of 48,349 mg, cellulose of microcrystallic 24,800 mg, croscarmellose sodium of 3,200 mg, hypro rod (5 Wednesday) of 1,600 mg, magnesium stearate of 1,600 mg;
Cover
Varnish of light orange 2,0000 mg or (alternatively): gipromelloza (5 Wednesday) of 1,0112 mg, macrogoal-6000 of 0,2024 mg, talc of 0,2024 mg, titanium dioxide of 0,5723 mg, dye ferrous oxide of yellow 0,0089 mg, dye ferrous oxide of red 0,0028 mg.

Description
The active combined tablet
Round biconvex tablets, film coated pink color, on one party with a stamping of "Z+" in the correct hexagon. Auxiliary vitamin tablet
Round biconvex tablets, film coated light orange color, on one party with a stamping "M +" in the correct hexagon.

Pharmacological properties:

Pharmacodynamics. Jes Plus - the combined estrogen-gestagenny low-dosed monophase peroral the contraceptive drug including active tablets and
the auxiliary vitamin tablets containing calcium левомефолат.
The contraceptive effect of drug Jes Plus is generally carried out due to suppression of an ovulation and increase in viscosity of cervical slime.
At the women accepting the combined oral contraceptives (COOK), the cycle becomes more regular, morbidity, intensity and duration of menstrualnopodobny bleedings therefore the risk of an iron deficiency anemia decreases decrease. Are available also this about decrease in risk of endometrial cancer and ovaries.
Drospirenon who is contained in drug Jes Plus possesses antimineralokortikoidny action and promotes the prevention of a hormonedependent delay of liquid that can be shown in decrease in body weight and reduction of probability of emergence of peripheral hypostases. Drospirenon also has anti-androgenic activity and promotes reduction of an acne (eels), fat content of skin and hair. Such effect of a drospirenon is similar to effect of the natural progesterone produced in a female body. It should be considered at the choice of a contraceptive, especially to women with a hormonedependent delay of liquid, and also to women with an acne and seborrhea. At the correct use Perl's index (the indicator reflecting number of pregnancies at 100 women applying a contraceptive within a year) makes less than 1. At the admission of tablets or the wrong use Perl's index can increase.
The acid form of calcium of a levomefolat, on the structure is identical natural to L - 5-metiltetragidrofolatu (L-5-metil-TGF), the main folatny form which is contained in food. Average concentration in a blood plasma of the people who are not using the food enriched with folic acid makes near the 15th nmol/l.
Levomefolat, unlike folic acid, is biologically active form of folate. Thanks to it it is acquired better, than folic acid. Lemofolat is shown for satisfaction of the increased requirement and ensuring necessary content of folates in the woman's organism during pregnancy and during feeding by a breast. Administration of calcium of a levomefolat in composition of peroral contraceptive drug reduces risk of development of defect of a neurotubule of a fruit if the woman becomes pregnant unexpectedly, at once after contraception phase-out (or, seldom or never, at use of peroral contraception).

Pharmacokinetics

• Drospirenon Absorbtion
At oral administration дроспиренон quickly and almost it is completely absorbed. After a single dose inside the maximum concentration (Cmax) of a drospirenon in plasma
blood, equal 35 ng/ml, are reached in 1-2 hours. Bioavailability fluctuates from 76 to 85%. In comparison with reception of a drospirenon next the heart, meal does not influence its bioavailability. Distribution
After oral administration two-phase decrease in level of drug in serum, with elimination half-lives, respectively, 1,6±0,7 hours and 27,0±7,5 hours is observed. Drospirenon contacts a seralbumin and the corticosteroid-the connecting globulin (CCG) does not contact the globulin, connecting sex hormones (G,CSH), or. Only 3-5% of the general concentration of substance in serum are present at quality of free hormone. The increase in GSPG induced by ethinylestradiol does not influence binding of a drospirenon proteins of a blood plasma. The average seeming volume of distribution makes 3,7±1,2 l/kg.

Metabolism
After oral administration дроспиренон it is extensively metabolized. The majority of metabolites in plasma are presented by acid forms of a drospirenon which are formed without involvement of system of P450 cytochrome. The isoenzyme of P450 3A4 cytochrome participates in the minimum degree in metabolism of a drospirenon, дроспиренон it is capable to reduce concentration of enzyme in a blood plasma and activity of isoenzymes of P450 1A1 cytochrome, P450 2C9 and P450 2C19 of in vitro.

Removal
Speed of metabolic clearance of a drospirenon in a blood plasma makes 1,5±0,2 ml/min. In not changed look дроспиренон it is excreted only in trace quantities. Metabolites of a drospirenon are excreted through digestive tract and kidneys in the ratio about 1,2:1,4. An elimination half-life for excretion of metabolites - about 40 hours.

Equilibrium concentration
During the first course use of drug an equilibrium condition of a drospirenon with concentration in a blood plasma about 60 ng/ml are reached from the 7th to the 14th day of use of drug. Increase in concentration of a drospirenon in a blood plasma approximately by 2-3 times was noted (due to cumulation) that was caused by an elimination half-life ratio in a terminal phase and a dosing interval. Further increase in concentration of a drospirenon in a blood plasma is noted through 1 - 6 courses of use of drug then increase in concentration is not observed.

At a renal failure
Concentration of a drospirenon in a blood plasma at achievement of an equilibrium state was comparable at women to an easy renal failure (the clearance of creatinine (CC) - 50-80 ml/min.) and at women to safe function of kidneys (KK - more than 80 ml/min.). Nevertheless, at women with a moderate renal failure (KK - 30-50 ml/min.) average concentration of a drospirenon in a blood plasma was 37% higher, than at patients with safe function of kidneys. Change of potassium concentration in a blood plasma at use of a drospirenon is noted.

At an abnormal liver function
At women with a moderate abnormal liver function (a class B on a scale of Chayld-Pyyu) the area under a curve "concentration time" (AUC) is comparable to the corresponding indicator at healthy women with close values Stakh in phases of absorption and distribution. T1/2 of a drospirenon at patients with a moderate abnormal liver function was 1,8 times higher, than at healthy volunteers with safe function of a liver.
At patients with a moderate abnormal liver function about 50% in comparison with women with safe function of a liver are noted decrease in clearance of a drospirenon, at the same time distinctions in potassium concentration in a blood plasma in the studied groups are noted. Potassium concentration changes even in case of a combination of the factors contributing to its increase are noted (the accompanying diabetes mellitus or treatment by Spironolactonum).

• Ethinylestradiol Absorption
After intake ethinylestradiol is quickly and completely absorbed. Cmax - about 33
the pg/ml,  is reached   within  1-2  hours.  Drug is exposed  to presistemny metabolism in a liver, its bioavailability at intake averages about 60%. The concomitant use of food in some cases is followed by decrease in bioavailability of ethinylestradiol by 25%. Distribution
Concentration of ethinylestradiol in a blood plasma decreases in 2 phases, the ethinylestradiol elimination half-life in the second phase makes about 24 hours. Ethinylestradiol possesses nonspecific, but strong linkng with blood plasma albumine (about 98,5%) and induces increase in concentration in GSPG plasma. The estimated volume of distribution makes about 5 l/kg. Metabolism
Ethinylestradiol is exposed to presistemny conjugation in a liver and in mucous a small bowel. The main way of metabolism of ethinylestradiol - an aromatic hydroxylation with formation of numerous metabolites which are as in the connected, and untied state. Ethinylestradiol removal speed - about 5 ml/min.

Removal
Ethinylestradiol is removed only in the form of metabolites by kidneys and through digestive tract in the ratio 4:6 with an elimination half-life about 24 hours.

Equilibrium concentration
The equilibrium state is reached in the second half of a course of treatment, concentration of ethinylestradiol in a blood plasma increases approximately by 1,4-2,1 times.

Ethnic origin
Influence of an ethnic origin on pharmacokinetics parameters in researches at single and repeated dosing of a drospirenon and ethinylestradiol at healthy women of Caucasian race was studied, and also at Japanese. It is not established influences of an ethnic origin on parameters of pharmacokinetics of a drospirenon and ethinylestradiol.

• Calcium левомефолат Absorption
After calcium intake левомефолат quickly is absorbed and joins in a pool of folates of an organism. After a single dose in 0,451 mg of calcium of a levomefolat in 0,5 - 1,5 hours of Cmax becomes 50 nmols/l higher than initial concentration.
Distribution
The pharmacokinetics of folates has two-phase character: decide a pool of folates with bystry and on slow metabolism. The pool with bystry metabolism is probably represented by the folates which again came to an organism that will be coordinated with calcium T1/2
levomefolat who makes about 4-5 hours after his single dose inside in a dose of 0,451 mg. The pool with slow metabolism reflects transformation of a polyglutamate of folate which T1/2 makes about 100 days. The folates and folates passing an enterohepatic cycle arriving from the outside provide maintenance of constant concentration L-5-metil-TGF in an organism.
L-5-metil-TGF represents the main form of existence of folates in an organism in which they are delivered to peripheral fabrics for participation in cellular folatny metabolism.

Metabolism
L-5-metil-TGF represents the main folatny transported form in a blood plasma. When comparing 0,451 mg of calcium of a levomefolat and 0,4 mg of folic acid, similar mechanisms of metabolism and for other significant folates were installed. Coenzymes of folates are involved in 3 main interfaced a metabolism cycle in cytoplasm of cells. These cycles are necessary for synthesis of thymidine and purines, predecessors of deoxyribonucleic (DNA) and ribonucleic (RNA) of acids, and also for synthesis of methionine from a gomotsistein and transformation of serine into glycine.

Removal
L-5-metil-TGF it is removed by kidneys in not changed look and in the form of metabolites, and also through digestive tract.
Equilibrium concentration
Equilibrium state L-5-metil-TGF in a blood plasma after intake of 0,451 mg of calcium of a levomefolat is reached in 8-16 weeks and depends on its initial concentration. In erythrocytes equilibrium concentration is reached in later terms because of life expectancy of erythrocytes which makes about 120 days.

Indications to use:

The contraception intended , first of all, for women with symptoms of a hormonedependent delay of liquid in an organism. Contraception and treatment of a moderate form of an acne (acne vulgaris) Contraception at women with deficit of folates.
Contraception and treatment of a severe form of a premenstrual syndrome (PMS)

Route of administration and doses:

How to accept Jes Plus
Pill should be taken inside on the order specified on packaging, every day at the same time without chewing, washing down with a small amount of water. Accept on 1 tablet a day continuously within 28 days. Reception of tablets from the following packaging begins right after completion of reception of tablets from the previous packaging. Bleeding of "cancellation", as a rule, begins for 2-3 day after the beginning of reception of inactive tablets and can not come to the end prior to reception of tablets from the following packaging yet.
Beginning of administration of drug of Dzhes®plus
• In the absence of reception of any hormonal contraceptive means last month.
Administration of drug Jes Plus begins in the first day of a menstrual cycle (i.e. in the first day of menstrual bleeding). The beginning of reception for 2-5 day of a menstrual cycle is allowed, but in this case it is recommended to use in addition a barrier method of contraception during the first 7 days of reception of tablets from the first packaging.

• Upon transition from other combined oral contraceptives, a vaginal ring or a contraceptive plaster

It is preferable to begin administration of drug of Dzhes® Plus next day after reception of the last active tablet from the previous packaging, but by no means no later than the next day after a usual 7-day break (for the drugs containing 21 tablets) or after reception of the last inactive tablet (for the drugs containing 28 tablets in packaging). Administration of drug of Dzhes® Plus should be begun in day of removal of a vaginal ring or plaster, but no later than day when the new ring has to be entered or the new plaster is pasted.

• Upon transition from the contraceptives containing only gestagena ("mini-drank", injection forms, an implant), or from the intrauterine contraceptive (Mirren) releasing гестаген.

The woman can pass with "mini-drank" on Dzhes® Plus in any day (without interruption), from an implant or an intrauterine contraceptive with gestageny - in day of its removal, from an injection contraceptive - in day when the following injection has to be made. In all cases it is necessary to use in addition barrier method of contraception during the first 7 days of reception of tablets.

• After abortion in the first trimester of pregnancy.

The woman can begin administration of drug immediately. At observance of this condition the woman does not need additional measures of contraception.

• After the delivery or abortion in the second trimester of pregnancy.

It is recommended to begin administration of drug for 21 - 28 days after the delivery or abortion in the second trimester of pregnancy. If reception is begun later, it is necessary to use in addition barrier method of contraception during the first 7 days of reception of tablets. However, if the sexual contact took place, prior to reception of Dzhes® Plus pregnancy has to be excluded or it is necessary to wait for the first periods.
Reception of the passed tablets

The admission of inactive tablets can be ignored. Nevertheless, they should be thrown out accidentally not to prolong the period of reception of inactive tablets. The following recommendations belong only to the admission of active tablets:

If delay in administration of drug made less than 24 hours, contraceptive protection does not decrease. The woman has to take the passed pill as soon as possible, and following to accept in usual time.

If delay in reception of tablets made more than 24 hours, contraceptive protection can be reduced. Than more tablets are passed, and the admission of tablets is closer to a phase of reception of inactive tablets, the probability of pregnancy is higher.

At the same time it is possible to be guided by the following two basic rules:
• administration of drug never has to be interrupted, more than for 7 days (please, pay attention that the recommended interval of reception of inactive tablets makes 4 days)
• for achievement of adequate suppression гипоталамо - pituitary and ovarian system 7 days of continuous reception of tablets are required.

Respectively, if delay in reception of active tablets made more than 24 hours, it is possible to recommend the following:

• With 1 - го till the 7th day:

The woman has to take the last passed pill at once as soon as she remembers it even if it means reception of two tablets at the same time. She continues to take the following pill in usual time. Besides, during the next 7 days it is necessary to use in addition a barrier method of contraception (for example, condom). If the sexual contact took place within 7 days before the admission of a tablet, it is necessary to consider a possibility of approach of pregnancy.

• From the 8th to the 14th day
The woman has to take the last passed pill at once as soon as she remembers it even if it means reception of two tablets at the same time. She continues to take the following pill in usual time.

Provided that the woman took a pill correctly within 7 days preceding the first passed tablet there is no need for use of additional measures of contraception. Otherwise, and also at the admission of two and more tablets it is necessary to use in addition barrier methods of contraception (for example, condom) within 7 days.

•       From the 15th to the 24th day

The risk of decrease in reliability is inevitable because of the coming phase of reception of inactive tablets. The woman has to adhere strictly to one of two following options. At the same time, if in 7 days preceding the first passed tablet all pill was taken correctly, there is no need to use additional contraceptive methods. Otherwise she needs to use the first of the following schemes and in addition to use a barrier method of contraception (for example, condom) within 7 days.
1. The woman has to take the last passed pill as soon as possible as soon as she remembers (even if it means reception of two tablets at the same time). The following takes a pill in usual time, active tablets in packaging will not end yet. Four inactive tablets should be thrown out and to immediately begin reception of tablets from the following packaging. Bleeding of "cancellation" is improbable, active tablets in the second packaging will not end yet, but the smearing allocations and breakthrough bleedings can be noted during reception of tablets.
2. The woman can also interrupt reception of tablets from the current packaging. Then it has to take a break no more than 4 days, including days of the admission of tablets, and then begin administration of drug from new packaging.

If the woman passed active tablets, and during reception of inactive tablets of bleeding of "cancellation" did not come, it is necessary to make sure of lack of pregnancy.

Recommendations at gastrointestinal frustration
At heavy gastrointestinal frustration absorption can be incomplete therefore it is necessary to take additional contraceptive measures.

If within 3-4 hours after reception of an active tablet there is vomiting, it is necessary to be guided by recommendations at the admission of tablets. If the woman does not want to change the usual scheme of reception and to move the beginning of periods the next day of week, the additional active pill should be taken from other packaging.

How to change cycles or how to delay approach of bleeding of "cancellation"

To delay approach of bleeding, the woman should continue reception of tablets from the following packaging of Dzhes® Plus, having passed inactive tablets from the current packaging. Thus, the cycle can be prolonged, at will, for any term, active tablets from the second packaging will not end yet. Against the background of administration of drug from the second packaging at the woman the smearing allocations or breakthrough uterine bleedings can be noted. Regular reception of Dzhes® Plus then is resumed after the termination of a phase of reception of inactive tablets.

To move the beginning of bleeding of "cancellation" the next day of week, the woman should reduce the following phase of reception of inactive tablets by the desirable number of days. The interval is shorter, the risk is higher that it will have no bleeding of "cancellation", and further there will be smearing allocations and breakthrough bleedings during reception of tablets from the second packaging.

Use for separate groups of patients For children
Efficiency and safety of drug Jes Plus as contraceptive means are studied at women of reproductive age. It is supposed that efficiency and safety of drug at post-pubertal age up to 18 years are similar to that at women after 18 years. Use of drug before menarche is not shown. At elderly
®
Drug Jes Plus is not applied after a menopause. At abnormal liver functions
Drug is contraindicated to use for women with heavy abnormal liver functions.
At renal failures
Drug is contraindicated to use for women with heavy renal failures and at an acute renal failure.

Features of use:

If any of the states, diseases and risk factors provided below are available in
the present, it is necessary to weigh carefully potential risk and the expected advantage of use of drug Jes Plus in each individual case and to discuss it with the woman before she decides to begin reception of this drug. Diseases of cardiovascular system
Results of epidemiological researches indicate existence of interrelation between use the COOK and increase in frequency of development of venous and arterial thromboses and thromboembolisms (such as deep vein thrombosis, thromboembolism of a pulmonary artery, myocardial infarction, cerebrovascular disturbances) at reception of the combined oral contraceptives. These diseases are noted seldom. The risk of development of a venous thromboembolism (VTE) is maximum in the first year of reception of such drugs. The increased risk is present after initial use of the combined oral contraceptives or resuming of use same or the different combined oral contraceptives (after a break between administrations of drug in 4 weeks and more). Data of a large prospective research with participation of 3 groups of patients show that this increased risk is present preferential within the first 3 months.
The general risk of a venous thromboembolism of VTE at the patients accepting the low-dosed combined oral contraceptives (<50 mkg of ethinylestradiol) is two-three times higher, than at nonpregnant patients who do not accept the COOK, nevertheless, this risk remains lower in comparison with risk of VTE at pregnancy and childbirth.
VTE can threaten life or lead to a lethal outcome (in 1-2% of cases). VTE which is shown as a deep vein thrombosis, or an embolism of a pulmonary artery can occur when using of any combined oral contraceptives. Extremely seldom when using of the combined oral contraceptives there is thrombosis of other blood vessels, for example, of hepatic, mesenteric, renal, brain veins and arteries or vessels of a retina. A consensus concerning communication between emergence of these events and use of the combined oral contraceptives is absent.
Symptoms of the deep vein thrombosis (DVT) include the following: unilateral hypostasis of the lower extremity or along a vein of the lower extremity, pain or discomfort in the lower extremity only in vertical position or when walking, local temperature increase in the affected lower extremity, reddening or change of coloring of integuments on the lower extremity.
Symptoms of a thromboembolism of a pulmonary artery (TELA) consist in the following: the complicated or hurried breathing; sudden cough, including with a pneumorrhagia; an acute pain in a thorax which can amplify at a deep breath; feeling of alarm; severe dizziness; the speeded-up or irregular heartbeat. Some of these symptoms (for example, "short wind", "cough") are nonspecific and can be interpreted incorrectly as signs of other more or less heavy events (for example, respiratory infection).
The arterial thromboembolism can lead to a stroke, occlusion of vessels or a myocardial infarction. Symptoms of a stroke are as follows: sudden weakness or anesthesia of the person, upper or lower extremities, especially on the one hand bodies, sudden confusion of consciousness, problem with the speech and understanding; sudden one - or bilateral loss of sight; sudden disturbance of gait, dizziness, loss of balance or coordination of movements; sudden, heavy or long headache for no apparent reason; a loss of consciousness or a syncope with an epileptic seizure or without it. Other signs of occlusion of vessels: sudden pain, puffiness and weak posineniye of extremities, acute abdomen.
Symptoms of a myocardial infarction include: pain, discomfort, pressure, weight, feeling of compression or a raspiraniye in a breast, in a hand or behind a breast; discomfort with irradiation in a back, a cheekbone, a throat, a hand, a stomach; cold sweat, nausea, vomiting or dizziness, strong weakness, alarm or asthma; the speeded-up or irregular heartbeat. The arterial thromboembolism can threaten life or lead to a lethal outcome. The risk of development of thrombosis (venous and/or arterial) and thromboembolisms increases:
- with age;
- at smokers (with increase in quantity of cigarettes or increase in age the risk increases, especially at women 35 years are more senior);
in the presence:
- obesity (index of body weight of more than 30 kg/sq.m);
- the family anamnesis (for example, a venous or arterial thromboembolism ever at close relatives or parents at rather young age). In case of the hereditary or acquired predisposition, the woman has to be examined by the corresponding specialist for the solution of a question of a possibility of administration of drug Jes Plus;
- long immobilization, serious surgical intervention, any operation
on the lower extremities or extensive injury. In these situations it is desirable to stop drug use Jes Plus (in case of the planned operation, at least, in four weeks prior to it) and not to resume reception within two weeks after the termination of an immobilization;
- dislipoproteinemiya;
- arterial hypertension;
- migraines;
- diseases of valves of heart;
- fibrillations of auricles.
The question of a possible role of a varicosity and superficial thrombophlebitis in development of a venous thromboembolism remains disputable.
It is necessary to consider the increased risk of development of thromboembolisms in a puerperal period. Disturbances of peripheric circulation can be also noted at a diabetes mellitus, a system  lupus erythematosus, a hemolitic uraemic syndrome, chronic inflammatory diseases   of intestines (a disease Krone or nonspecific ulcer colitis) and a sickemia.
Increase in frequency and weight of migraine during drug Dzhes®plus use (that can precede cerebrovascular disturbances) can be the basis for the immediate termination of reception of this drug.
The following belongs to the biochemical indicators indicating the hereditary or acquired predisposition to venous or arterial thrombosis: resistance to the activated protein C, a gipergomotsisteinemiya, a lack of antithrombin-III, a lack of protein C, a lack of protein S, anti-phospholipidic antibodies (anti-cardiolipin antibodies, lupus anticoagulant).
At assessment of a ratio of risk and advantage, it is necessary to consider that adequate treatment of the corresponding state can reduce the related risk of thrombosis. Also it is necessary to consider that the risk of thromboses and thromboembolisms at pregnancy is higher, than at reception of the low-dosed oral contraceptives (<0,05 mg of ethinylestradiol). Tumors
The most essential risk factor of development of cancer of neck of uterus is the persistent human papillomavirus infection. There are messages on some increase in risk of development of cancer of neck of uterus at prolonged use the COOK. However communication with reception the COOK is not proved. The possibility of interrelation of these data with screening of diseases of a neck of uterus and is discussed with features of a sexual behavior (more rare use of barrier methods of contraception).
Meta-analysis of 54 epidemiological researches showed that there is a little increased relative risk of development of the breast cancer diagnosed for the women accepting the COOK now (relative risk 1,24). The increased risk gradually disappears within 10 years after the termination of reception of these drugs. Because the breast cancer is noted seldom at women to 40 years, increase in number of diagnoses of a breast cancer at the women accepting the COOK now or accepting recently is insignificant in relation to the general risk of this disease. Its communication with reception the COOK is not proved. Observed increase in risk can be a consequence of careful observation and earlier diagnosis of a breast cancer at the women applying the COOK. At the women ever applying the COOK earlier stages of a breast cancer, than at women, never their applying come to light.
In rare instances against the background of use the COOK development high-quality, and in extremely exceptional cases - malignant new growths of a liver which at certain patients led to life-threatening intra belly bleeding was observed.
At emergence of severe pains in a stomach, increase in a liver or symptoms of intra belly bleeding, it should be considered when carrying out the differential diagnosis.
Tumors can threaten life or lead to a lethal outcome. Other states
Clinical trials showed lack of influence of a drospirenon on potassium concentration in plasma of patients with a slight and moderate renal failure. Nevertheless, at patients with a renal failure and initial potassium concentration on the upper bound of norm it is impossible to exclude risk of development of a hyperpotassemia against the background of reception of the medicines leading to a potassium delay in an organism.
At women with a gipertriglitseridemiya (or existence of this state in the family anamnesis)
increase in risk of development of pancreatitis is possible during reception the COOK.
In spite of the fact that small increase in the ABP was described at many women,
accepting the COOK, clinically significant increases were noted seldom. Nevertheless, if during administration of drug Jes Plus develops permanent, clinically significant increase in the ABP, it is necessary to cancel this drug and to begin treatment of arterial hypertension. Administration of drug can be continued if by means of hypotensive therapy the ABP normal values are reached.
The following states as it was reported, develop or worsen both during pregnancy, and at reception the COOK, but their communication with reception the COOK is not proved: jaundice and/or the itch connected with a cholestasia; formation of stones in a gall bladder; porphyria; system lupus erythematosus; gemolitiko-uraemic syndrome; Sydenham's chorea; herpes of pregnant women; the hearing loss connected with an otosclerosis. Disease cases Krone and ulcer colitis against the background of use the COOK are also described.
At women with hereditary forms of a Quincke's disease exogenous estrogen can cause or worsen symptoms of a Quincke's disease.
Acute or chronic abnormal liver functions can demand the termination of administration of drug Jes Plus until indicators of function of a liver do not return to norm. Recurrent cholestatic jaundice which develops for the first time in time
pregnancy or the previous reception of sex hormones, Jes Plus demands the termination of administration of drug.
Though the COOK can exert impact on resistance to insulin and tolerance to glucose, the patients with a diabetes mellitus using drug Jes Plus have no need of change of the therapeutic mode. Nevertheless, women with a diabetes mellitus have to be observed carefully during reception of this drug.
The hloazma can sometimes develop, especially women with existence in the anamnesis have hloazma of pregnant women. Women with tendency to a hloazma during administration of drug Jes Plus have to avoid long stay to the sun and influences of ultraviolet radiation.
Folates can mask shortage of vitamin B 12. Preclinical data on safety
The preclinical data obtained during the standard researches for detection of toxicity at multiple dose of doses of drug, and also genotoxicity, cancerogenic potential and toxicity for reproductive system do not indicate existence of extra risk for the person. Nevertheless, it is necessary to remember that sex hormones can promote growth of some hormonedependent fabrics and tumors. The preclinical data obtained during the standard researches of a levomefolinat of calcium for detection of toxicity at multiple dose of doses of drug, and also genotoxicity and toxicity for reproductive system do not indicate existence of extra risk for the person. Laboratory tests
Administration of drug Jes Plus can influence results of some laboratory tests, including indicators of function of a liver, kidneys, a thyroid gland, adrenal glands, concentration of transport proteins in plasma, indicators of carbohydrate metabolism, parameters of a blood coagulation and fibrinolysis. Changes usually do not overstep the bounds of normal values. Drospirenon increases activity of a renin of plasma and concentration of Aldosteronum that is connected with its antimineralokortikoidny effect.
There is a theoretical possibility of increase in potassium concentration in a blood plasma for the women receiving drug Jes Plus along with other drugs which can increase the content of potassium in a blood plasma. Antagonists of receptors of angiotensin II, kaliysberegayushchy diuretics and antagonists of Aldosteronum treat these drugs. However in the researches estimating interaction of a drospirenon with inhibitors of an angiotensin-converting enzyme (APF) or indometacin reliable distinction between potassium concentration in plasma in comparison with placebo was not revealed.
Decrease in efficiency
Efficiency of drug Jes Plus can be reduced in the following cases: at the admission of tablets, at vomiting and diarrhea or as a result of medicinal interaction. Frequency and expressiveness of menstrualnopodobny bleedings.
Against the background of administration of drug Jes Plus irregular (acyclic) bloody allocations and bleedings from a vagina (the smearing bloody allocations or "breakthrough" uterine bleedings), especially within the first months of use can be noted. Therefore assessment of any irregular bleedings has to be carried out after the period of adaptation making about 3 cycles.
If irregular bleedings repeat or develop after the previous regular cycles, it is necessary to conduct careful examination for an exception of malignant new growths or pregnancy.
At some women during a break in reception of tablets bleeding of "cancellation" can not develop. If drug Jes Plus was accepted according to recommendations, it is improbable that the woman is pregnant. Nevertheless, at irregular use of drug Jes Plus and absence of two in a row bleedings of "cancellation", administration of drug cannot be continued to a pregnancy exception. Medical examinations
Before the beginning or resuming of use of drug it is necessary to study the anamnesis of life, the family anamnesis of the woman, to conduct careful physical examination (including measurement of the ABP, heart rate, definition of an index of body weight, inspection of mammary glands), gynecologic inspection, a cytologic research of a neck of uterus (the test across  Papanikolau), to exclude pregnancy. When resuming administration of drug Jes Plus the volume of additional researches and frequency of control surveys are defined individually, but at least 1 time in 6 months.

It is necessary to warn the woman that Jes Plus does not protect drug from HIV infection and other diseases, sexually transmitted! Influence on ability of control of vehicles and mechanisms.
It was not reported about cases of adverse influence of drug Jes Plus on the speed of psychomotor reactions; researches on studying of influence of drug on the speed of psychomotor reactions were not conducted.

Interaction with other medicines:

Interaction of oral contraceptives with other medicines can lead to "breakthrough" uterine bleedings and/or decrease in reliability of contraception.

The interactions leading to decrease in efficiency of drug Jes Plus Vliyaniye on hepatic metabolism: use of the drugs inducing microsomal enzymes of a liver can lead to increase of clearance of sex hormones. Treat such medicines: Phenytoinum, barbiturates, Primidonum, carbamazepine, rifampicin, it is possible also - окскарбазепин, топирамат, фелбамат, the griseofulvin and drugs containing the St. John's Wort which is made a hole. HIV protease inhibitors (for example, ритонавир) and nenukleozidny inhibitors of the return transcriptase (for example, not Virapinum) and their combinations also potentially can influence metabolism in a liver.
Influence on enterohepatic recirculation: according to separate researches, some antibiotics (for example, penicillin and tetracycline) can reduce enterohepatic recirculation of estrogen, thereby reducing concentration of ethinylestradiol.
During administration of drugs, influencing microsomal enzymes of a liver, and within 28 days after their cancellation it is necessary to apply a barrier method of contraception in addition.
 
During reception of antibiotics (except for rifampicin and griseofulvin) and within 7 days after their cancellation it is necessary to apply a barrier method of contraception in addition. If the period of use of a barrier method of contraception comes to an end later, than gormonosoderzhashchy pink tablets in packaging, it is necessary to miss reception of the remained auxiliary light orange tablets and to begin administration of drug Jes Plus from new packaging without interruption in reception of tablets. The interactions reducing efficiency of calcium of a levomefolat Influence on metabolism of folates: some medicines reduce concentration of folates in blood or reduce efficiency of calcium of a levomefolat by digidrofolatreduktaza enzyme inhibition (for example, a methotrexate, Trimethoprimum, Sulfasalazinum and Triamterenum) or due to reduction of absorption of folates (for example, холестирамин) or at the expense of unknown mechanisms (for example, antiepileptic drugs: carbamazepine, Phenytoinum, phenobarbital, Primidonum and valproic acid).
Influence on metabolism COOK (inhibitors of enzymes)
The main metabolites of a drospirenon are formed in plasma without participation of system of P450 cytochrome. Therefore influence of inhibitors of system of P450 cytochrome on metabolism of a drospirenon is improbable.
 Influence the COOK or calcium of a levomefolat on activity of other medicines
The COOK can influence metabolism of other drugs that leads to increase (for example, cyclosporine) or to decrease (for example, ламотриджин) their concentration in a blood plasma and fabrics.
On the basis of interaction researches, and also researches it is possible to conclude with participation of the female volunteers accepting омепразол, симвастатин and midazolam as the studied substrates that influence of a drospirenon in a dose of 3 mg on metabolism of other medicines is improbable.
Folates can change pharmacokinetics or a pharmacodynamics of some drugs influencing exchange of folates, for example, of antiepileptic drugs (Phenytoinum), a methotrexate or Pyrimethaminum that can be followed by decrease (generally reversible, under a condition increase in a dose of the drug influencing exchange of folates) their therapeutic action. Purpose of folates against the background of treatment by such drugs is recommended, mainly, for decrease in toxicity of the last.

Contraindications:

Drug Jes Plus is contraindicated in the presence of any of the states/diseases which are listed below. If any of these states / diseases develop for the first time against the background of reception, drug has to be immediately cancelled.
• Thrombosis (venous and arterial) and a thromboembolism now or in the anamnesis (including a deep vein thrombosis, a thromboembolism of a pulmonary artery, a myocardial infarction, a stroke), cerebrovascular disturbances.
• The states preceding thrombosis (including, the tranzitorny ischemic attacks, stenocardia) now or in the anamnesis.
• Existence of the multiple or expressed risk factors of venous or arterial thrombosis.
Migraine with focal neurologic symptoms now or in the anamnesis.
• A diabetes mellitus with vascular complications.
• A liver failure and a serious illness of a liver (before normalization of hepatic tests).
• Heavy and/or acute renal failure.
• Liver tumors (high-quality or malignant) now or in the anamnesis.
• The revealed hormonedependent malignant new growths (including generative organs or mammary glands) or suspicion on them.
• Bleeding from a vagina of not clear genesis.
• Pregnancy or suspicion on it.
• Feeding period breast.
• Hypersensitivity or intolerance of any of drug components Jes Plus.
• Drug Jes Plus contains lactose therefore it is contraindicated to patients with a rare hereditary lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption.

With care
It is necessary to estimate potential risk and the expected advantage of use of drug
Jes Plus in each individual case in the presence of the following diseases / states and risk factors:
• Risk factors of development of thrombosis and thromboembolisms: smoking, obesity, a dislipoproteinemiya, controlled arterial hypertension, migraine without focal neurologic symptomatology, uncomplicated defects of valves of heart, genetic predisposition to thrombosis (thromboses, a myocardial infarction or disturbance of cerebral circulation at young age at any of the immediate family);
• Other diseases at which disturbances of peripheric circulation can be noted: a diabetes mellitus without vascular complications, a system lupus erythematosus, a gemolitiko-uraemic syndrome, a disease Krone and ulcer colitis, a sickemia, phlebitis of superficial veins;
• Hereditary Quincke's disease;
• Gipertriglitseridemiya;
• The liver diseases which are not relating to contraindications (see. "Contraindications");
• The diseases which for the first time arose or aggravated during pregnancy or against the background of the previous reception of sex hormones (for example, the jaundice and/or an itch connected with a cholestasia, a cholelithiasis, an otosclerosis with deterioration in hearing, a porphyria, herpes of pregnant women, Sydenham's trochee);
• Puerperal period.
Use at pregnancy and in the period of a lactation
Pregnancy
Drug is contraindicated during pregnancy. If pregnancy comes to light during administration of drug Jes Plus, drug should be cancelled at once. Data on results of administration of drug Jes Plus during pregnancy are limited, and do not allow to draw any conclusions on a negative impact of drug to pregnancy, health of a fruit and the newborn child. At the same time, extensive epidemiological researches did not reveal the increased risk of defects of development in the children born by the women accepting the COOK before pregnancy or teratogenic action in cases
reception the COOK on imprudence in early durations of gestation. Specific epidemiological researches concerning drug Jes Plus were not conducted. Lactation
Drug is contraindicated during feeding by a breast. Reception the COOK can reduce amounts of breast milk and change its structure therefore their use is not recommended before the breastfeeding termination. A small amount of sex hormones and/or their metabolites can be removed with milk, however there is no confirmation of their negative impact on health of the child.

Overdose:

About drug overdose cases Jes Plus it was not reported.
Symptoms which can be noted at overdose: the nausea, vomiting smearing bloody allocations from a vagina or a metrorrhagia (is more often at young women). There is no specific antidote, it is necessary to carry out a symptomatic treatment. Calcium левомефолат and its metabolites are identical to the folates which are a part of natural products which daily consumption does not do harm to an organism. Reception of calcium of a levomefolat in a dose of 17 mg / дн (the dose is 37 times higher contained in 1 tablet of drug Jes Plus) within 12 weeks was well transferred.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated. Set: on 24 active combined tablets and 4 auxiliary vitamin tablets place in a blister strip packaging (blister) from multilayer material - PVC-PE-EVOH-PE-PCTFE and seal aluminum foil. On 1 blister (set) paste directly in the cardboard book folding bed. On 1 or 3 books folding beds with the pasted block of self-adhesive stickers for registration of a calendar of reception together with the application instruction seal in a transparent film. In case of 3 sets the packaging sticker is applied on a film.