Jess plus pill №28

Latin name of the drug Jess ^® A plus

Yaz^® plus

ATH

Pharmacological group

• Nosological classification (ICD-10)

Dosage form and composition

Description of the dosage form

Active Combination Tablet: round, biconvex, film-coated pink, on one side with “Z +” embossed in a regular hexagon.

Vitamin Auxiliary Tablet: round, biconvex, film-coated in light orange color, on one side with “M +” embossed in a regular hexagon.

Mechanism of action

pharmachologic effect - contraceptive.

Pharmacodynamics

Jess^® Plus - a low-dose monophasic oral combined estrogen-gestagenic contraceptive drug, which includes active pills and auxiliary vitamin pills containing Calcium levofemolat.

Contraceptive effect of the drug Jess^® Plus, mainly due to the suppression of ovulation and increase the viscosity of cervical mucus.

In women taking combined oral contraceptives (COCs), the cycle becomes more regular, soreness, intensity and duration of menstrual-like bleeding decrease, resulting in a reduced risk of iron deficiency anemia. There is also evidence of a reduction in the risk of endometrial and ovarian cancer.

Drospirenone contained in the preparation of Jes^® Plus, it has anti-mineralocorticoid action and helps prevent hormone-dependent fluid retention, which can manifest itself in weight loss and a reduced likelihood of peripheral edema. Drospirenone also has antiandrogenic activity and helps reduce acne (acne), oily skin and hair.This effect of drospirenone is similar to the action of natural Progesterone, produced in the female body. This should be considered when choosing a contraceptive, especially for women with hormone-dependent fluid retention, as well as women with acne and seborrhea. If used correctly, the Pearl Index (a measure reflecting the number of pregnancies in 100 women using a contraceptive during the year) is less than 1. If you skip pills or misuse, the Pearl index may increase.

The acidic form of calcium levomefolata, in its structure is identical to the natural L-5-methyltetrahydrofolate (L-5-methyl-THF), the main folate form contained in food. The average concentration in the blood plasma of people who do not use food enriched with folic acid is about 15 nmol / l.

Levomefolat, unlike folic acid, is a biologically active form of folate. Because of this, it is absorbed better than folic acid. Levomefolat is indicated to meet the increased need and provide the necessary folate content in the woman’s body during pregnancy and during breastfeeding. The introduction of calcium levomefolata in the oral contraceptive reduces the risk of developing a defect in the fetal neural tube if a woman unexpectedly becomes pregnant immediately after discontinuation of the use of contraception (or in very rare cases when using oral contraception).

Pharmacokinetics

Drospirenone

Absorption. When taken orally, drospirenone is rapidly and almost completely absorbed. After a single oral administration C_max Drospirenone in blood plasma, equal to 35 ng / ml, is achieved in 1–2 hours. Bioavailability ranges from 76 to 85%. Compared with taking drospirenone on an empty stomach, eating does not affect its bioavailability.

Distribution. After oral administration, there is a two-phase decrease in serum level of the drug with T_1/2 respectively (1.6 ± 0.7) h and (27.0 ± 7.5) h. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CGC). Only 3-5% of the total concentration of the substance in the serum is present as a free hormone. An ethinyl estradiol-induced increase in SHBG does not affect the binding of drospirenone to plasma proteins. Average apparent v_d makes (3,7 ± 1,2) l / kg.

Metabolism. After oral administration, drospirenone is extensively metabolized. Most plasma metabolites are represented by the acidic forms of drospirenone, which are formed without the involvement of the cytochrome P450 system. The cytochrome P4503A4 isoenzyme participates to a minimum extent in the metabolism of drospirenone, drospirenone is able to reduce the concentration of the enzyme in the blood plasma and the activity of cytochrome P4501A1, P4502С9 and P4502С19in vitro.

Inference. The rate of metabolic clearance of drospirenone in plasma is (1.5 ± 0.2) ml / min / kg.In unchanged form, drospirenone is excreted only in trace amounts. The metabolites of drospirenone are excreted through the gastrointestinal tract and kidneys in a ratio of approximately 1.2: 1.4. T_1/2 for excretion of metabolites - about 40 hours.

Equilibrium concentration. During the first course of use of the drug C_ssDrospirenone in plasma about 60 ng / ml is achieved from the 7th to the 14th day of the drug. There was an increase in the concentration of drospirenone in plasma approximately 2-3 times (due to cumulation), which was determined by the ratio T_1/2 in the terminal phase and dosing interval. A further increase in the concentration of drospirenone in plasma is noted after 1-6 courses of use of the drug, after which there is no increase in concentration.

Impaired renal function. Plasma concentration of drospirenone when reaching an equilibrium state was comparable in women with mild renal dysfunction (Cl creatinine - 50–80 ml / min) and in women with intact kidney function (Cl creatinine> 80 ml / min). However, in women with moderate renal impairment (creatinine Cl - 30–50 ml / min), the average concentration of drospirenone in the blood plasma was 37% higher than in patients with preserved renal function. No marked changes in the concentration of potassium in the blood plasma when using drospirenone.

Liver dysfunction. In women with moderate hepatic impairment (Child-Pugh grade B), AUC is comparable to that in healthy women with similar C values._max in the phases of absorption and distribution. T_1/2drospirenone in patients with moderate liver dysfunction was 1.8 times higher than in healthy volunteers with intact liver function.

In patients with moderately impaired liver function, there was a decrease in the clearance of drospirenone by about 50% compared with women with intact liver function, and there were no differences in plasma potassium concentrations in the studied groups. Changes in the concentration of potassium are not observed even in the case of a combination of factors predisposing to its increase (concomitant diabetes mellitus or treatment with spironolactone).

Ethinyl Estradiol

Absorption. After oral administration, ethinyl estradiol is rapidly and completely absorbed. C_max - about 33 pg / ml - achieved within 1–2 hours. The drug is subjected to a first-pass metabolism in the liver, its bioavailability when taken orally is on average about 60%. Simultaneous food intake in some cases is accompanied by a decrease in the bioavailability of ethinyl estradiol by 25%.

Distribution. The concentration of ethinyl estradiol in the blood plasma decreases in 2 phases, T_1/2Ethinyl estradiol in the second phase is about 24 hours. Ethinyl estradiol has a nonspecific but strong binding to plasma albumin (about 98.5%) and induces an increase in plasma concentration of SHBG. Estimated V_d makes about 5 l / kg.

Metabolism. Ethinyl estradiol undergoes presystemic conjugation in the liver and in the mucosa of the small intestine. The main metabolic pathway of ethinyl estradiol is aromatic hydroxylation with the formation of numerous metabolites that are in both bound and unbound state.The rate of elimination of ethinyl estradiol is about 5 ml / min / kg.

Inference. Ethinyl estradiol is derived only in the form of metabolites by the kidneys and through the gastrointestinal tract in the ratio 4: 6 with T_1/2 about 24 hours

Equilibrium concentration. The equilibrium state is reached in the second half of the course of treatment, the concentration of ethinyl estradiol in the blood plasma increases by about 1.4-2.1 times.

Ethnicity. The effect of ethnicity on pharmacokinetic parameters was studied in single and multiple dosing studies of drospirenone and ethinyl estradiol in healthy women of the European race, as well as in Japanese women. The effect of ethnicity on the pharmacokinetic parameters of drospirenone and ethinyl estradiol has not been established.

Calcium levomefolat

Absorption. After ingestion of calcium, levomefolat is rapidly absorbed and incorporated into the body folate pool. After a single dose of 0.451 mg of calcium levomefolat after 0.5–1.5 hours C_max becomes 50 nmol / l higher than the initial concentration.

Distribution. Folate pharmacokinetics has a biphasic character: folate pool is determined with a fast and slow metabolism. A fast metabolized pool is likely to represent folate re-ingested, which is consistent with T_1/2 calcium levomefolat, which is about 4-5 hours after a single dose of 0.451 mg. A slow metabolism pool reflects polyglutamate folate conversion, T_1/2 which is about 100 days.Inbound folates and folates, going through the enterohepatic cycle, maintain a constant concentration of L-5-methyl-THF in the body.

L-5-methyl-THF is the main form of folate in the body, in which they are delivered to peripheral tissues to participate in cellular folate metabolism.

Metabolism. L-5-methyl-THF is the main folate transported form in plasma. When comparing 0.451 mg of calcium levomefolata and 0.4 mg of folic acid, similar mechanisms of metabolism were established for other significant folates. Folate coenzymes are involved in 3 major conjugated metabolic cycles in the cytoplasm of cells. These cycles are necessary for the synthesis of thymidine and purines, precursors of deoxyribonucleic (DNA) and ribonucleic (RNA) acids, as well as for the synthesis of methionine from homocysteine ​​and the conversion of serine to Glycine.

Inference. L-5-methyl-THF is excreted by the kidneys unchanged and in the form of metabolites, as well as through the gastrointestinal tract.

Equilibrium concentration. The equilibrium state of L-5-methyl-THF in the blood plasma after ingestion of 0.451 mg of calcium levomefolata is achieved in 8–16 weeks and depends on its initial concentration. In red blood cells C_ss is achieved at a later date due to the life span of red blood cells, which is about 120 days.

Indications drug jess^® A plus

contraception, intended primarily for women with symptoms of hormone-dependent fluid retention in the body;

contraception and treatment of moderate acne(acne vulgaris);

contraception in women with folate deficiency;

contraception and treatment of severe premenstrual syndrome (PMS).

Contraindications

Drug jess^® Plus is contraindicated in the presence of any of the conditions / diseases listed below. If any of these conditions / diseases develop for the first time while receiving, the drug should be immediately canceled:

hypersensitivity or intolerance to any of the components of the drug Jess^® A plus;

Thrombosis (venous and arterial) and thromboembolism at present or in history (including deep vein thrombosis, thromboembolism of the pulmonary artery, myocardial infarction, stroke), cerebrovascular disorders;

the conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) at present or in history;

the presence of multiple or pronounced risk factors for venous or arterial thrombosis;

migraine with focal neurological symptoms now or in history;

diabetes with vascular complications;

liver failure and severe liver disease (until normalization of liver tests);

severe and / or acute renal failure ;

liver tumors (benign or malignant) now or in history;

identified hormone-dependent malignant neoplasms (including the genitals or mammary glands) or suspicion of them;

bleeding from the vagina of unknown origin;

pregnancy or suspicion of it;

breastfeeding period;

the presence of rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

The potential risk and expected benefit of using Jess should be assessed.^® Plus in each individual case in the presence of the following diseases / conditions and risk factors:

thrombosis risk factors and venous thromboembolism: smoking, obesity, dislipoproteinemia controlled hypertension, migraine without focal neurological symptoms, uncomplicated valvular disease, a genetic predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age, someone from the next relatives);

other diseases in which disorders of the peripheral circulation can be observed: diabetes mellitus without vascular complications, systemic lupus erythematosus, hemolytic uremic syndrome, Crohn's disease and ulcerative colitis, sickle cell anemia, phlebitis of superficial veins; hereditary angioedema;

hypertriglyceridemia;

liver disease, not related to contraindications (see "Contraindications");

diseases first arisen or aggravated during pregnancy or against the background of previous intake of sex hormones (for example jaundice and / or itching associated with cholestasis, cholelithiasis, otosclerosis with impaired hearing, porphyria, herpes of pregnant women, Sydenhamma chorea);

postpartum period.

Use during pregnancy and lactation

Pregnancy

The drug is contraindicated during pregnancy. If pregnancy is detected while taking the drug Jess^® Plus, the drug should be immediately lifted. Data on the results of taking the drug Jess^® Plus during pregnancy is limited, and do not allow to draw any conclusions about the negative impact of the drug on pregnancy, the health of the fetus and the newborn child. At the same time, extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who took COCs before pregnancy or are teratogenic in cases of COC carelessness in the early stages of pregnancy. Specific epidemiological studies on the drug Jes^® Plus was not carried out.

Lactation

The drug is contraindicated during lactation. Taking COCs can reduce the amount of breast milk and alter its composition, so their use is not recommended until breastfeeding is stopped. A small amount of sex hormones and / or their metabolites may be excreted in milk, but there is no evidence of their negative impact on the health of the child.

Side effects

The most common adverse reactions reported in connection with the use of the drug Jes^®, the following: nausea, pain in the mammary glands, irregular uterine bleeding, bleeding from the genital tract of unspecified genesis (more than 3% of women using the drug according to the indications "Contraception" and "Contraception and treatment of the moderate form of acne(acne vulgaris)": Nausea, pain in the mammary glands, irregular uterine bleeding (more than 10% of women using the drug as indicated by" Contraception and treatment of severe premenstrual syndrome (PMS). "

Serious adverse reactions are arterial and venous thromboembolism. The table below shows the incidence of adverse reactions reported in clinical trials of Jess drugs.^® and jess^® Plus, according to the testimony "Contraception", as well as according to the testimony "Contraception and treatment of moderate forms of acne(acne vulgaris)"(N = 3565) and" Contraception and treatment of severe premenstrual syndrome (PMS) "(N = 289) for the drug Jes^®. Within each group, selected depending on the frequency of occurrence, adverse reactions are presented in order of decreasing severity. In terms of frequency, they are divided into: developing often (≥1 / 100 and <1/10); infrequently (≥1 / 1000 and <1/100) and rarely (≥1 / 10000 and <1/1000). For additional adverse reactions identified only in the process of post-marketing observations, and for which it was not possible to estimate the frequency of occurrence, the “frequency is not known” is indicated.

Table

* Approximate frequency of epidemiological studies covering the KOC group. Frequency bordered on very rare.

* Venous or arterial thromboembolism includes the following nosological units: peripheral deep vein occlusion, thrombosis, and pulmonary vascular embolism / occlusion, thrombosis, embolism, and myocardial / cerebral infarction and hemorrhagic stroke.

¹ The frequency of cases in the course of studies evaluating PMS was very frequent -> 1/10

² The frequency of cases in the course of studies evaluating PMS was frequent - ≥1 / 100

For venous and arterial thromboembolism, migraine, see also "Contraindications" and "Special instructions".

Adverse events were classified using the MedDRA (Medical Dictionary of Regulatory Activities) dictionary. Different MedDRA terms, reflecting the same symptom, were grouped together and presented as the only adverse reaction, in order to avoid weakening or blurring the true effect.

Additional Information

The following are the side reactions with a very rare occurrence or delayed symptoms, which are believed to be associated with taking drugs from the COC group (see also "Contraindications" and "Special Instructions").

Tumors

- the frequency of diagnosis of breast cancer in women taking COCs is slightly increased. Due to the fact that breast cancer is rarely observed in women under 40 years old, an increase in the number of breast cancer diagnoses in women taking COCs is insignificant relative to the overall risk of the disease;

- liver tumors (benign and malignant).

Other states

- erythema nodosum;

- hypertriglyceridemia (increased risk of pancreatitis while taking COCs);

- increase in blood pressure;

- conditions that develop or worsen while taking COCs, but their relationship has not been proven: jaundice and / or itching associated with cholestasis; the formation of gallstones; porphyria;

- Systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea, herpes pregnant, hearing loss associated with otosclerosis;

- in women with hereditary angioedema, estrogen administration may cause or aggravate its symptoms;

- abnormal liver function;

- changes in glucose tolerance or the effect on peripheral insulin resistance;

- Crohn's disease, ulcerative colitis;

- chloasma;

- hypersensitivity (including symptoms such as rash, urticaria).

Interaction. The interaction of oral contraceptives with other drugs (enzyme inducers, some antibiotics) can lead to breakthrough bleeding and / or a decrease in contraceptive effectiveness (see. "Interaction").

Interaction

The interaction of oral contraceptives with other drugs can lead to breakthrough uterine bleeding and / or decrease the reliability of contraception.

The interactions leading to a decrease in the effectiveness of the drug Jes^® A plus

Effect on hepatic metabolism. The use of drugs that induce liver microsomal enzymes, can lead to an increase in the clearance of sex hormones.Such drugs include: phenytoin, barbiturates, primidone, Carbamazepine, rifampicin, possibly also oxcarbazepine, topiramate, felbamate, Griseofulvin, and preparations containing St. John's wort. HIV protease inhibitors (for example, ritonavir) and non-nucleoside reverse transcriptase inhibitors (for example, nevirapine) and their combinations also have the potential to affect liver metabolism.

Effects on enterohepatic recirculation. According to separate researches, some antibiotics (for example penicillins and tetracycline) can reduce enterohepatic recirculation of estrogen. thereby reducing the concentration of ethinyl estradiol.

During the taking of drugs that affect the microsomal liver enzymes, and within 28 days after their withdrawal, a barrier method of contraception should be additionally used.

During the reception of antibiotics (with the exception of rifampicin and griseofulvin) and within 7 days after their cancellation, a barrier method of contraception should be additionally used. If the period of use of the barrier method of contraception ends later than the hormone-containing pink pills in the package, you should skip taking the remaining auxiliary light-orange pills and start taking the drug Jes^® Plus from the new packaging without interruption in taking the pills.

Interactions that reduce the effectiveness of calcium levomefolata

Effect on folate metabolism. Some medications reduce the concentration of folate in the blood or reduce the effectiveness of calcium levomefolata by inhibiting the enzyme dihydrofolate reductase (for example, Methotrexate, trimethoprim,sulfasalazine and triamteren) or by reducing folate absorption (for example, cholestyramine) or by unknown mechanisms (for example, antiepileptic drugs: carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid).

Effect on COC metabolism (enzyme inhibitors). The major metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of cytochrome P450 inhibitors on the metabolism of drospirenone is unlikely.

The effect of COC or calcium levomefolata on the activity of other drugs

COCs can affect the metabolism of other drugs, which leads to an increase (for example, cyclosporine) or a decrease (for example, lamotrigine) in their concentration in blood plasma and tissues.

Based on research interactions, as well as studies involving female volunteers who take Omeprazole, Simvastatin, and midazolam as the substrates studied, it can be concluded that the effect of drospirenone in a dose of 3 mg on the metabolism of other drugs is unlikely.

Folates may alter the pharmacokinetics or pharmacodynamics of certain drugs that affect folate metabolism, such as antiepileptic drugs (phenytoin), methotrexate, or pyrimethamine, which may be accompanied by a decrease (mainly reversible, subject to an increase in the dose affecting the folate metabolism of the drug) of their therapeutic effect. The appointment of folate during treatment with such drugs is recommended mainly to reduce the toxicity of the latter.

Dosage and administration

Inside in the order indicated on the packaging, every day at approximately the same time, without chewing, with a small amount of water.

Take 1 tab. per day, continuously, for 28 days. Taking the pills from the next pack begins immediately after the end of the previous one.

Start taking the drug Jess^®A plus

Taking the drug jess^®Plus starts on the first day of the menstrual cycle (i.e., on the first day of the menstrual bleeding).

Recommendations in case of vomiting and diarrhea

In case of vomiting or diarrhea up to 4 hours after taking the pills, absorption may not be complete, and additional measures should be taken to prevent unwanted pregnancy.

Use in certain groups of patients

Children. Efficacy and safety of the drug Jess^®Plus as a contraceptive studied in women of reproductive age. It is assumed that the efficacy and safety of the drug in post-pubertal age up to 18 years of age are similar to those in women over 18 years of age. The use of the drug before the onset of menarche is not shown.

Elderly patients. Drug jess^® Plus does not apply after menopause.

Liver dysfunction. The drug is contraindicated for use in women with severely impaired liver function.

Impaired renal function. The drug is contraindicated for use in women with severe impaired renal function and in acute renal failure.

Overdose

Cases of drug overdose Jess^® Plus not reported.

Symptoms: nausea, vomiting, spotting from the vagina, or metrorrhagia (more often in young women).

Treatment: there is no specific antidote, symptomatic treatment should be carried out. Calcium levomefolat and its metabolites are identical to folates, which are part of natural products, the daily consumption of which does not harm the body. Calcium levomefolata at a dose of 17 mg per day (the dose is 37 times higher than that contained in 1 table. Of the drug Jess^® Plus) for 12 weeks was well tolerated.

special instructions

If any of the conditions, diseases, and risk factors listed below are presently present, the potential risk and the expected benefits of using the drug should be carefully weighed.^® Plus in each individual case and discuss it with a woman before she decides to start taking this drug.

Diseases of the cardiovascular system

The results of epidemiological studies indicate a relationship between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders). These diseases are rare.

The risk of venous thromboembolism (VTE) is maximum in the first year of taking such drugs. Increased risk is present after the initial use of the COC or the resumption of use of the same or different COCs (after a break between taking the drug in 4 weeks or more).Data from a large prospective study involving 3 groups of patients show that this increased risk is predominantly present during the first 3 months.

The overall risk of developing VTE in patients taking low-dose COCs (<50 μg of ethinyl estradiol) is 2–3 times higher than in non-pregnant patients who do not take COC, however, this risk remains lower compared to the risk of VTE during pregnancy and childbirth.

VTE can be life threatening or fatal (1–2% of cases). VTE, which is manifested as deep vein thrombosis or pulmonary embolism, can occur with any COC. Thrombosis of other blood vessels, such as the hepatic, mesenteric, renal, cerebral veins and retinal arteries or vessels, is extremely rare with COCs. There is no consensus regarding the relationship between the occurrence of these events and the use of KOC.

Symptoms of deep vein thrombosis (DVT) include the following: one-sided swelling of the lower limb or along the vein of the lower limb, pain or discomfort in the lower limb only in a vertical position or when walking, local temperature increase in the affected lower limb, redness or change in skin color on the lower limbs.

The symptoms of pulmonary thromboembolism (pulmonary embolism) are as follows: difficulty breathing or rapid breathing; sudden cough, incl. with hemoptysis: acute chest pain, which may worsen with a deep breath; anxiety: severe dizziness; rapid or irregular heartbeat.Some of these symptoms (for example, shortness of breath, cough) are nonspecific and can be interpreted incorrectly as signs of other more or less severe events (for example, an infection of the respiratory tract).

Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction. The symptoms of a stroke include the following: sudden weakness or loss of sensitivity of the face, upper or lower limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden one or two-sided vision loss; sudden gait disturbance, dizziness, loss of balance or coordination of movements; sudden severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without epileptic seizures. Other signs of vascular occlusion are: sudden pain, swelling and weak blue in the limbs, acute abdomen.

Symptoms