Instructions for use YARINA®PLUS

Compound

Pharmacodynamics

Yarina® Plus is a low-dose monophasic oral combined estrogen-progestogen contraceptive drug, including active tablets and auxiliary vitamin tablets containing calcium levomefolate.

The contraceptive effect of Yarina® Plus is mainly achieved by suppressing ovulation and increasing the viscosity of cervical mucus. In women taking COCs, the cycle becomes more regular, the pain, intensity and duration of menstrual bleeding decrease, resulting in a reduced risk of iron deficiency anemia. There is also evidence of a reduced risk of endometrial and ovarian cancer.

Drospirenone, contained in Yarina® Plus, has an antimineralocorticoid effect and helps prevent hormone-dependent fluid retention, which can manifest itself in weight loss and a decrease in the likelihood of peripheral edema. Drospirenone also has antiandrogenic activity and helps reduce acne (blackheads), oily skin and hair. This effect of drospirenone is similar to the effect of natural progesterone produced in the female body. This should be taken into account when choosing a contraceptive, especially for women with hormone-dependent fluid retention, as well as women with acne and seborrhea. When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using a contraceptive during the year) is less than 1. If pills are missed or used incorrectly, the Pearl index may increase.

Calcium levomefolate. The acid form of calcium levomefolate is structurally identical to naturally occurring L-5-methyltetrahydrofolate (L-5-methyl-THF), the main form of folate found in food. The average concentration in the blood plasma of people who do not consume foods fortified with folic acid is about 15 nmol/l.

Levomefolate, unlike folic acid, is a biologically active form of folate. Thanks to this, it is absorbed better than folic acid. Levomefolate is indicated to meet the increased need and ensure the necessary folate content in a woman’s body during pregnancy and lactation. The addition of calcium levomefolate to COCs reduces the risk of developing a neural tube defect if a woman becomes unexpectedly pregnant immediately after stopping 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 dose, the Cmax of drospirenone in the blood plasma, equal to 37 ng/ml, is achieved after 1–2 hours. Bioavailability ranges from 76 to 85%. Compared to taking drospirenone on an empty stomach, food intake does not affect its bioavailability.

Distribution. Drospirenone binds to serum albumin and does not bind to SHBG or corticosteroid binding globulin (CBG). Only 3–5% of the total concentration of the substance in serum is present as a free hormone, 95–97% is nonspecifically bound to albumin. The increase in SHBG induced by ethinyl estradiol does not affect the binding of drospirenone to plasma proteins. The average apparent Vd is 3.7–4.2 l/kg.

Metabolism. After oral administration, drospirenone is completely metabolized. Most metabolites in plasma are represented by acidic forms of drospirenone, derivatives of drospirenone, which are formed without the involvement of the cytochrome P450 system. According to in vitro studies, the cytochrome P450CYP3A4 isoenzyme is involved to a minimal extent in the metabolism of drospirenone. The clearance of drospirenone is 1.2–1.5 ml/min/kg. No interaction has been established with simultaneous use with ethinyl estradiol.

Excretion. The concentration of drospirenone in blood plasma decreases in 2 phases. The second, final phase has a T1/2 of about 31 hours. Drospirenone is not excreted unchanged. Its metabolites are excreted through the gastrointestinal tract and kidneys in a ratio of approximately 1.2:1.4. T1/2 for excretion of metabolites is about 1.7 days.

Css. The concentration of SHBG does not affect the pharmacokinetics of drospirenone. With daily oral use of the drug, the concentration of drospirenone in the blood plasma increases 2-3 times, an equilibrium state is achieved in the second half of the cyclic treatment.

Renal dysfunction. Css of drospirenone in blood plasma was comparable in women with mild renal impairment (Cl creatinine - 50-80 ml/min) and in women with preserved renal function (Cl creatinine - more than 80 ml/min). However, in women with moderate renal impairment (Cl creatinine 30–50 ml/min), the average plasma concentration of drospirenone was 37% higher than in patients with preserved renal function. There was no change in the concentration of potassium in the blood plasma when using drospirenone.

Liver dysfunction. In women with moderate liver dysfunction (class B on the Child-Pugh scale), AUC is comparable to the corresponding indicator in healthy women with similar Cmax values ​​​​in the absorption and distribution phases. T1/2 of drospirenone in patients with moderate liver dysfunction was 1.8 times higher than in healthy volunteers with intact liver function. In patients with moderate liver dysfunction, a decrease in the clearance of drospirenone by about 50% was observed compared to women with preserved liver function, while there were no differences in the concentration of potassium in the blood plasma in the studied groups. When diabetes mellitus is detected and concomitant use of spironolactone (both conditions are regarded as factors predisposing to the development of hyperkalemia), an increase in the concentration of potassium in the blood plasma has not been established. Drospirenone is well tolerated in women with mild to moderate liver dysfunction (Child-Pugh class B).

Ethinyl estradiol

Absorption. After oral administration, ethinyl estradiol is rapidly and completely absorbed. Cmax - 54-100 pg/ml, achieved within 1-2 hours. The drug undergoes first-pass metabolism in the liver, its bioavailability when taken orally averages about 45% with high interindividual variability - from 20 to 65%. Simultaneous ingestion of food in some cases is accompanied by a decrease in the bioavailability of ethinyl estradiol by 25%.

Distribution. Ethinyl estradiol has a nonspecific but strong binding to plasma albumin (about 98%) and induces an increase in plasma concentrations of SHBG. The estimated Vd is about 2.8–8.6 l/kg.

Metabolism. Ethinyl estradiol undergoes presystemic conjugation in the liver and in the mucous membrane of the small intestine. The main route of metabolism of ethinyl estradiol is aromatic hydroxylation with the formation of numerous metabolites, which are found both in the associated state with glucuronides and sulfate, and in the unbound state.

The elimination rate of ethinyl estradiol is about 2.3–7 ml/min/kg.

Excretion. Ethinyl estradiol is excreted only in the form of metabolites by the kidneys and through the gastrointestinal tract in a ratio of 4:6 with T1/2 for about 24 hours.

Css. An equilibrium state is achieved in the second half of the course of treatment, when the concentration of ethinyl estradiol in the blood plasma increases by 40–110% compared to a single dose.

Ethnicity. The effect of ethnicity on pharmacokinetic parameters was studied in single and multiple dose studies of drospirenone and ethinyl estradiol in healthy Caucasian and Japanese women. The influence of ethnicity on the pharmacokinetic parameters of drospirenone and ethinyl estradiol has not been established.

Calcium levomefolate

Absorption. After oral administration of calcium, levomefolate is rapidly absorbed and included in the body's folate pool. After a single oral dose of 0.451 mg of calcium levomefolate after 0.5–1.5 hours, Cmax becomes 50 nmol/l higher than the initial concentration.

Distribution. The pharmacokinetics of folates has a two-phase character: a pool of folates with fast and slow metabolism is determined. The rapidly metabolized pool likely represents newly absorbed folate, which is consistent with the T1/2 of levomefolate calcium, which is approximately 4–5 hours after a single oral dose of 0.451 mg. The slow metabolizing pool reflects the conversion of folate polyglutamate, which has a T1/2 of about 100 days. External folates and folates passing through the enterohepatic cycle ensure the maintenance of a constant concentration of L-5-methyl-THF in the body.

L-5-methyl-THF represents the main form of existence of folates 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 transported form of folate in plasma. When comparing 0.451 mg calcium levomefolate and 0.4 mg folic acid, similar metabolic mechanisms were established for other significant folates. Folate coenzymes are involved in 3 main coupled metabolic cycles in the cytoplasm of cells. These cycles are necessary for the synthesis of thymidine and purines, precursors to DNA and RNA, as well as for the synthesis of methionine from homocysteine ​​and the conversion of serine to glycine.

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

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

Yarina Plus tablet on film pack contact cell/pack of cards x28

YARINA® PLUS Representative office: Bayer Health Care AG ATX code: G03AA12 Marketing authorization holder: BAYER SCHERING PHARMA, AG ethinylestradiol + drospirenone + levomefolate calcium Release form, composition and packaging Film-coated tablets (active combined) orange, round , biconvex, on one side with “Y+” embossed in a regular hexagon (21 per blister). 1 tab. ethinyl estradiol (micronized, in the form of betadex clathrate) 30 mcg drospirenone (micronized) 3 mg calcium levomefolate (micronized) 451 mcg Excipients: lactose monohydrate - 45.319 mg, microcrystalline cellulose - 24.8 mg, croscarmellose sodium - 3.2 mg, hyprolose (5 cP) - 1.6 mg, magnesium stearate - 1.6 mg.

Shell composition: orange varnish - 2 mg or (alternatively): hypromellose (5 cP) - 1.0112 mg, macrogol 6000 - 202.4 mcg, talc - 202.4 mcg, titanium dioxide - 527.1 mcg, iron dye yellow oxide - 44.6 mcg, iron dye oxide red - 12.3 mcg.

Film-coated tablets (vitamin supplements) are light orange, round, biconvex, on one side with “M+” embossed in a regular hexagon (7 in a blister). 1 tab. calcium levomefolate (micronized) 451 mg Excipients: lactose monohydrate - 48.349 mg, microcrystalline cellulose - 24.8 mg, croscarmellose sodium - 3.2 mg, hyprolose (5 cP) - 1.6 mg, magnesium stearate - 1.6 mg. Shell composition: light orange varnish - 2 mg or (alternatively): hypromellose (5 cP) - 1.0112 mg, macrogol 6000 - 202.4 mcg, talc - 202.4 mcg, titanium dioxide - 572.3 mcg, iron oxide yellow dye - 8.9 mcg, dye iron oxide red - 2.8 mcg. 28 - blisters (1) complete with a block of self-adhesive stickers for registration of the appointment calendar - cardboard packs. 28 - blisters (3) complete with a block of self-adhesive stickers for registration of the appointment calendar - cardboard packs.

Clinical and pharmacological group: Monophasic oral contraceptive with antiandrogenic properties Registration Nos.: •tablets, film-coated: 28 or 84 per set. with a block of stickers for registration of the reception calendar - LP-001186, 11.11.11. Active. ——————————————————————————— The description of the drug YARINA® PLUS is based on the officially approved instructions for use of the drug YARINA® PLUS for specialists and approved by the company - manufacturer for the 2013 edition. ——————————————————————————— Pharmacological action | Pharmacokinetics | Indications | Dosage regimen | Side effect | Contraindications | Pregnancy and lactation | Special instructions | Overdose | Drug interactions | Terms of release from pharmacies | Storage conditions and expiration dates —————————————————————————— Pharmacological action of Yarina® Plus is a low-dose monophasic oral combined estrogen-progestogen contraceptive drug, including active tablets and supplementary vitamin tablets containing calcium levomefolate. The contraceptive effect of Yarina® Plus is mainly achieved by suppressing ovulation and increasing the viscosity of cervical mucus. In women taking combined oral contraceptives (COCs), the cycle becomes more regular, the pain, intensity and duration of menstrual bleeding decrease, resulting in a reduced risk of iron deficiency anemia. There is also evidence of a reduced risk of endometrial and ovarian cancer. Drospirenone, contained in Yarina® Plus, has an antimineralocorticoid effect and helps prevent hormone-dependent fluid retention, which can manifest itself in weight loss and a decrease in the likelihood of peripheral edema. Drospirenone also has antiandrogenic activity and helps reduce acne (blackheads), oily skin and hair. This effect of drospirenone is similar to the effect of natural progesterone produced in the female body. This should be taken into account when choosing a contraceptive, especially for women with hormone-dependent fluid retention, as well as women with acne and seborrhea. When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using a contraceptive during the year) is less than 1. If pills are missed or used incorrectly, the Pearl index may increase. The acid form of calcium levomefolate is structurally identical to naturally occurring L-5-methyltetrahydrofolate (L-5-methyl-THF), the main folate form found in food. The average concentration in the blood plasma of people who do not consume foods fortified with folic acid is about 15 nmol/l. Levomefolate, unlike folic acid, is a biologically active form of folate. Thanks to this, it is absorbed better than folic acid. Levomefolate is indicated to meet the increased need and ensure the necessary folate content in a woman’s body during pregnancy and lactation. The addition of levomefolate calcium to an oral contraceptive reduces the risk of developing a neural tube defect if a woman becomes unexpectedly pregnant immediately after stopping contraception (or, in very rare cases, when using oral contraception).

Pharmacokinetics Drospirenone Absorption After oral administration, drospirenone is rapidly and almost completely absorbed. After a single oral dose, the Cmax of drospirenone in the blood plasma, equal to 37 ng/ml, is achieved after 1-2 hours. Bioavailability ranges from 76 to 85%. Compared to taking drospirenone on an empty stomach, food intake does not affect its bioavailability. Distribution Drospirenone binds to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG). Only 3-5% of the total serum concentration is present as free hormone. The increase in SHBG induced by ethinyl estradiol does not affect the binding of drospirenone to plasma proteins. The average apparent Vd is 3.7±4.2 l/kg. The concentration of SHBG does not affect the pharmacokinetics of drospirenone. With daily oral use of the drug, the concentration of drospirenone in the blood plasma increases 2-3 times, an equilibrium state is achieved in the second half of the cyclic treatment. Metabolism: After oral administration, drospirenone is extensively metabolized. Most metabolites in plasma are represented by acidic forms of drospirenone, which are formed without the involvement of the cytochrome P450 system. According to in vitro studies, cytochrome P450 isoenzyme 3A4 is involved to a minimal extent in the metabolism of drospirenone. No interaction has been established with simultaneous use with ethinyl estradiol. Elimination The clearance of drospirenone is 1.2-1.5 ml/min/kg. The concentration of drospirenone in blood plasma decreases in 2 phases. T1/2 of drospirenone in the second phase is about 31 hours. Drospirenone is not excreted unchanged. Its metabolites are excreted through the gastrointestinal tract and kidneys in a ratio of approximately 1.2:1.4. T1/2 of metabolites is about 1.7 days. Pharmacokinetics in special clinical cases The concentration of drospirenone in the blood plasma when reaching an equilibrium state was comparable in women with mild renal impairment (creatinine clearance 50-80 ml/min) and in women with preserved renal function (creatinine clearance more than 80 ml/min). However, in women with moderate renal impairment (creatinine clearance 30-50 ml/min), the average plasma concentration of drospirenone was 37% higher than in patients with preserved renal function. There were no changes in the concentration of potassium in the blood plasma when using drospirenone. In women with moderate liver dysfunction (class B on the Child-Pugh scale), AUC is comparable to the corresponding indicator in healthy women with similar Cmax values ​​​​in the absorption and distribution phases. T1/2 of drospirenone in patients with moderate liver dysfunction was 1.8 times higher than in healthy volunteers with intact liver function. In patients with moderate liver dysfunction, a decrease in the clearance of drospirenone by about 50% was observed compared to women with preserved liver function, while there were no differences in the concentration of potassium in the blood plasma in the studied groups. There were no changes in potassium concentration even in the case of a combination of factors predisposing to its increase (concomitant diabetes mellitus or treatment with spironolactone). Drospirenone is well tolerated in women with mild to moderate liver dysfunction (Child-Pugh class B).

Ethinyl estradiol Absorption Following oral administration, ethinyl estradiol is rapidly and completely absorbed. Cmax is about 54-100 pg/ml, achieved within 1-2 hours. The drug undergoes first-pass metabolism in the liver, its bioavailability when taken orally averages about 45% with high interindividual variability - from 20 to 65%. Simultaneous ingestion of food in some cases is accompanied by a decrease in the bioavailability of ethinyl estradiol by 25%. Distribution Ethinyl estradiol has a nonspecific but strong binding to plasma albumin (about 98%) and induces an increase in plasma concentrations of SHBG. The estimated Vd is about 2.8-8.6 l/kg. An equilibrium state is achieved in the second half of the course of treatment, when the concentration of ethinyl estradiol in the blood plasma increases by 40-110% compared to a single dose. Metabolism Ethinyl estradiol undergoes presystemic conjugation in the liver and in the mucosa of the small intestine. The main route of metabolism of ethinyl estradiol is aromatic hydroxylation with the formation of numerous metabolites, which are found in both bound (with glucuronides and sulfate) and unbound states. The excretion rate of ethinyl estradiol is about 2.3-7 ml/min/kg. Excretion Ethinyl estradiol is excreted only in the form of metabolites by the kidneys and through the gastrointestinal tract in a ratio of 4:6. T1/2 of ethinyl estradiol is about 24 hours. Pharmacokinetics in special clinical situations The effect of ethnicity on pharmacokinetic parameters was studied in studies with single and multiple dosing of drospirenone and ethinyl estradiol in healthy Caucasian women, as well as in Japanese women. The influence of ethnicity on the pharmacokinetic parameters of drospirenone and ethinyl estradiol has not been established. Calcium levomefolate Absorption After oral administration of calcium, levomefolate is rapidly absorbed and included in the body's folate pool. After a single oral dose of 451 mcg of calcium levomefolate, after 0.5-1.5 hours, Cmax becomes 50 nmol/l higher than the initial concentration. Distribution The pharmacokinetics of folates has a two-phase character: a pool of folates with fast and slow metabolism is determined. The rapidly metabolized pool likely represents newly absorbed folate, which is consistent with the T1/2 of levomefolate calcium, which is approximately 4-5 hours after a single oral dose of 451 mcg. The slow metabolizing pool reflects the conversion of folate polyglutamate, whose T1/2 is about 100 days. Folates coming from outside and folates passing through the enterohepatic cycle ensure the maintenance of a constant concentration of L-5-methyl-TTP in the body. L-5-methyl-THF represents the main form of existence of folates in the body, in which they are delivered to peripheral tissues to participate in cellular folate metabolism. The equilibrium state of L-5-methyl-THF in the blood plasma after oral administration of 451 mcg of calcium levomefolate is achieved after 8-16 weeks and depends on its initial concentration. In red blood cells, Css is achieved at a later date due to the lifespan of red blood cells, which is about 120 days. Metabolism L-5-methyl-THF is the main transported form of folate in plasma. When comparing 451 mcg calcium levomefolate and 400 mcg folic acid, similar metabolic mechanisms were established for other significant folates. Folate coenzymes are involved in 3 main coupled metabolic cycles in the cytoplasm of cells. These cycles are necessary for the synthesis of thymidine and purines, precursors of DNA and RNA acids, as well as for the synthesis of methionine from homocysteine ​​and the conversion of serine to glycine. Excretion L-5-methyl-TTP is excreted unchanged and in the form of metabolites by the kidneys, as well as through the intestines.

Indications for use of the drug YARINA® PLUS - contraception, intended primarily for women with symptoms of hormone-dependent fluid retention in the body, - contraception and treatment of moderate forms of acne (acne vulgaris), - contraception in women with folate deficiency.

Dosage regimen The tablets should be taken orally in the order indicated on the package, every day at the same time, without chewing, with a small amount of water. Take 1 tablet per day continuously for 28 days. Taking tablets from the next package begins immediately after completing the previous one.

Taking Yarina® Plus begins on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding). If vomiting or diarrhea occurs within 4 hours of taking the tablets, absorption may not be complete and additional measures should be taken to protect against unwanted pregnancy. The effectiveness and safety of Yarina® Plus as a contraceptive have been studied in women of reproductive age. It is assumed that the effectiveness and safety of the drug in post-pubertal age up to 18 years are similar to those in women after 18 years. The use of the drug before menarche is not indicated.

The drug Yarina® Plus is not used after menopause. The drug is contraindicated for use in women with severe liver dysfunction. The drug is contraindicated for use in women with severe renal impairment and acute renal failure.

Side effects Data on the frequency of adverse reactions reported during clinical trials of Yarina® involving 2614 patients are shown in the table below. The adverse reactions described for Yarina can also be attributed to the drug Yarina® Plus (the difference is only in the presence of calcium levomefolate, which is a stabilized salt of natural folates contained in food). Within each group, allocated depending on the frequency of occurrence, adverse reactions are presented in order of decreasing severity. According to frequency, they are divided into frequent (≥1/100 and From the central nervous system: often - headache, migraine. Mental disorders: often - depressed mood, infrequently - changes in libido, frequency unknown - mood swings. From the cardiovascular system: infrequently - increased blood pressure, decreased blood pressure, rarely - thromboembolism. From the respiratory system: rarely - bronchial asthma. From the digestive system: often - nausea, infrequently - vomiting, frequency unknown abdominal pain, diarrhea. From the skin: infrequently - acne, eczema, itching, frequency unknown - rash, urticaria, erythema nodosum, erythema multiforme. From the organ of vision: frequency unknown - intolerance to contact lenses. From the organ of hearing: hypoacusis. From the reproductive system and mammary glands: often - pain in the mammary glands (including engorgement of the mammary glands), leucorrhoea (including vaginal discharge), vaginal candidiasis, menstrual irregularities, acyclic bleeding (acyclic bleeding usually decreases with prolonged use of the drug), infrequently - vaginitis, rarely - discharge from the mammary glands, frequency unknown - enlargement of the mammary glands iron Other: infrequently - changes in body weight, fluid retention, frequency unknown - hypersensitivity reactions. Adverse events were classified using the MedDRA (Medical Dictionary of Regulatory Activities) dictionary. Synonyms or conditions associated with adverse reactions are not listed, but should also be taken into account.

The following serious adverse reactions have been reported in women using combined oral contraceptives. - venous thromboembolic disorders, - arterial thromboembolic disorders, - cerebrovascular disorders, - increased blood pressure, - hyperkalemia (in patients with impaired renal function and potassium levels exceeding reference values ​​before the start of the value), - hypertriglyceridemia, - changes in glucose tolerance or effects on peripheral insulin resistance, - liver tumors (benign and malignant), - impaired liver function, - chloasma, - in women with hereditary angioedema, exogenous estrogens can cause or intensify the symptoms of angioedema, - the onset or worsening of conditions for which the connection with the use of combined oral contraceptives is not indisputable: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes of pregnancy, hearing loss associated with otosclerosis, Crohn's disease, ulcerative colitis , cervical cancer. The incidence of breast cancer diagnosis in women using oral contraceptives is increased only slightly. Breast cancer is rarely observed in women under 40 years of age, the excess incidence is insignificant in relation to the overall risk of breast cancer. The causal relationship between the occurrence of breast cancer and the use of combined oral contraceptives has not been established.

Contraindications to the use of the drug YARINA® PLUS The drug Yarina® 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 taking the drug, the drug should be discontinued immediately. - thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders, - conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) currently or in history, - the presence of multiple or severe risk factors for venous or arterial thrombosis, - migraine with focal neurological symptoms currently or in history, - diabetes mellitus with vascular complications, - liver failure and severe illness liver (before normalization of liver tests), - severe and/or acute renal failure, - liver tumors (benign or malignant) currently or in history, - identified hormone-dependent malignant neoplasms (including genital or mammary glands) or suspicion of them, - bleeding from the vagina of unknown origin, - pregnancy or suspicion of it, - breastfeeding, - rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to lactose content), - hypersensitivity or intolerance to any from the components of the drug Yarina® Plus.

With caution, the potential risk and expected benefit of using the drug Yarina® Plus should be assessed in each individual case in the presence of the following diseases/conditions and risk factors: - risk factors for the development of thrombosis and thromboembolism: smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve defects, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in one of the close relatives), - other diseases in which peripheral circulatory disorders may be observed: diabetes mellitus without vascular complications, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn's disease and ulcerative colitis, sickle cell anemia, phlebitis of the superficial veins, - hereditary angioedema, - hypertriglyceridemia: - liver diseases not related to contraindications, - diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice and/or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes of pregnancy, Sydenham's chorea) - the postpartum period.

Use of the drug YARINA® PLUS during pregnancy and breastfeeding The drug is contraindicated during pregnancy. If pregnancy is detected while taking Yarina® Plus, the drug should be discontinued immediately. Data on the results of taking Yarina® Plus during pregnancy are limited and do not allow us to draw any conclusions about the negative impact of the drug on pregnancy, the health of the fetus and 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 teratogenic effects in cases of inadvertent use of COCs in early pregnancy. Specific epidemiological studies have not been conducted on the drug Yarina® Plus. The drug is contraindicated during breastfeeding. Taking COCs can reduce the amount of breast milk and change its composition, so their use is not recommended until you stop breastfeeding. Small amounts of sex hormones and/or their metabolites may be excreted in milk, but there is no evidence of their negative effects on the health of the child.

Use for liver dysfunction The drug is contraindicated for use in women with severe liver dysfunction.

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

Use in elderly patients Yarina® Plus is not used after menopause.

Use in children It is assumed that the effectiveness and safety of the drug in post-pubertal age up to 18 years are similar to those in women after 18 years. The use of the drug before menarche is not indicated.

Special instructions If any of the conditions, diseases and risk factors listed below currently exist, the potential risks and expected benefits of using Yarina® Plus should be carefully weighed in each individual case and discussed with the woman before she decides 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) when taking combined oral contraceptives. These diseases are rare. The risk of developing venous thromboembolism (VTE) is greatest in the first year of taking such drugs. An increased risk is present after initial use of combined oral contraceptives or resumption of use of the same or different combined oral contraceptives (after a dosing interval of 4 weeks or more). Data from a large prospective study involving 3 groups of patients suggest that this increased risk is predominantly present during the first 3 months. Overall risk of venous thromboembolism VTE in patients taking low-dose combined oral contraceptives (Data from a large prospective study of 3 patient groups show that in women with or without risk factors for VTE using ethinyl estradiol/drospirenone containing contraceptives at a dosage of 0.03 mg/3 mg, respectively , the incidence of VTE is the same as with levonorgestrel-containing oral contraceptives. VTE can be life-threatening or fatal (in 1-2% of cases). VTE, manifested as deep vein thrombosis, or pulmonary embolism, can occur when using any combined oral contraceptives. It is extremely rare that thrombosis of other blood vessels, such as the hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels, occurs when using combined oral contraceptives. There is no consensus on the relationship between the occurrence of these events and the use of combined oral contraceptives . Symptoms of deep vein thrombosis (DVT): unilateral swelling of the lower extremity or along a vein of the lower extremity, pain or discomfort in the lower extremity only in an upright position or when walking, local increase in temperature in the affected lower extremity, redness or discoloration of the skin on the lower extremity. Symptoms of pulmonary embolism (PE): difficulty or rapid breathing, sudden cough, including coughing up blood, sharp chest pain that may get worse with deep breaths, anxiety, severe dizziness, fast or irregular heartbeat. Some of these symptoms (eg, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more or less severe events (eg, respiratory tract infection). Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction. Symptoms of a stroke: sudden weakness or loss of sensation in the face, upper or lower extremities, especially on one side of the body, sudden confusion, problems with speech and comprehension, sudden loss of vision on one or both sides, sudden disturbance in gait, dizziness, loss of balance or coordination , sudden, severe or prolonged headache for no apparent reason, loss of consciousness or fainting with or without an epileptic seizure. Other signs of vascular occlusion: sudden pain, swelling and slight blue discoloration of the extremities, acute abdomen. Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, a feeling of squeezing or fullness in the chest, arm or chest, discomfort radiating to the back, cheekbone, larynx, arm, stomach, cold sweat, nausea, vomiting or dizziness, severe weakness , anxiety or shortness of breath, fast or irregular heartbeat. Arterial thromboembolism can be life-threatening or fatal. The risk of developing thrombosis (venous and/or arterial) and thromboembolism increases: - with age, - in smokers (with increasing number of cigarettes or increasing age, the risk increases, especially in women over 35 years old), in the presence of: - obesity (body mass index more than than 30 kg/m2) - family history (for example, venous or arterial thromboembolism ever in close relatives or parents at a relatively young age). In the case of a hereditary or acquired predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking the drug Yarina® Plus - prolonged immobilization, serious surgery, any operation on the lower extremities or extensive trauma. In these situations, it is advisable to stop using the drug Yarina® Plus (in the case of a planned operation, at least 4 weeks before it) and not to resume taking it for two weeks after the end of immobilization, - dyslipoproteinemia, - arterial hypertension, - migraine, - diseases heart valves, atrial fibrillation. The possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial. The increased risk of thromboembolism in the postpartum period should be taken into account. Peripheral circulatory disorders may also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia. An increase in the frequency and severity of migraine during use of Yarina® Plus (which may precede cerebrovascular events) may be grounds for immediate discontinuation of this drug. Biochemical indicators indicating a hereditary or acquired predisposition to venous or arterial thrombosis include the following: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the relevant condition may reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose oral contraceptives (Tumors The most significant risk factor for the development of cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing cervical cancer with long-term use of COCs. However, there are reports of a slight increase in the risk of developing cervical cancer with long-term use of COCs. However, the connection with the use of COCs has not been proven. The possibility of a relationship between these data and screening for cervical diseases and with sexual behavior (less frequent use of barrier methods of contraception) is discussed. A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer, diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs. Because breast cancer is rare in women under 40 years of age, an increase in the number of cancer diagnoses breast cancer in women currently or recently taking COCs is insignificant relative to the overall risk of this disease. Its connection with the use of COCs has not been proven. The observed increased risk may be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using COCs. Women who have ever used COCs are diagnosed with earlier stages of breast cancer than women who have never used them. In rare cases, during the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors was observed, which in some patients led to life-threatening intra-abdominal bleeding. If severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding occur, this should be taken into account when making a differential diagnosis. Other conditions Clinical studies have shown no effect of drospirenone on plasma potassium concentrations in patients with mild to moderate renal impairment. However, in patients with impaired renal function and an initial potassium concentration at the upper limit of normal, the risk of developing hyperkalemia cannot be excluded while taking medications that lead to potassium retention in the body. Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of developing pancreatitis while taking COCs. Although slight increases in blood pressure have been described in many women taking COCs, clinically significant increases have rarely been observed. However, if a persistent, clinically significant increase in blood pressure develops while taking Yarina® Plus, this drug should be discontinued and treatment of arterial hypertension should be started. The drug can be continued if normal blood pressure values ​​are achieved with antihypertensive therapy. The following conditions have been reported to develop or worsen both during pregnancy and while taking COCs, but their relationship with COC use has not been proven: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus : hemolytic-uremic syndrome, Sydenham's chorea, herpes of pregnancy, hearing loss associated with otosclerosis. Cases of Crohn's disease and ulcerative colitis have also been described with the use of COCs. In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema. Acute or chronic liver dysfunction may require discontinuation of Yarina® Plus until liver function tests return to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of the drug Yarina® Plus. Although COCs may have an effect on insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using Yarina® Plus. However, women with diabetes should be closely monitored while taking this drug. Chloasma can sometimes develop, especially in women with a history of chloasma during pregnancy. Women with a tendency to chloasma while taking Yarina® Plus should avoid prolonged exposure to the sun and exposure to ultraviolet radiation. Folates may mask vitamin B12 deficiency. Preclinical Safety Data Preclinical data obtained from routine studies to determine repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Contraindications

Yarina® 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 taking the drug, the drug should be discontinued immediately.

hypersensitivity or intolerance to any of the components of the drug Yarina® Plus;

thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, stroke), cerebrovascular disorders;

conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history;

identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant);

presence of a high risk of venous or arterial thrombosis (see “Special Instructions”);

migraine with focal neurological symptoms currently or in history;

pancreatitis with severe hypertriglyceridemia currently or in history;

diabetes mellitus with vascular complications;

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

severe and/or acute renal failure;

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

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

bleeding from the vagina of unknown origin;

patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose);

pregnancy or suspicion of it;

breastfeeding period.

CAREFULLY

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

risk factors for the development of thrombosis and thromboembolism - smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated valvular heart disease, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in someone close to relatives);

other diseases in which peripheral circulatory disorders may occur - diabetes mellitus without vascular complications, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn's disease and ulcerative colitis, sickle cell anemia, phlebitis of the superficial veins;

hereditary angioedema;

hypertriglyceridemia:

liver diseases that are not contraindications (see “Contraindications”);

diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice and/or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, pregnancy herpes, Sydenham's chorea);

the postpartum period no earlier than 21–28 days after birth, in the absence of breastfeeding.

Instructions for use YARINA®PLUS

If any of the conditions, diseases and risk factors listed below currently exist, the potential risks and expected benefits of using Yarina® Plus should be carefully weighed in each individual case and discussed with the woman before she decides to start taking this medicine. If any of these conditions, diseases or risk factors worsen, intensify or manifest for the first time, you should consult your doctor, who may decide whether to discontinue the drug.

Risk of developing venous thromboembolism (VTE)

The use of any combined hormonal contraceptives (CHCs) increases the risk of developing venous thromboembolism (VTE) compared to the case of not using this group of drugs. Medicines containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Other medicines, such as Yarina® Plus, can increase this risk level by up to two times. The decision to use any CHC, including those with the lowest risk of VTE, should be made only after discussing with the woman her understanding of the risks of developing VTE associated with taking the drug Yarina® Plus; factors that increase the risk of developing VTE; and also that the risk of developing VTE is higher during the first year of CHC use. The risk of developing VTE also increases after a break of 4 weeks or more between doses of CHCs.

In women not taking CHCs, the risk of developing VTE is 2 cases per 10,000 women per year. However, this risk can increase significantly depending on each woman's individual risk factors.

It has been established1 that in women taking CHCs containing drospirenone, the risk of developing VTE ranges from 9 to 12 cases per 10,000 women per year, which is comparable to the risk of 6 to 2 cases per 10,000 women per year for levonorgestrel.

In both cases, the incidence of VTE is lower than expected during pregnancy and the postpartum period.

VTE can lead to death in 1-2% of cases.

Very rarely, when using COCs, thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.

1 These incidence rates were estimated from a pooled epidemiological study using relative risks for different products compared with levonorgestrel-containing COCs.

2 Midpoint of range 5–7 per 10,000 patient-years, based on relative risk for levonorgestrel-containing COCs versus no use of approximately 2.3–3.6

Risk factors for developing VTE

The risk of developing venous thromboembolic complications in women using CHCs may be significantly higher in the presence of additional risk factors, especially multiple ones (see table).

The drug Yarina® Plus is contraindicated for women with several risk factors for developing VTE. If a woman has more than one risk factor for venous thrombosis, the increase in risk is greater than the sum of the individual risk factors - then the total risk must be assessed. If the benefit-risk ratio is negative, then the drug should not be prescribed.

Table: risk factors for developing VTE

The possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial.

Attention should be paid to the increased risk of thromboembolism during pregnancy and the postpartum period, especially within 6 weeks after birth (for information on pregnancy and lactation, see Pregnancy and Breastfeeding).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If any of the following symptoms occur, women should be advised to consult a doctor immediately and report that they are using CHCs.

Symptoms of DVT may include:

- unilateral swelling of the lower limb and/or foot or swelling along a vein in the leg;

- pain or increased sensitivity in the leg, can only be felt while standing or walking;

- increased sensation of warmth in the sore leg, redness or discoloration of the skin of the lower limb.

Symptoms of pulmonary embolism (PE) may include:

- sudden shortness of breath of unknown origin or rapid breathing;

- sudden cough, may be accompanied by hemoptysis;

- acute pain in the chest;

- dizziness

- fast or irregular heartbeat.

Some of these symptoms (eg, shortness of breath, cough) are not specific and may be misinterpreted as signs of other more common or less severe symptoms (eg, respiratory tract infection).

Other signs of vascular occlusion may include: sudden pain, swelling, slight blue discoloration of the limb.

With occlusion of the vessels of the eye, the symptomatology may be blurred vision, not accompanied by pain and which can progress to loss of vision. Sometimes vision loss develops almost instantly.

Risk of developing arterial thromboembolism (ATE)

According to epidemiological studies, the use of any COC is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for developing ATE

When using CHCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see table). The use of the drug Yarina® Plus is contraindicated if women have one serious or multiple risk factors for the development of ATE, which may increase the risk of developing arterial thrombosis (see section Contraindications). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section Contraindications).

Table: risk factors for developing ATE

Symptoms of ATE

If any of the following symptoms occur, women should be advised to contact their doctor immediately and report that they are using CHCs.
Symptoms of a stroke may include: - sudden numbness or weakness in the muscles of the face, arms or legs, especially on one side of the body; - sudden disturbance in gait, dizziness, loss of balance or loss of coordination; - sudden confusion, problems speaking or understanding language; - sudden loss of vision in one or both eyes; - sudden, severe or prolonged headache without an obvious cause; - loss of consciousness or fainting with or without an epileptic seizure. The transient nature of symptoms may indicate a transient ischemic attack. Symptoms of myocardial infarction may include: - pain, discomfort, pressure, a feeling of heaviness, squeezing or fullness in the chest, arm or behind the breastbone; - discomfort radiating to the back, jaw, larynx, arms, stomach; - a feeling of fullness, indigestion and an attack of suffocation; - sweating, nausea, vomiting or dizziness; - severe weakness, anxiety, shortness of breath; - fast or irregular heartbeat. • Tumors
Some epidemiological studies have reported an increased risk of cervical cancer with long-term COC use (more than 5 years), but this is still controversial because the extent to which the studies took into account confounding factors such as sexual behavior and other factors is unclear. factors, such as human papillomavirus infection.
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years of stopping these medications. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in current or recent COC users is small relative to the overall risk of breast cancer. Its connection with COC use has not been proven. The observed increased risk may also be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using combined oral contraceptives. Women who have ever used COCs are diagnosed with earlier stages of breast cancer than women who have never used them. In rare cases, during the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors, which in some cases led to life-threatening intra-abdominal bleeding, was observed. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when making a differential diagnosis. When using COCs in higher doses (50 mcg ethinyl estradiol), the risk of developing endometrial and ovarian cancer is reduced. It remains unclear whether this applies to low-dose COCs. • Other conditions
The progestin component of the drug Yarina® Plus is an aldosterone antagonist with potassium-sparing properties.
In most cases, potassium levels are not expected to increase. But in a clinical study in some patients with mild to moderate renal impairment, concomitant use of potassium-sparing agents did not significantly increase serum potassium levels when taking drospirenone. Therefore, it is recommended to check serum potassium levels during the first cycle of treatment in patients with renal failure whose pre-treatment serum potassium levels were at the upper limit of normal and who are additionally using potassium-sparing agents. Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of developing pancreatitis while taking COCs. Although slight increases in blood pressure have been described in many women taking COCs, clinically significant increases have rarely been reported. However, if a persistent, clinically significant increase in blood pressure develops while taking the drug, these drugs should be discontinued and treatment of arterial hypertension should be initiated. The drug can be continued if normal blood pressure values ​​are achieved with antihypertensive therapy. The following conditions have been reported to develop or worsen both during pregnancy and while taking COCs, but their relationship with COC use has not been proven: jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis. In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema. Acute or chronic liver dysfunction may require discontinuation of the drug until liver function tests return to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of the drug. Although COCs may have an effect on insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose combined oral contraceptives (<0.05 mg ethinyl estradiol). However, women with diabetes should be monitored closely while taking this drug. Cases of Crohn's disease and ulcerative colitis, as well as worsening endogenous depression and epilepsy, have been described with the use of COCs. Chloasma can sometimes develop, especially in women with a history of pregnancy chloasma. Women with a tendency to chloasma while taking the drug Yarina® Plus should avoid prolonged exposure to the sun and exposure to ultraviolet radiation. Folates may mask vitamin B12 deficiency. The drug Yarina® Plus contains 45 mg of lactose in an orange (hormone-containing) tablet and 48 mg of lactose in a light orange (inactive) tablet. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome who are on a lactose-controlled diet should take this amount into account. Medical examinations
Before starting or resuming the use of the drug Yarina® Plus, it is necessary to familiarize yourself with the woman’s life history and family history, conduct a thorough general medical and gynecological examination, and exclude pregnancy.
As a rule, blood pressure and heart rate are measured, body mass index is determined, the condition of the mammary glands, abdominal cavity and pelvic organs is checked, including a cytological examination of the cervical epithelium (Papanicolaou test). It is important to draw the attention of women to information about arterial and venous thromboembolism, including the risk of blood clots when taking the drug Yarina® Plus in comparison with other CHCs; symptoms of arterial and venous thromboembolism; factors that increase the risk of blood clots and the necessary actions in case of suspected thrombosis. You should carefully read the instructions for use and strictly follow them. It must be kept in mind that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases! Reduced effectiveness
The effectiveness of the drug Yarina® Plus may be reduced in the following cases: when active orange tablets are missed, with vomiting and diarrhea, or as a result of drug interactions (see sections Dosage regimen and Drug interactions).
Insufficient control of the menstrual cycle
While taking the drug Yarina® Plus, irregular (acyclic) spotting/bleeding from the vagina (spotting or “breakthrough” bleeding) may be observed, especially during the first months of use. Therefore, evaluation of any irregular menstrual-like bleeding should be carried out after an adaptation period of approximately three cycles. If irregular menstrual-like bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignancy or pregnancy. This may include curettage. Some women may not develop withdrawal bleeding during a pill-free break. If the drug Yarina® Plus was taken according to the recommendations, then pregnancy is unlikely. However, if the drug is not used regularly and there are no two consecutive menstrual-like bleedings, the drug cannot be continued until pregnancy is ruled out.

Preclinical safety data

Preclinical data from routine repeated-dose toxicity studies of drospirenone and ethinyl estradiol, genotoxicity, carcinogenic potential and reproductive toxicity do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of certain hormone-dependent tissues and tumors.

Preclinical data from routine repeated dose toxicity, genotoxicity, and reproductive toxicity studies of levomefolate calcium do not indicate a particular risk to humans.

Impact on the ability to drive a car and equipment.

Not found.

Use during pregnancy and breastfeeding

The drug is contraindicated during pregnancy. If pregnancy is detected while taking Yarina® Plus, the drug should be discontinued immediately. Data on the results of taking Yarina® Plus during pregnancy are limited and do not allow us to draw any conclusions about the negative impact of the drug on pregnancy, the health of the fetus and 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 teratogenic effects in cases of inadvertent use of COCs in early pregnancy. Specific epidemiological studies have not been conducted on the drug Yarina® Plus.

Lactation. The drug is contraindicated during breastfeeding. Taking the drug can reduce the amount of breast milk and change its composition, so their use is not recommended until breastfeeding is stopped. Small amounts of sex hormones and/or their metabolites may be excreted in milk, but there is no evidence of their negative effects on the health of the child.

Side effects

Data on the incidence of adverse reactions reported during clinical trials of Yarina® involving 2614 patients are shown in the table below. The adverse reactions described for the drug Yarina® can also be attributed to the drug Yarina® Plus (the only difference is the presence of calcium levomefolate, which is a stabilized salt of natural folates contained in food).

Within each group, allocated depending on the frequency of occurrence, adverse reactions are presented in order of decreasing severity. By frequency they are divided into frequent (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100) and rare (≥1/10000 and <1/1000). For additional adverse reactions identified only during post-marketing studies, and for which it was not possible to estimate the frequency of occurrence, “frequency unknown” is indicated.

Table

* Including breast engorgement.

** Including vaginal discharge.

*** Acyclic bleeding usually decreases with prolonged use of the drug.

The table lists the most commonly used MedDRA terms to describe specific adverse reactions. Synonyms or conditions associated with adverse reactions are not listed, but should also be taken into account.

The following serious adverse reactions and events have been reported in women using COCs. These adverse reactions are described in the “Special Instructions” section:

- venous thromboembolic disorders;

- arterial thromboembolic disorders;

- cerebrovascular disorders;

- increased blood pressure;

- hyperkalemia (in patients with impaired renal function and potassium levels exceeding reference values ​​before starting treatment);

- hypertriglyceridemia;

- change in glucose tolerance or effect on peripheral insulin resistance;

- liver tumors (benign and malignant);

- violation of liver functional parameters;

- chloasma;

- in women with hereditary angioedema, exogenous estrogens can cause or intensify the symptoms of angioedema;

- the onset or worsening of conditions for which the connection with the use of COCs is not indisputable: jaundice and/or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis; Crohn's disease; ulcerative colitis; cervical cancer.

The incidence of breast cancer diagnosis in women using oral contraceptives is increased only slightly. Breast cancer is rarely observed in women under 40 years of age, the excess incidence is insignificant in relation to the overall risk of breast cancer. The causal relationship between the occurrence of breast cancer and the use of COCs has not been established. For additional information, see “Contraindications” and “Special Instructions”.

Yarina® Plus

If any of the conditions, diseases and risk factors listed below currently exist, the potential risks and expected benefits of using Yarina® Plus should be carefully weighed in each individual case and discussed with the woman before she decides to start taking of this drug.

For disorders 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) when taking COCs. These diseases are rare.

The risk of developing venous thromboembolism (VTE) is greatest in the first year of taking COCs.

An increased risk is present after initial use of a COC or resumption of use of the same or a different COC (after a dosing interval of 4 weeks or more). Data from a large prospective study involving 3 groups of patients indicate that this increased risk is predominantly present during the first 3 months.

The overall risk of VTE in women taking low-dose COCs (<0.05 mg ethinyl estradiol) is two to three times higher than in non-pregnant patients not taking COCs, although the risk remains lower than the risk of VTE in pregnancy and childbirth

VTE can be life-threatening or lead to death (in 1-2% of cases).

VTE, manifested as deep vein thrombosis or pulmonary embolism, can occur with the use of any COC.

It is extremely rare when using COCs that thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.

Symptoms of deep vein thrombosis: unilateral swelling of the lower limb or along a vein in the lower limb, pain or discomfort in the lower limb only in an upright position or when walking, local increase in temperature in the affected lower limb, redness or discoloration of the skin of the lower limb.

Symptoms of pulmonary embolism: difficulty or rapid breathing; sudden cough, including with hemoptysis; sharp pain in the chest, which may intensify with deep inspiration; sense of anxiety; severe dizziness; fast or irregular heartbeat. Some of these symptoms (eg, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions (eg, respiratory tract infection).

Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction. Symptoms of a stroke include: sudden weakness or loss of sensation in the face or limbs, especially on one side of the body, sudden confusion, problems with speech and comprehension; sudden unilateral or bilateral vision loss; sudden disturbance in gait, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without convulsions. Other signs of vascular occlusion: sudden pain, swelling and slight cyanosis of the extremities, “acute” abdomen.

Symptoms of myocardial infarction:

pain, discomfort, pressure, heaviness, a feeling of compression or swelling in the chest or behind the sternum, radiating to the back, jaw, left upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; fast or irregular heartbeat.

Arterial thromboembolism can be life-threatening or fatal.

In women with a combination of several risk factors or high severity of one of them (for example, complicated heart valve diseases, uncontrolled arterial hypertension, extensive surgical interventions with prolonged immobilization, etc.), the possibility of their mutual reinforcement should be considered. In such cases, the total value of the existing risk factors increases. In this case, taking Yarina® Plus is contraindicated (see section “Contraindications”).

The risk of developing thrombosis (venous and/or arterial), thromboembolism or cerebrovascular disorders increases:

- with age;

- in smokers (with an increase in the number of cigarettes or an increase in age, the risk increases, especially in women over 35 years old);

in the presence of:

— obesity (body mass index more than 30 kg/m2);

- family history (for example, venous or arterial thromboembolism ever in close relatives or parents under the age of 50 years).

In the case of a hereditary or acquired predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking the drug Yarina® Plus;

- prolonged immobilization, major surgery, any operation on the lower extremities or major trauma.

In these situations, taking Yarina® Plus should be stopped (in the case of a planned operation at least four weeks before it) and not resumed for two weeks after the end of immobilization.

Temporary immobilization (eg, air travel lasting more than 4 hours) may also be a risk factor for the development of venous thromboembolism, especially in the presence of other risk factors;

- dislipoproteinemia;

- arterial hypertension;

- migraine;

— diseases of the heart valves;

- atrial fibrillation.

The use of any combined hormonal contraceptives increases the risk of developing VTE. The use of drugs containing levonorgestrel, norgestimate or norethisterone carries the lowest risk of developing VTE.

The use of other drugs, such as Yarina® Plus, can lead to a twofold increase in risk. The choice to use a COC with a higher risk of developing VTE can only be made after consultation with the patient to ensure that she fully understands the risk of VTE associated with the use of Yarina® Plus, the effect of the drug on her existing risk factors and that The risk of developing VTE is greatest during the first year of using the drug. The possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

The increased risk of thromboembolism in the postpartum period should be taken into account.

Peripheral circulatory disorders may also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine during use of Yarina® Plus (which may precede cerebrovascular events) is grounds for immediate discontinuation of this drug.

Biochemical indicators indicating a hereditary or acquired predisposition to venous or arterial thrombosis include: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the relevant condition can reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose oral contraceptives (<0.05 mg ethinyl estradiol).

Tumors

The most significant risk factor for developing cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing cervical cancer with long-term use of COCs. However, the connection with taking COCs has not been proven. The possibility of the relationship of these data with screening for cervical diseases and with characteristics of sexual behavior (less frequent use of barrier methods of contraception) is discussed.

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years of stopping these drugs. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in current or recent COC users is small relative to the overall risk of breast cancer. Its connection with COC use has not been proven. The observed increased risk may be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using COCs, the biological effects of sex hormones, or a combination of both factors. Women who have ever used COCs are diagnosed with earlier stages of breast cancer than women who have never used them.

In rare cases, during the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors was observed, which in some patients led to life-threatening intra-abdominal bleeding. If severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding occur, this should be taken into account when making a differential diagnosis.

Other states

Clinical studies have shown no effect of drospirenone on plasma potassium concentrations in patients with mild to moderate renal failure. However, in patients with impaired renal function and an initial potassium concentration at the upper limit of normal, the risk of developing hyperkalemia cannot be excluded while taking medications that lead to potassium retention in the body.

Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of developing pancreatitis while taking COCs.

Although slight increases in blood pressure (BP) have been described in many women taking COCs, clinically significant increases have rarely been reported. However, if a persistent, clinically significant increase in blood pressure develops while taking Yarina® Plus, this drug should be discontinued and treatment of arterial hypertension should be started. The drug can be continued if normal blood pressure values ​​are achieved with the help of antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and while taking COCs, but their relationship with COC use has not been proven: jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis. Cases of worsening the course of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis during the use of COCs have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver dysfunction may require discontinuation of Yarina® Plus until liver function tests return to normal. Recurrence of cholestatic jaundice, which developed for the first time during a previous pregnancy or previous use of sex hormones, requires discontinuation of taking Yarina® Plus.

Although COCs may have an effect on insulin resistance and glucose tolerance, there is usually no need to adjust the dose of hypoglycemic drugs in patients with diabetes mellitus using low-dose oral contraceptives (<0.05 mg ethinyl estradiol). However, women with diabetes mellitus should be carefully monitored while taking COCs.

Chloasma can sometimes develop, especially in women with a history of chloasma during pregnancy. Women with a tendency to chloasma while taking Yarina® Plus should avoid prolonged exposure to the sun and exposure to ultraviolet radiation.

Folates may mask vitamin B12 deficiency.

Laboratory tests

Taking Yarina® Plus may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal function, the concentration of transport proteins in plasma, indicators of carbohydrate metabolism, parameters of blood coagulation and fibrinolysis. Changes usually do not go beyond normal values. Drospirenone increases plasma renin activity and aldosterone concentrations, which is associated with its antimineralocorticoid effect.

There is a theoretical possibility of increasing the concentration of potassium in the blood plasma in women receiving Yarina® Plus simultaneously with other drugs that can increase the content of potassium in the blood plasma. These drugs include angiotensin II receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or indomethacin, there was no significant difference in plasma potassium concentrations compared with placebo.

Reduced efficiency

The contraceptive effectiveness of Yarina® Plus may be reduced in the following cases: if a dose is missed or gastrointestinal disorders occur while taking tablets containing hormones (orange tablets), or as a result of drug interactions.

Frequency and severity of menstrual-like bleeding

While taking Yarina® Plus during the first few months, irregular (acyclic) bleeding from the vagina may be observed (“spotting” spotting or “breakthrough” uterine bleeding). You should use hygiene products and continue taking your pills as usual. Any irregular bleeding should be assessed after an adaptation period of approximately 3 cycles of dosing.

If irregular bleeding recurs or develops after previous regular cycles, careful evaluation should be performed to rule out malignancy or pregnancy.

No regular menstrual bleeding

Some women may not develop bleeding while taking auxiliary light orange tablets “ooContraindications” and “With caution”;

— Local compaction in the mammary gland;

- Concomitant use of other medications (see also section “Interaction with other medications and other types of interactions”);

- If prolonged immobility is expected (for example, a cast is applied to the lower limb), hospitalization or surgery is planned (at least 4 weeks before the proposed operation);

- Unusually heavy bleeding from the vagina;

- Missed a pill in the first week of taking the package and had sexual intercourse seven days or less before;

— Absence of regular menstrual-like bleeding two times in a row or suspicion of pregnancy (you should not start taking pills from the next package before consulting your doctor).

You should stop taking the tablets and seek medical help immediately if there are possible signs of thrombosis, myocardial infarction or stroke: unusual cough; unusually severe pain behind the sternum, radiating to the left arm; unexpected shortness of breath, unusual, severe and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell, or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in the lower limb or sudden swelling of any of the lower limbs.

Interaction

The interaction of oral contraceptives with other drugs may lead to breakthrough uterine bleeding and/or decreased contraceptive reliability.

Interactions leading to a decrease in the effectiveness of Yarina® 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. These drugs include: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and preparations containing St. John's wort. HIV protease inhibitors (eg ritonavir) and non-nucleoside reverse transcriptase inhibitors (eg nevirapine) and combinations thereof also have the potential to affect hepatic metabolism.

Effect on enterohepatic recirculation: According to individual studies, some antibiotics (for example, penicillins and tetracyclines) may reduce the enterohepatic recirculation of estrogens, thereby reducing the concentration of ethinyl estradiol.

While taking medications that affect microsomal liver enzymes, and for 28 days after their discontinuation, a barrier method of contraception should be additionally used.

While taking antibiotics (except for rifampicin and griseofulvin) and for 7 days after their discontinuation, 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 orange tablets in the package, you should skip taking the remaining auxiliary light orange tablets and start taking Yarina® Plus from a new package without interruption in taking the tablets.

Interactions that reduce the effectiveness of calcium levomefolate

Effect on folate metabolism: Some drugs reduce blood folate concentrations or reduce the effectiveness of levomefolate calcium by inhibiting the enzyme dihydrofolate reductase (eg methotrexate, trimethoprim, sulfasalazine and triamterene), or by reducing folate absorption (eg cholestyramine), or through unknown mechanisms (eg antiepileptic drugs - carbamazepine, phenytoin, phenobarbital, primidone and valproic acid).

Effect on metabolism of COCs (enzyme inhibitors)

The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely.

Effect of COCs or calcium levomefolate 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 concentrations in blood plasma and tissues.

Based on interaction studies, as well as studies involving female volunteers taking omeprazole, simvastatin and midazolam as test substrates, it can be concluded that the effect of drospirenone 3 mg on the metabolism of other drugs is unlikely.

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

In patients with unimpaired renal function, the combined use of drospirenone and ACE inhibitors or NSAIDs does not have a significant effect on plasma potassium concentrations. However, the combined use of Yarina® Plus with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, the concentration of potassium in the blood plasma must be monitored during the 1st dosage cycle.

YARINA PLUS film-coated tablets No. 28x3

The tablets should be taken orally in the order indicated on the package, every day at the same time, without chewing, with a small amount of water. Take 1 tablet/day continuously for 28 days. Taking tablets from the next package should begin immediately after completing the previous package. Withdrawal bleeding usually begins 2-3 days after starting to take inactive tablets and may not yet be complete before you start taking tablets from the next pack. The packaging of Yarina® Plus includes 1 or 3 blisters containing 21 active tablets and 7 auxiliary tablets (last row). The package also includes an appointment calendar, consisting of 7 self-adhesive strips with the names of the days of the week marked on them. You must select the strip where the first day of the week on which you start taking the pills is indicated. For example, if you start taking pills on Wednesday, you should use a strip that starts with “Wed.” The strip should be glued along the top of the package, so that the first day designation is located above the tablet to which the arrow with the inscription “Start” is directed. This will show you which day of the week you should take each tablet. Starting taking Yarina® Plus If you have not taken any hormonal contraceptives in the previous month, taking Yarina® Plus should start on the 1st day of the menstrual cycle (i.e. on the 1st day of menstrual bleeding). The drug Yarina®Plus begins to act immediately, so there is no need to use additional barrier methods of contraception. It is allowed to start taking the drug on the 2-5th day of the menstrual cycle, but in this case it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the tablets from the first package. When switching from other combined contraceptive drugs, a vaginal ring or a transdermal patch, it is preferable to start taking Yarina® Plus the next day after taking the last active tablet from the previous package, but in no case later than the next day after the usual 7-day break (for drugs containing 21 tablets) or after taking the last inactive tablet (for drugs containing 28 tablets per package). Taking Yarina® Plus should begin on the day the vaginal ring or patch is removed, but no later than the day when a new ring is to be inserted or a new patch is applied. When switching from contraceptives containing only gestagens (“mini-pills”, injection forms, implants), or from an intrauterine therapeutic system with gestagen release, you can switch from the “mini-pill” to the drug Yarina® Plus on any day (without a break), from an implant or IUD with progestin - on the day of its removal, from an injectable contraceptive - on the day when the next injection is due. In all cases, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the pills. After an abortion (including spontaneous) in the first trimester of pregnancy, you can start taking the drug immediately. If this condition is met, the woman does not need additional contraception. After childbirth (in the absence of breastfeeding) or abortion (including spontaneous) in the second trimester of pregnancy, it is recommended to start taking the drug no earlier than 21-28 days after childbirth (in the absence of breastfeeding) or abortion in the second trimester of pregnancy. If use is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the pills. If sexual contact took place before starting to take the drug Yarina® Plus, it is necessary to exclude pregnancy or wait until the first menstruation. Taking missed pills Missing inactive pills can be ignored. However, they should be thrown away to avoid accidentally prolonging the period of taking inactive tablets. The following recommendations apply only to skipping active pills: If the delay in taking any active pill is less than 12 hours, the contraceptive protection of Yarina® Plus is maintained. You should take the missed tablet as soon as possible and take the next tablet at the usual time. If the delay in taking any active pill is more than 12 hours, contraceptive protection may be reduced. The more pills in a row are missed and the closer the missed dose is to the start or end of the dose, the greater the likelihood of pregnancy. In this case, you can be guided by the following two basic rules: 1. Taking the drug should never be interrupted for more than 7 days. 2. To achieve adequate suppression of hypothalamic-pituitary-ovarian regulation, 7 days of continuous use of active tablets are required. Accordingly, if the delay in taking active pills is more than 12 hours (the interval since the last pill is more than 36 hours), the following can be recommended: First week of taking the drug It is necessary to take the missed pill as soon as possible, as soon as the woman remembers it (even if this means taking two tablets at the same time). The following tablets should be taken at the usual time. In addition, over the next 7 days it is necessary to additionally use a barrier method of contraception (for example, a condom). If sexual intercourse took place within 7 days before missing a pill, the possibility of pregnancy must be taken into account. Second week of taking the drug It is necessary to take the missed pill as soon as possible, as soon as the woman remembers (even if this means taking two pills at the same time). The following tablets should be taken at the usual time. Provided you follow the pill regimen for 7 days preceding the first missed pill, there is no need to use additional contraceptive measures. Otherwise, as well as if you miss two or more tablets, you must additionally use barrier methods of contraception for 7 days. Third week of taking the drug The risk of pregnancy increases due to the approaching phase of taking inactive pills. It is necessary to strictly adhere to one of the following two options: - if during the 7 days preceding the first missed pill, all pills were taken correctly, there is no need to use additional contraceptive methods. When taking missed tablets, follow points 1 or 2; - if during the 7 days preceding the first missed tablet the tablets were taken incorrectly, then during the next 7 days it is necessary to additionally use a barrier method of contraception (for example, a condom) and in this case you should follow point 1 for taking the missed tablets. 1. It is necessary to take the missed pill as soon as possible, as soon as the woman remembers (even if this means taking two pills at the same time). The following tablets are taken at the usual time until the orange (active) tablets in the package are gone. The seven light orange (helper) tablets should be thrown away and the orange (active) tablets from a new package should be started immediately. Until the orange (active) tablets from the second package are used up, withdrawal bleeding is unlikely, but spotting and/or breakthrough bleeding may occur. 2. Stop taking the orange (active) tablets from the current package, then take a break of 7 days or less (including days you missed tablets), after which you should start taking the drug from a new package. If a woman misses taking orange (active) tablets and does not experience withdrawal bleeding while taking light orange (auxiliary) tablets, it is necessary to ensure that she is not pregnant. Recommendations for gastrointestinal disorders In severe gastrointestinal disorders, absorption may be incomplete, so an additional barrier method of contraception should be used. If vomiting or diarrhea develops within 3-4 hours after taking an active tablet, you should follow the recommendations for skipping tablets. If a woman does not want to change her usual dosing regimen and postpone the onset of menstruation to another day of the week, an additional active tablet should be taken from a different package. Delaying the onset of menstrual bleeding In order to delay the onset of menstrual bleeding, you should skip taking 7 inactive (light orange) tablets from the current package and start taking active (orange) tablets from the next package of Yarina® Plus. If a woman has taken all the active tablets from the second pack, she should also take 7 inactive (light orange) tablets and immediately start taking the tablets from the new pack. Thus, the cycle can be extended at will for any period, up to 3 weeks, incl. until all active tablets from the second package have been taken. If it is necessary for menstrual-like bleeding to begin earlier, you should stop taking the active (orange) tablets from the second package, throw it away and take a break from taking the drug for no more than 7 days, and then start taking tablets from a new package. In this case, menstrual-like bleeding will begin approximately 2-3 days after taking the last active (orange) tablet from the second package. While taking Yarina® Plus from the second package, spotting and/or breakthrough bleeding may occur. Changing the day your menstrual bleeding starts If a woman takes the pills as recommended, her menstrual bleeding will occur on approximately the same day every 4 weeks. If a woman wants to change the day her menstrual bleeding starts, she should stop taking the inactive (light orange) tablets for the number of days she needs to change the start of her menstrual bleeding. For example, if the cycle usually starts on Friday, and in the future the woman wants it to start on Tuesday (3 days earlier), taking the pills from the next package should be started 3 days earlier than usual, i.e. Do not take the last 3 inactive (light orange) tablets from the current package and start taking tablets from the next package. The fewer inactive (light orange) pills a woman takes, the more likely it is that menstrual bleeding will not occur. While taking Yarina® Plus from the following package, spotting and/or breakthrough bleeding may occur. Stopping taking Yarina® Plus You can stop taking Yarina® Plus at any time. If pregnancy is not planned, other methods of contraception should be considered. If you are planning a pregnancy, you should simply stop taking the drug. Special categories of patients The effectiveness and safety of Yarina® Plus have been studied in women of reproductive age. It is assumed that the effectiveness and safety of the drug in post-pubertal age up to 18 years are similar to those in women after 18 years. The use of the drug is contraindicated until the menstrual cycle has been established. The drug is not indicated after menopause. The drug is contraindicated for use in women with severe liver dysfunction. The drug is contraindicated for use in women with severe renal impairment and acute renal failure.