Yarina® plus

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT YARINA® PLUS (YARINA® PLUS)

Composition:

Active substances: ethinylestradiol, drospirenone, levomefolate calcium;

1 pack contains 28 film-coated tablets (21 orange tablets and 7 light-orange tablets);

1 orange tablet contains ethinylestradiol 0.03 mg, drospirenone 3 mg, and levomefolate calcium 0.451 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, magnesium stearate, hypromellose, polyethylene glycol 6000, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172);

1 light-orange tablet contains levomefolate calcium 0.451 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, magnesium stearate, hypromellose, polyethylene glycol 6000, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• Hormone-containing film-coated tablets are round, biconvex, orange in color, with "Y+" embossed on one side within a regular hexagon;
• Film-coated tablets containing only levomefolate calcium are round, biconvex, light-orange in color, with "M+" embossed on one side within a regular hexagon.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of the genital system. Systemic hormonal contraceptives.

ATC code G03A A12.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Combined oral contraceptives (COCs) reduce the risk of pregnancy primarily by suppressing ovulation. Other possible mechanisms include changes in cervical mucus that make sperm penetration more difficult, and alterations in the endometrium that reduce the likelihood of implantation.

Pharmacodynamic Properties

Drospirenone is a spironolactone analogue with anti-mineralocorticoid and anti-androgenic properties. The estrogenic component of the drug Yarina® Plus is ethinylestradiol.

Contraceptive Effect

No specific studies on the pharmacodynamic properties of Yarina® Plus have been conducted.

Folate Supplement

The effect of Yarina® Plus on plasma and red blood cell folate levels was evaluated in two studies. In a randomized, double-blind, active-controlled, parallel-group study, plasma and erythrocyte folate levels were compared in women (patients) from the United States during 24 weeks of treatment with 3 mg drospirenone/0.02 mg ethinylestradiol (drug "Jazz") plus 0.451 mg calcium levomefolate versus treatment with "Jazz" alone. The pharmacodynamic impact on plasma and erythrocyte folate levels and circulating folate metabolite profiles was assessed over 24 weeks of treatment with either 0.451 mg calcium levomefolate or 0.4 mg folic acid (equimolar dose of 0.451 mg calcium levomefolate) in combination with 3 mg drospirenone/0.03 mg ethinylestradiol (Yarina®), followed by an open-label phase of 20 weeks with Yarina® alone (elimination phase).

Pharmacokinetics

Yarina® Plus and Yarina are bioequivalent with respect to drospirenone and ethinylestradiol.

The absolute bioavailability of drospirenone following administration of a tablet containing drospirenone alone is approximately 76%. The absolute bioavailability of ethinylestradiol is about 40%, due to presystemic conjugation and first-pass effect. The absolute bioavailability of Yarina® Plus, which contains a combination of drospirenone and ethinylestradiol stabilized as a betadex clathrate (molecular complex), has not been studied. Ethinylestradiol has the same bioavailability when administered as a betadex clathrate complex as when given as a free steroid. Serum concentrations of drospirenone and ethinylestradiol reach peak levels within 1–2 hours after administration of Yarina® Plus.

The pharmacokinetics of drospirenone after single doses ranging from 1 to 10 mg are dose-dependent. At steady state, drospirenone concentrations are achieved after 8 days of daily administration of Yarina®. Following multiple doses of Yarina®, there was an almost 2- to 3-fold increase in Cmax and AUC (0–24 hours) of drospirenone in serum (see Table 1).

For ethinylestradiol, steady-state conditions are reached during the second half of the treatment cycle. With daily administration of Yarina®, serum Cmax and AUC (0–24 hours) of ethinylestradiol increase by approximately 1.5- to 2-fold (see Table 1).

Calcium levomefolate is structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9. The mean baseline concentration in individuals not consuming folic acid-fortified foods but with a normal nutritional diet is about 15 nmol/L. After oral administration, calcium levomefolate is absorbed and accumulates in the body. Peak plasma concentration, which is 50 nmol/L above baseline, is reached within 0.5–1.5 hours after a single oral dose of 0.451 mg calcium levomefolate.

Steady-state conditions for total plasma folate levels after administration of 0.451 mg calcium levomefolate are reached within approximately 8–16 weeks, depending on baseline levels. Steady-state concentration of calcium levomefolate in erythrocytes is achieved somewhat later, due to the longer lifespan of erythrocytes—120 days.

Table 1

Pharmacokinetic parameters of Yarina® (3 mg drospirenone and 0.03 mg ethinylestradiol)

Effect of food

The rate of absorption of drospirenone and ethinylestradiol after single administration of drugs similar to Yasmin® Plus was lower when administered after food (high in fat content), with the mean serum concentration (Cmax) of both substances decreasing by almost 40%. However, the extent of absorption of drospirenone remained unchanged. In contrast, the extent of absorption of ethinylestradiol decreased by almost 20% when administered after food.

The effect of food on the absorption of calcium levomefolate when administering Yasmin® Plus has not been studied.

Distribution

Serum concentrations of drospirenone and ethinylestradiol decline in a biphasic manner. The apparent volume of distribution of drospirenone is approximately 4 L/kg, and that of ethinylestradiol is about 4–5 L/kg.

Drospirenone does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), but binding to other serum proteins is about 97%. After repeated administration over more than 3 cycles, no changes in free fraction (based on minimum concentration values) were observed. Ethinylestradiol is reported to bind actively, but non-specifically, to serum albumin (about 98.5%) and stimulates increased serum concentrations of both SHBG and CBG. This effect on SHBG and CBG, induced by ethinylestradiol, was not altered by changes in drospirenone doses within the range of 2–3 mg.

A biphasic kinetics of folates with rapid and slow turnover of their stores has been reported. The rapid turnover, which may reflect recently absorbed folates, corresponds to an elimination half-life of approximately 4–5 hours after a single oral dose of 0.451 mg calcium levomefolate. For the slow turnover, reflecting polyglutamate folate metabolism, the mean residence time is 100 days or more.

Metabolism

Two major metabolites of drospirenone identified in human plasma are the open-ring acid form of drospirenone, formed by lactone ring opening, and 4,5-dihydro-drospirenone-3-sulfate, resulting from reduction followed by sulfation. These metabolites have been shown to be pharmacologically inactive. Drospirenone is also subject to oxidative metabolism by CYP3A4.

Ethinylestradiol undergoes significant presystemic metabolism in the intestine and liver. Metabolism of ethinylestradiol and its oxidative metabolites occurs primarily via conjugation with glucuronide or sulfate. CYP3A4 in the liver is responsible for 2-hydroxylation, the main oxidative reaction. The 2-hydroxy metabolite undergoes further transformation via methylation and glucuronidation before being excreted in urine and feces.

L-5-methyl-THF is the predominant folate compound in the systemic circulation under physiological conditions and during administration of folic acid and calcium levomefolate.

Excretion

Serum concentrations of drospirenone exhibit a terminal elimination half-life of about 30 hours after both single and multiple doses. Elimination of drospirenone from the body was nearly complete within 10 days, with slightly higher amounts excreted in feces than in urine. Drospirenone undergoes extensive metabolism, and only negligible amounts of unchanged drospirenone are excreted in urine and feces. At least 20 different metabolites have been identified in urine and feces. Approximately 38–47% of metabolites in urine are glucuronide and sulfate conjugates. Nearly 17–20% of metabolites found in feces are excreted as glucuronides and sulfates.

The terminal elimination half-life of ethinylestradiol in the distribution phase has been reported to be approximately 24 hours. Ethinylestradiol is not excreted unchanged. It is excreted in urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.

L-5-methyl-THF is eliminated from the body in urine as unchanged folates and catabolites, and in feces via biphasic kinetics.

Use in special patient groups

Use in children. The safety and efficacy of Yasmin® Plus have been established in women of reproductive age. The drug is expected to have similar efficacy in post-pubertal adolescents up to 18 years of age and in patients aged 18 years and older. This medicinal product is not intended for use before the onset of menstruation.

Use in elderly. The use of Yasmin® Plus in postmenopausal women has not been studied; the drug is not indicated for this patient group.

Racial differences. No clinically significant differences in the pharmacokinetic properties of drospirenone or ethinylestradiol have been observed between Japanese women and Caucasian women (aged 25–35 years) receiving a daily dose of a preparation containing 3 mg drospirenone/0.02 mg ethinylestradiol for 21 days. Specific studies in other ethnic groups have not been conducted.

Renal impairment. Yasmin® Plus is contraindicated in patients with renal impairment.

The effect of renal impairment on the pharmacokinetic properties of drospirenone (3 mg daily for 14 days) and the effect of drospirenone on serum potassium concentration were studied in three separate groups of women (n = 28, aged 30–65). All subjects were on a low-potassium diet. Seven individuals continued to take potassium-sparing agents for their underlying condition during the study. On day 14 of drospirenone therapy (steady state), serum concentrations of drospirenone in the group with creatinine clearance of 50–79 mL/min were similar to those in the group with creatinine clearance ≥ 80 mL/min. In individuals with creatinine clearance of 30–49 mL/min, serum concentrations of drospirenone were on average 37% higher than in the control group. Treatment with drospirenone did not result in any clinically significant effect on serum potassium levels. Although hyperkalemia was not observed in the study, mean serum potassium concentration increased by 0.33 mEq/L in 5 out of 7 individuals who continued potassium-sparing agents during the study (see sections "Contraindications" and "Special warnings and precautions for use").

Hepatic impairment. Yasmin® Plus is contraindicated in patients with liver disease.

Average exposure to drospirenone in women with moderate hepatic impairment is nearly three times higher than in women with normal liver function. Yasmin® Plus has not been studied in women with severe hepatic impairment (see sections "Contraindications" and "Special warnings and precautions for use").

Drug interactions

For more detailed information on interactions with hormonal contraceptives or possible enzyme changes, refer to the prescribing information of all medicinal products administered concomitantly with this drug.

Effect of other medicinal products on COCs.

Substances that reduce the efficacy of COCs. Medicinal products or herbal preparations that induce certain enzymes, including CYP3A4, may reduce the efficacy of COCs or increase breakthrough bleeding.

Substances that increase plasma concentrations of COCs. Concomitant use of atorvastatin and certain COCs containing ethinylestradiol has been associated with an increase in AUC of ethinylestradiol by almost 20%. Ascorbic acid and acetaminophen may increase plasma concentrations of ethinylestradiol, likely due to inhibition of conjugation. In a clinical interaction study involving 20 premenopausal women, daily administration of tablets containing 3 mg drospirenone and 0.02 mg ethinylestradiol concomitantly with the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily for 10 days) resulted in a 2.68-fold increase (90% CI: 2.44, 2.95) in AUC (0–24) of drospirenone and a 1.4-fold increase (90% CI: 1.31, 1.49) in AUC of ethinylestradiol. Cmax increased by 1.97-fold (90% CI: 1.79, 2.17) and 1.39-fold (90% CI: 1.28, 1.52) for drospirenone and ethinylestradiol, respectively. Despite no clinically significant effects on safety or laboratory parameters, including serum potassium levels, it should be noted that subjects were observed for only 10 days in this study. The clinical consequences of concomitant use of COCs containing drospirenone with continuous administration of CYP3A4/5 inhibitors are unknown (see section "Special warnings and precautions for use").

HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors. In some cases, significant changes (increases or decreases) in plasma concentrations of estrogen and progestin have been observed when COCs are used concomitantly with HIV/HCV protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Antibiotics. There are reports of pregnancy occurring during concomitant use of hormonal contraceptives and antibiotics; however, clinical studies investigating pharmacokinetic properties have not demonstrated a consistent effect of antibiotics on plasma concentrations of synthetic steroids.

Effect of COCs on other medicinal products

COCs containing ethinylestradiol may inhibit the metabolism of other drugs. COCs have been shown to significantly reduce plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may lead to reduced seizure control, and dose adjustment of lamotrigine may be required. For more detailed information on interactions with COCs or possible enzyme changes, refer to the prescribing information of all medicinal products administered concomitantly with this drug.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and a non-reversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. The metabolism of drospirenone and its potential effect on hepatic CYP enzymes were studied in vitro and in vivo. In two in vitro studies, drospirenone did not affect the metabolism of model substrates for CYP1A2 and CYP2D6, but inhibited the metabolism of model substrates for CYP1A1, CYP2C9, CYP2C19, and CYP2A4, with CYP2C19 being the most sensitive enzyme. The potential effect of drospirenone on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In a study involving 24 postmenopausal women (12 women with homozygous (wild-type) CYP2C19 genotype and 12 with heterozygous CYP2C19 genotype), daily oral administration of drospirenone 3 mg for 14 days did not affect the clearance of omeprazole (40 mg, single oral dose) or its metabolite 5-hydroxyomeprazole formed by CYP2C19. Additionally, no significant effect of drospirenone on systemic clearance of omeprazole sulfone, a metabolite formed by CYP3A4, was observed. These results indicate that drospirenone does not inhibit CYP2C19 or CYP3A4 in vivo.

Two additional clinical studies investigating drug interactions using simvastatin and midazolam as marker substrates for CYP3A4 were conducted, each involving 24 healthy postmenopausal women. Results showed that drospirenone at steady-state concentrations achieved after 3 mg/day administration does not affect the pharmacokinetics of CYP3A4 substrates.

Women receiving thyroid hormone replacement therapy may require higher doses of thyroid hormone, as serum concentration of thyroid hormone-binding globulin increases during COC use.

Interaction with drugs that may increase serum potassium levels. Women taking Yasmin® Plus concomitantly with other drugs that may increase serum potassium levels may be at risk of elevated serum potassium concentration (see section "Special warnings and precautions for use").

A drug interaction study compared drospirenone 3 mg/estradiol 1 mg versus placebo in 24 postmenopausal women with moderate arterial hypertension receiving enalapril maleate 10 mg twice daily. Serum potassium levels were monitored every other day for 2 weeks. Mean serum potassium concentration in the drospirenone/estradiol group was 0.22 mEq/L higher than baseline compared to the placebo group. Additionally, serum potassium levels were measured at specific time points over 24 hours at baseline and on day 14. On day 14, the ratio of Cmax and AUC of serum potassium between the drospirenone/estradiol group and placebo group was 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either group developed hyperkalemia (serum potassium > 5.5 mEq/L).

Effect of folates on other drugs. Folate-containing compounds such as folic acid and calcium levomefolate may alter the pharmacokinetic or pharmacodynamic properties of certain antifolates (e.g., antiepileptic drugs, methotrexate).

Effect of other drugs on folates. It has been reported that certain drugs (methotrexate, sulfasalazine, cholestyramine, antiepileptic drugs) may reduce folate levels.

Preclinical safety data

In a 24-month carcinogenicity study in animals, oral administration of drospirenone at 10 mg/kg/day or drospirenone and ethinylestradiol at 1+0.01, 3+0.03, and 10+0.1 mg/kg/day (representing 0.1–2 times the human exposure (AUC of drospirenone) in women using contraceptives) resulted in an increased incidence of adenocarcinoma of the cervix in the group receiving high-dose drospirenone monotherapy. In a similar study in another animal species, oral administration of drospirenone at 10 mg/kg/day or drospirenone and ethinylestradiol at 0.3+0.003, 3+0.03, and 10+0.1 mg/kg/day (representing 0.8–10 times human exposure) resulted in an increased incidence of benign and total (benign and malignant) pheochromocytomas of the adrenal glands in the group receiving high-dose drospirenone monotherapy. Mutagenicity studies of drospirenone conducted in vivo and in vitro showed no evidence of mutagenic activity.

Long-term animal studies to assess the carcinogenic potential of levomefolate have not been conducted. Mutagenicity studies of levomefolate conducted in vivo and in vitro showed no evidence of mutagenic activity.

Clinical characteristics.

Indications.

• Oral contraception.

Yarina® Plus is indicated for use in women for the prevention of pregnancy.

• Folate status support.

Yarina® Plus is indicated for use in women who have chosen oral contraception as a method of preventing pregnancy, to increase folate levels with the aim of reducing the risk of neural tube defect occurrence.

Contraindications.

Yarina® Plus must not be administered to women who have any of the conditions or diseases listed below.

• Renal function disorders.
• Adrenal insufficiency.
• High risk of arterial or venous thrombosis. This category includes, in particular, women who:
  • smoke and are over 35 years of age (see section "Special precautions");
  • have deep vein thrombosis or pulmonary artery thromboembolism (PE), including in their medical history (see section "Special precautions");
  • have cerebrovascular disease (see section "Special precautions");
  • have ischemic heart disease (see section "Special precautions");
  • have thrombogenic heart valve defects or thrombogenic cardiac rhythm disorders (e.g., subacute bacterial endocarditis with valve involvement or atrial fibrillation) (see section "Special precautions");
  • have hereditary or acquired hypercoagulopathy (see section "Special precautions");
  • have uncontrolled arterial hypertension (see section "Special precautions");
  • have diabetes mellitus with vascular complications (see section "Special precautions");
  • suffer from headaches with focal neurological symptoms or migraines with or without aura and are over 35 years of age (see section "Special precautions").
• Abnormal uterine bleeding of unknown etiology (see section "Special precautions").
• Breast cancer or other types of cancer sensitive to estrogens or progestins, including in medical history (see section "Special precautions").
• Liver tumors, benign or malignant, or liver disease (see section "Special precautions", "Method of administration and dosage").
• Pregnancy (due to lack of need for COC use during pregnancy) (see section "Special precautions", "Use during pregnancy or breastfeeding").
• Concomitant use of medicinal products for the treatment of hepatitis C containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir due to potential ALT elevation (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

For more detailed information on interactions with hormonal contraceptives or possible enzymatic changes, refer to the package leaflets of all medicinal products prescribed concurrently with this medicinal product.

Effect of other medicinal products on COCs

Substances that may reduce COC efficacy

Medicinal products and herbal preparations that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may reduce the efficacy of COCs or cause breakthrough bleeding. Medicinal products that may reduce the efficacy of hormonal contraceptives include: phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, and medicinal products containing St. John's wort. Interaction between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or loss of contraceptive efficacy. When treating with enzyme-inducing medicinal products, an alternative or additional contraceptive method should be used throughout the duration of treatment with the respective medicinal product and for an additional 28 days after discontinuation of its use to ensure adequate contraception.

Substances that may increase COC plasma concentrations

Concomitant use of atorvastatin and certain COCs containing ethinylestradiol has been associated with an approximately 20% increase in ethinylestradiol AUC. Ascorbic acid and acetaminophen may increase ethinylestradiol plasma concentrations, likely due to inhibition of conjugation.

Concomitant use of moderate or strong CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice, may increase plasma concentrations of estrogen, progestin, or both. In a clinical drug interaction study conducted in perimenopausal women, administration once daily of a product containing 3 mg drospirenone/0.02 mg ethinylestradiol together with the potent CYP3A4 inhibitor ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase in systemic exposure to drospirenone. Exposure to ethinylestradiol increased slightly (see sections "Special precautions" and "Pharmacological properties").

Protease inhibitors of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and non-nucleoside reverse transcriptase inhibitors

In some cases, significant changes (increases or decreases) in plasma concentrations of estrogen and progestin have been observed when COCs are used concomitantly with HIV/HCV protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Antibacterial agents

There have been reports of pregnancy occurring during concomitant use of hormonal contraceptives and antibiotics; however, clinical pharmacokinetic studies have not demonstrated a consistent effect of antibiotics on plasma concentrations of synthetic steroids.

Effect of COCs on other medicinal products

COCs containing ethinylestradiol may inhibit the metabolism of other medicinal products. It has been established that COCs significantly reduce lamotrigine plasma concentrations, likely due to induction of lamotrigine glucuronidation. As a result, seizure control may be reduced, and dose adjustment of lamotrigine may be required. For more detailed information on interactions with COCs or possible enzymatic changes, refer to the package leaflets of all medicinal products prescribed concurrently with this medicinal product.

COCs that increase plasma concentrations of cytochrome CYP450 enzymes

Clinical studies have shown that during use of hormonal contraceptives containing ethinylestradiol, increases in plasma concentrations of CYP3A4 substrates (e.g., midazolam) were absent or minimal, whereas plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) may increase to a minor or moderate extent.

Clinical studies have not indicated any inhibitory potential of drospirenone on human CYP enzymes at clinically relevant concentrations (see section "Pharmacological properties").

Women receiving thyroid hormone replacement therapy may require higher doses of thyroid hormone, as serum concentration of thyroid hormone-binding globulin increases during COC use.

Interaction with medicinal products that may increase serum potassium levels

In women taking Yarina® Plus concomitantly with other medicinal products that may increase serum potassium levels, there is a possibility of increased serum potassium concentration (see sections "Special precautions", "Pharmacological properties").

Effect of folates on other medicinal products

Folates may alter the pharmacokinetic or pharmacodynamic properties of certain antifolate medicinal products, including antiepileptic agents (e.g., phenytoin), methotrexate, or pyrimethamine, potentially leading to reduced pharmacological effect of antifolate agents.

Effect of other medicinal products on folates

It has been reported that certain medicinal products may reduce folate levels by inhibiting the enzyme dihydrofolate reductase (e.g., methotrexate and sulfasalazine), by reducing folate absorption (e.g., cholestyramine), or via unknown mechanisms (e.g., antiepileptic agents such as carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid).

Effect on laboratory test results

Use of contraceptive steroids may affect the results of certain laboratory tests, particularly coagulation factors, lipid levels, glucose tolerance, and binding proteins. Drospirenone increases plasma renin and aldosterone activity, induced by its moderate antimineralocorticoid activity. Folate may mask vitamin B12 deficiency (see section "Special precautions" and subsection "Effect of COCs on other medicinal products" in section "Interaction with other medicinal products and other forms of interaction").

Special precautions.

Smoking and serious cardiovascular complications

Smoking increases the risk of developing serious cardiovascular complications during use of COCs. This risk increases with age and with the number of cigarettes smoked per day. Therefore, COCs should not be used in women over 35 years of age who smoke (see section "Contraindications").

Thromboembolic disorders and other vascular diseases

Use of Yarina® Plus should be discontinued if arterial or venous thromboembolic complications develop.

Based on available data regarding COCs containing drospirenone and 0.03 mg ethinylestradiol (product "Yarina®"), COCs containing drospirenone are associated with a higher risk of venous thromboembolism (VTE) compared to COCs containing levonorgestrel or other progestins. Epidemiological studies comparing VTE risks have indicated a possible range from no increase in risk at all to a three-fold increase. Before initiating Yarina® Plus in women who have not previously used COCs, or in women switching from another contraceptive not containing drospirenone, the risks and benefits of using drospirenone-containing COCs should be carefully evaluated with regard to the potential risk of VTE. In addition to other factors that contraindicate COC use, established risk factors for VTE include smoking, obesity, and personal or family history of VTE (see section "Contraindications").

Several studies have compared the risk of VTE in women taking Yarina® (containing 0.03 mg ethinylestradiol and 3 mg drospirenone) with those using other COCs, including those containing levonorgestrel. Results from studies conducted at the request of or with support from regulatory authorities are summarized in Table 2.

Table 2

Estimated data (relative risk) of developing venous thromboembolism in women taking Yarina® compared to women using oral contraceptives containing other progestins

a) including women who have not used combined hormonal contraceptives for at least the previous 6 months

b) including low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate

c) including low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chloromadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone

d) including low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel

In addition to the above-mentioned "regulatory studies," other studies with various objectives have also been conducted. Overall, two prospective cohort studies were performed (see Table 2): the post-marketing safety study (USA) Ingenix (Seeger 2007) and the European post-marketing safety study EURAS (European Active Surveillance Study) (Dinger 2007). The Long-term Active Surveillance Study (LASS), a continuation of the EURAS study, did not enroll additional participants but continued to assess the risk of VTE. Three retrospective cohort studies were also conducted: one in the USA funded by the FDA (see Table 2), and two in Denmark (Lidegaard 2009, Lidegaard 2011). Additionally, two case-control studies were performed: one in Denmark—the MEGA analytical study (van Hylckama Vlieg 2009)—and one in Germany (Dinger 2010). Furthermore, two cohort case-control studies evaluating the risk of non-fatal idiopathic VTE were conducted: the PharMetrics study (Jick 2011) and the GPRD study (Parkin 2011). The results of all these studies are presented in Figure 1.

Figure 1. Risk of VTE with the use of "Yarina®" and with COCs containing levonorgestrel (adjusted risk#)

Risk ratios are presented on a logarithmic scale; risk ratios <1 indicate a lower risk of VTE with drospirenone use, while ratios >1 indicate a higher risk of VTE with drospirenone.

*Reference product "other COCs," including those containing levonorgestrel.

†LASS – continuation of the EURAS study.

#Additional parameters indicated by superscript letters: a) heavy smoking; b) arterial hypertension; c) obesity; d) family history; e) age; f) BMI; g) duration of use; h) history of VTE; i) inclusion period; j) calendar year; k) education; l) duration of use; m) fertility; n) chronic disease; o) concomitant medications; p) smoking; q) exposure duration; r) location

(References: Ingenix (Seeger 2007), EURAS (European Active Surveillance Study) (Dinger 2007), LASS (Long-term Active Surveillance Study) (Dinger, unpublished data), FDA-funded study (Sidney 2011), Danish study (Lidegaard 2009), Danish re-analysis (Lidegaard 2011), MEGA study (van Hylckama Vlieg 2009), German case-control study (Dinger 2010), PharMetrics (Jick 2011), GPRD study (Parkin 2011)10).

Despite the increased absolute risk of VTE in women using hormonal contraceptives compared to non-users, the incidence of VTE during pregnancy is even higher, especially in the postpartum period (see Figure 2). It is estimated that the risk of VTE in women using COCs ranges from 3 to 9 cases per 10,000 woman-years. The highest risk of VTE occurs during the first year of COC use. Data from a large prospective cohort study evaluating the safety of various COCs suggest that this increased risk, compared to non-users, is highest during the first 6 months of COC use. The results of this study indicate that the greatest risk of VTE occurs at the beginning of COC use or after resuming use (following a break of 4 weeks or longer) of the same or a different COC.

After discontinuation of COCs, the risk of thromboembolic complications associated with oral contraceptive use gradually disappears.

Figure 2 illustrates the risk of VTE in women who are neither pregnant nor using oral contraceptives; in women taking oral contraceptives; in pregnant women; and in women during the postpartum period. The projected risk of VTE is as follows: if the health of 10,000 non-pregnant women not using oral contraceptives is monitored over 1 year, VTE will occur in 1–5 of these women.

Figure 2. Probability of VTE development

*Data for pregnant women were calculated based on the actual duration of pregnancy according to control study results. Based on data indicating that pregnancy lasts nine calendar months, the frequency is 7–27 cases per 10,000 woman-years.

If possible, use of Yarina® Plus should be discontinued at least 4 weeks before major surgery or other surgical procedures associated with an increased risk of thromboembolism, and the drug should not be used for 2 weeks after such procedures.

Women who are not breastfeeding may start taking Yarina® Plus no earlier than 4 weeks after childbirth. The risk of postpartum thromboembolism decreases 3 weeks after delivery, while the risk of ovulation increases at this time.

The use of COCs also increases the risk of arterial thrombosis, including stroke and myocardial infarction, particularly in women with other risk factors for these disorders.

It has been established that COCs increase both the relative and population risk of cerebrovascular events (ischemic and hemorrhagic stroke), although the overall risk is higher in older women (>35 years), those with arterial hypertension, and smokers. COC use also increases the risk of stroke in women with other major risk factors.

The use of oral contraceptives in women with risk factors for cerebrovascular disorders requires caution.

Yarina® Plus should be discontinued in cases of unexplained vision loss, proptosis, diplopia, optic nerve disc edema, or retinal vascular lesions. An immediate examination should be performed to rule out possible retinal vein thrombosis (see section "Adverse Reactions").

Hyperkalemia

Yarina® Plus contains 3 mg of the progestin drospirenone, which has antimineralocorticoid properties and may cause hyperkalemia in patients at increased risk. This property of drospirenone is similar to that of spironolactone at a dose of 25 mg. Yarina® Plus is contraindicated in patients with conditions predisposing to hyperkalemia (e.g., impaired kidney function, impaired liver function, or adrenal insufficiency). In women receiving daily long-term therapy for chronic conditions or diseases with drugs capable of increasing serum potassium levels, serum potassium concentration should be monitored throughout the treatment course. Drugs that may increase serum potassium levels include ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, potassium supplements, heparin, aldosterone antagonists, and NSAIDs. Monitoring of serum potassium concentrations should be considered in high-risk patients undergoing concomitant long-term therapy with a potent cytochrome CYP3A4 inhibitor. Potent CYP3A4 inhibitors include azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin (see section "Pharmacological Properties").

Breast and reproductive organ cancer

Yarina® Plus should not be taken by women who currently have or have previously had breast cancer, as breast cancer is a hormone-dependent tumor.

There is convincing evidence that COCs do not increase the incidence of breast cancer. Although some studies have suggested that COCs may increase the frequency of breast cancer, recent data do not confirm this.

Results of some studies indicate that COC use is associated with an increased risk of cervical cancer or intraepithelial neoplasia. However, there is no consensus on how much these results may be influenced by differences in sexual behavior and other factors.

The most important risk factor for cervical cancer is human papillomavirus infection.

Liver disorders

Yarina® Plus should be discontinued if jaundice occurs. In patients with impaired liver function, metabolism of steroid hormones may be altered. In cases of acute or chronic liver dysfunction, discontinuation of COC use may be necessary until liver function tests return to normal and a causal relationship with COC use is ruled out.

Hepatic adenoma has been associated with COC use. It is estimated that this risk is 3.3 cases per 100,000 women using COCs. Rupture of a hepatic adenoma can be fatal due to intraperitoneal hemorrhage.

Studies have shown an increased risk of hepatocellular carcinoma in individuals using COCs for a prolonged period (>8 years). However, the risk of liver cancer in women using COCs is less than 1 case per million individuals.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women using COCs, which in some cases have led to life-threatening intraperitoneal hemorrhage. In cases of complaints of severe epigastric pain, hepatomegaly, or signs of intraperitoneal hemorrhage, the possibility of a liver tumor associated with COC use should be considered in differential diagnosis.

Women with a history of cholestasis related to pregnancy may develop cholestasis associated with the use of oral contraceptives. Women with cholestasis due to COCs may experience recurrences upon re-exposure to COCs.

Increased risk of elevated liver enzymes with concomitant use of drugs for hepatitis C treatment

In clinical trials involving patients receiving hepatitis C therapy with drugs containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevations in ALT levels more than 5 times above the upper limit of normal (ULN), including some cases exceeding 20 times ULN, were observed significantly more frequently in women using drugs containing ethinylestradiol, such as COCs. Yarina® Plus should be discontinued before starting therapy with ombitasvir/paritaprevir/ritonavir with or without dasabuvir (see section "Contraindications"). Yarina® Plus may be restarted approximately 2 weeks after completion of hepatitis C treatment.

Increased blood pressure

In women with well-controlled hypertension, blood pressure should be monitored, and Yarina® Plus should be discontinued if a significant increase occurs. Women with uncontrolled hypertension or hypertension with concomitant vascular diseases should not use COCs.

Elevated blood pressure has been observed in women using COCs, occurring more frequently in older women and with prolonged use of the drug. The incidence of hypertension increases with higher progestin concentrations.

Gallbladder disorders

Study results indicate a slight increase in the relative risk of gallbladder disorders in women using COCs.

Effects on carbohydrate and lipid metabolism

Women with a predisposition to diabetes and diabetic patients should be closely monitored during Yarina® Plus use. COCs may cause dose-dependent decreases in glucose tolerance.

For women with uncontrolled dyslipidemia, alternative contraceptive methods should be considered. A small proportion of women may experience unfavorable changes in lipid metabolism during COC use.

In women with hypertriglyceridemia or a family history of this disorder, the risk of pancreatitis increases during COC use.

Headache

If a woman taking Yarina® Plus experiences recurrent, persistent, or severe headaches, a thorough evaluation should be performed, and Yarina® Plus should be discontinued if necessary.

An increase in the frequency or severity of migraines during COC use (which may be a precursor to cerebrovascular disorders) may be a reason for immediate discontinuation of COCs.

Irregular bleeding

During COC use, patients may occasionally experience irregular (breakthrough or intermenstrual) bleeding and spotting, especially during the first three months of use. In cases of persistent bleeding or bleeding after a previous regular cycle, the woman should be evaluated for pregnancy and malignant neoplasms. If pathology and pregnancy are ruled out, irregular bleeding may resolve over time or after switching to another COC.

Data from ten clinical studies on the contraceptive efficacy of Yarina® (N = 2467) showed that the number of women using Yarina® who experienced unplanned bleeding decreased from 12% in cycle 2 to 6% (cycle 13). Twenty-five patients out of 3009 in studies on Yarina® and Yarina® Plus (<1%) discontinued participation due to bleeding complaints. Complaints were described as metrorrhagia, vaginal bleeding, menorrhagia, withdrawal bleeding abnormalities, and menometrorrhagia.

The average number of bleeding days in most patients (86–88%) was 4–7 days. In women using Yarina® Plus, absence of withdrawal bleeding may occur, even if they are not pregnant. According to patient diary entries analyzed during contraceptive efficacy studies of Yarina®, 6–10% had cycles without withdrawal bleeding during cycles 2–13. Amenorrhea or oligomenorrhea may occur in some women due to contraceptive pills, especially if such disorders were previously observed.

In the absence of withdrawal bleeding, pregnancy should be considered. If the patient did not follow the prescribed regimen (missed one or more hormone-containing tablets or started taking them one day later than scheduled), the possibility of pregnancy should be considered and appropriate diagnostic measures taken at the first absence of withdrawal bleeding. If the patient followed the prescribed regimen and two consecutive withdrawal bleedings are absent, pregnancy should be ruled out.

Use of COCs before or during early pregnancy

Extended epidemiological studies have not shown any increased risk of fetal congenital malformations in women who used oral contraceptives before pregnancy. Studies have also not shown evidence of teratogenic effects, including no abnormalities in heart development or limb reduction defects, with unintentional use of the drug during early pregnancy. Upon confirmation of pregnancy, Yarina® Plus should be discontinued and prenatal vitamin supplements containing folic acid should be initiated.

Oral contraceptives should not be used to induce withdrawal bleeding as a pregnancy test (see section "Dosage and Administration").

Depression

Women with a history of depression should be closely monitored; Yarina® Plus should be discontinued in cases of severe depressive relapse.

Effects on laboratory test results

The use of contraceptive steroids may affect the results of certain laboratory tests, particularly coagulation factors, lipid levels, glucose tolerance, and binding proteins. Women receiving thyroid hormone replacement therapy may require higher doses of thyroid hormone, as serum concentration of thyroid hormone-binding globulin increases during COC use. Drospirenone increases plasma renin and aldosterone activity, induced by its moderate antimineralocorticoid activity. Folic acid may mask vitamin B12 deficiency.

Monitoring

Women taking COCs should visit their physician annually for blood pressure monitoring and other necessary examinations.

Other conditions

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma may develop in isolated cases, particularly in women who previously had chloasma of pregnancy. Women predisposed to chloasma should avoid exposure to sunlight or ultraviolet radiation during COC use.

Cases of Crohn's disease and ulcerative colitis have also been reported during COC use.

Each orange tablet of the drug contains 45 mg of lactose, and each light-orange tablet contains 48 mg of lactose. In cases of rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, or when on a lactose-free diet, this amount of lactose should be taken into account.

Use during pregnancy or breastfeeding.

Pregnancy. In women who unintentionally used COCs during early pregnancy, the risk of infant developmental defects is slightly increased or not increased at all. Epidemiological studies and meta-analysis results have not shown an increased risk of congenital malformations of sexual and other organs (including heart defects and limb reduction defects) after use of low-dose COCs before conception or during early pregnancy.

The use of COCs to stimulate withdrawal bleeding should not be used as a pregnancy test. COCs should not be taken during pregnancy to treat threatened miscarriage or recurrent miscarriages.

Women who are not breastfeeding may start using COCs no earlier than 4 weeks after childbirth.

Breastfeeding women. Women who are breastfeeding should be advised, if possible, to use alternative contraceptive methods until breastfeeding is discontinued. COCs containing estrogens may reduce milk production in breastfeeding women. After breastfeeding is established, such suppression is unlikely, but it may occur in individual women at any time. Steroid hormones contained in oral contraceptives or their metabolites pass into breast milk in small amounts.

After oral administration of tablets containing 3 mg drospirenone and 0.03 mg ethinylestradiol (Yarina®), approximately 0.02% of the drospirenone dose was detected in breast milk of postpartum women over 24 hours. Thus, the maximum daily dose received by the infant is about 0.003 mg drospirenone.

Available study results indicate no adverse effects of folic acid on infants who are breastfed.

Ability to affect reaction speed when driving vehicles or operating machinery.

No studies have been conducted on the effect on the ability to drive vehicles or operate machinery. No effects on the ability to drive vehicles or operate machinery have been reported in women taking combined oral contraceptives.

Dosage and Administration.

How to take Yarina® Plus

Take 1 tablet orally at the same time each day. If a tablet is missed or the drug is used incorrectly, effectiveness may be reduced.

To achieve maximum contraceptive efficacy, Yarina® Plus should be used as directed and in accordance with the instructions on the blister pack. If a tablet is missed, it should be taken as soon as possible.

How to start taking Yarina® Plus

Yarina® Plus should be started either on the first day of the menstrual cycle (Day 1 start) or on the first Sunday after the onset of menstruation (Sunday start).

• Day 1 start

During the first cycle of Yarina® Plus use, a woman should take 1 orange tablet daily, beginning on the first day of the menstrual cycle (the first day of menstruation is Day 1). The patient should take 1 orange tablet of Yarina® Plus daily for 21 consecutive days, followed by 1 light-orange tablet daily from days 22 to 28 of the cycle. Yarina® Plus should be taken according to the instructions on the packaging, at the same time each day, preferably after dinner or before bedtime, with a small amount of liquid, if needed. The administration of Yarina® Plus is independent of food intake. If the first tablet of Yarina® Plus is taken later than Day 1 of the menstrual cycle, contraceptive efficacy will only be achieved after 7 consecutive days of continuous use. In such cases, additional non-hormonal contraceptive methods should be used during the first 7 days of taking Yarina® Plus. The possibility of ovulation and fertilization prior to starting the medication should be considered.

• Sunday start

During the first cycle of Yarina® Plus use, a woman should take 1 orange tablet of Yarina® Plus daily for 21 consecutive days, followed by 1 light-orange tablet daily from days 22 to 28 of the cycle. Yarina® Plus should be taken according to the instructions on the packaging, at the same time each day, preferably after dinner or before bedtime, with a small amount of liquid, if needed. The administration of Yarina® Plus is independent of food intake. Contraceptive efficacy of Yarina® Plus is achieved no earlier than 7 days after continuous use. Additional non-hormonal contraceptive methods must be used during the first 7 days of taking Yarina® Plus. The possibility of ovulation and fertilization prior to starting the medication should be considered.

The patient should start the second and all subsequent 28-day courses of Yarina® Plus on the same day of the week as the first course, following the same administration schedule. The next course of orange tablets should begin the day after the last light-orange tablet containing folate is taken, regardless of whether menstruation has started or is still expected. Whenever the next course of Yarina® Plus is started later than the day following the last light-orange tablet, the patient should use an alternative contraceptive method until 7 consecutive days of taking the orange tablets of Yarina® Plus have been completed.

Switching from other oral contraceptives

When switching from other oral contraceptives, start taking Yarina® Plus on the day the next pack of the previous oral contraceptive would have been started.

Switching from other contraceptive methods, except oral contraceptives

When switching from a transdermal patch or vaginal ring, start taking Yarina® Plus on the day the next application of these contraceptive methods would have occurred. When switching from injectable contraceptives, start Yarina® Plus on the day the next injection would have been administered. When switching from an intrauterine device or implant, start taking Yarina® Plus on the day of its removal.

Withdrawal bleeding usually occurs within 3 days after taking the last orange tablet. If spotting or breakthrough bleeding occurs during Yarina® Plus use, continue taking the medication according to the regimen described above. Such bleeding is usually temporary and not clinically significant; however, if persistent or prolonged bleeding occurs, the woman should be examined by a physician.

Although the rate of pregnancy while using Yarina® Plus as directed is low, the possibility of pregnancy should be considered if withdrawal bleeding does not occur. If the patient has not followed the prescribed regimen (e.g., missed 1 or more active tablets or started taking them later than required), the possibility of pregnancy should be considered at the first absence of withdrawal bleeding, and appropriate diagnostic measures should be taken. If the patient has followed the prescribed regimen and misses two consecutive withdrawal bleedings, pregnancy should be ruled out. If pregnancy is confirmed, Yarina® Plus should be discontinued.

The risk of pregnancy increases with each missed active orange tablet.

What to do if a tablet is missed

One orange tablet in the pack is missed.

Take the tablet as soon as the patient remembers. Take the next tablet at the usual time. This means that 2 tablets may be taken in one day.

There is no need for additional contraceptive methods during sexual intercourse.

Two consecutive orange tablets are missed during "Week 1" or "Week 2" of the blister pack.

Take 2 tablets on the day the missed dose is remembered and 2 tablets the next day.

Then continue taking 1 tablet daily until the pack is finished.

If sexual intercourse occurs within the next 7 days after resuming tablet intake, the possibility of pregnancy should be considered. An additional contraceptive method (e.g., condom and spermicide) should be used during these 7 days.

Two consecutive orange tablets are missed during "Week 3" of the blister pack.

If Yarina® Plus was started on Day 1 of the cycle, discontinue the current pack and start a new pack on the same day.

If Yarina® Plus was started on a Sunday, continue taking 1 tablet daily until Sunday. On Sunday, discontinue the current pack and start a new pack on the same day.

If sexual intercourse occurs within the next 7 days after resuming tablet intake, the possibility of pregnancy should be considered. An additional contraceptive method (e.g., condom and spermicide) should be used during these 7 days.

Withdrawal bleeding is expected to be absent in this cycle. However, if two consecutive withdrawal bleedings are absent in two cycles, pregnancy should be ruled out.

Three or more consecutive orange tablets are missed during any week

If Yarina® Plus was started on Day 1 of the cycle, discontinue the current pack and start a new pack on the same day.

If Yarina® Plus was started on a Sunday, continue taking 1 tablet daily until Sunday. On Sunday, discontinue the current pack and start a new pack on the same day.

If sexual intercourse occurs within the next 7 days after resuming tablet intake, the possibility of pregnancy should be considered. An additional contraceptive method (e.g., condom and spermicide) should be used during these 7 days.

Withdrawal bleeding is expected to be absent in this cycle. However, if two consecutive withdrawal bleedings are absent in two cycles, pregnancy should be ruled out.

Any of the 7 light-orange tablets during "Week 4" is missed

Remove the missed tablet from the blister pack.

Continue taking 1 tablet daily until all tablets in the blister pack are used.

There is no need for additional contraceptive methods.

If, despite the above recommendations, the patient is unsure how to proceed after missing tablets

Use an additional contraceptive method (e.g., condom and spermicide) during sexual intercourse.

Consult a physician and continue taking 1 active orange tablet daily unless otherwise instructed.

If breakthrough bleeding occurs after missing tablets, this is usually temporary and without consequence. If the patient misses one or more light-orange tablets, contraceptive protection is maintained provided she starts the next course of orange tablets on the correct day.

Due to the increased risk of thromboembolism, women in the postpartum period who are not breastfeeding, and women after second-trimester abortion, should not start taking Yarina® Plus earlier than 4 weeks after delivery. If a woman starts taking Yarina® Plus after delivery and has not yet had a menstrual period, she should be tested for pregnancy and informed about the need to use an additional contraceptive method until she has taken Yarina® Plus tablets continuously for 7 days.

Recommendations in case of gastrointestinal disturbances.

In case of severe vomiting or diarrhea, incomplete absorption of the drug may occur. In such cases, additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking a Yarina® Plus tablet, this situation is similar to missing a dose; therefore, follow the recommendations for missed tablets.

Folates.

The U.S. Preventive Services Task Force recommends that women of reproductive age supplement their diet daily with at least 0.4 mg (400 mcg) of folic acid. Before prescribing Yarina® Plus, it is necessary to determine whether the woman is taking folates and to consider this. If Yarina® Plus is discontinued due to pregnancy, continued intake of folates by the woman should be ensured.

Use in elderly patients.

The use of Yarina® Plus in postmenopausal women has not been studied; the drug should not be prescribed to patients in this age group.

Patients with renal impairment.

Yarina® Plus is contraindicated in patients with impaired renal function.

The effect of renal impairment on the pharmacokinetic properties of drospirenone (3 mg daily for 14 days) and the effect of drospirenone on serum potassium concentration were studied in three separate groups of women (n = 28, age 30–65). All subjects were on a low-potassium diet. During the study, 7 individuals continued taking potassium-sparing medications for their underlying condition. On Day 14 of drospirenone therapy (steady state), serum concentrations of drospirenone in the group with creatinine clearance of 50–79 mL/min were similar to those in the group with creatinine clearance ≥ 80 mL/min. In individuals with creatinine clearance of 30–49 mL/min, serum concentrations of drospirenone were on average 37% higher than in the control group. Drospirenone treatment did not show any clinically significant effect on serum potassium levels. Although hyperkalemia was not observed in the study, mean serum potassium concentration increased by 0.33 mEq/L in 5 out of 7 individuals who continued using potassium-sparing medications during the study (see sections "Contraindications" and "Special precautions").

Patients with hepatic impairment.

Yarina® Plus is contraindicated in patients with liver disease.

The mean exposure to drospirenone in women with moderate hepatic impairment is nearly three times higher than in women with normal liver function. Yarina® Plus has not been studied in women with severe hepatic impairment (see sections "Contraindications" and "Special precautions").

Race differences.

No clinically significant differences in the pharmacokinetic properties of drospirenone or ethinylestradiol were observed between Japanese women and Caucasian women (aged 25–35 years) receiving a daily dose of a 3 mg drospirenone/0.02 mg ethinylestradiol formulation for 21 days. No specific studies have been conducted in other ethnic groups.

Children.

The safety and efficacy of Yarina® Plus have been established in women of reproductive age. The drug is expected to have similar efficacy in post-pubertal adolescents under 18 years of age and in patients aged 18 years and older. This medicinal product should not be administered before the onset of menstruation.

Overdose.

There are no reports of serious adverse outcomes from overdose, including in cases of ingestion by children. Overdose may cause withdrawal bleeding and nausea in women.

Drospirenone is a spironolactone analogue with antimineralocorticoid properties. In case of overdose, serum potassium and sodium concentrations should be monitored, and signs of metabolic acidosis should be observed.

Levomefolate calcium at a dose of 17 mg per day (37 times higher than the levomefolate calcium dose in Yarina® Plus) was well tolerated during prolonged treatment up to 12 weeks.

Adverse Reactions

Serious adverse reactions associated with the use of COCs are described in other sections of this package leaflet:

• Serious cardiovascular disorders and stroke (see section "Special Warnings and Precautions for Use");
• Vascular events (see section "Special Warnings and Precautions for Use");
• Liver disease (see section "Special Warnings and Precautions for Use").

Common adverse reactions observed in women using COCs:

• Irregular uterine bleeding;
• Nausea;
• Breast tenderness;
• Headache.

Clinical Trial Data

Because clinical trial conditions vary widely, the frequency of adverse reactions observed in one trial may not be directly comparable to frequencies in other clinical trials and may not reflect the frequency observed in clinical practice.

Clinical trials assessing contraceptive efficacy and folate status maintenance

The data reflect the experience of using the drug "Yasmin®" (3 mg drospirenone / 0.03 mg ethinylestradiol) in an adequate controlled trial assessing contraceptive efficacy (N = 2837) and folate status maintenance (N = 172).

Regarding contraceptive efficacy (N = 326), a multicenter, open-label study was conducted in the United States involving healthy women aged 18 to 35 years who used "Yasmin®" for up to 13 cycles. A second registration clinical trial (N = 442) was a multicenter, randomized, open-label, comparative European study of "Yasmin®" versus 0.150 mg desogestrel / 0.03 mg ethinylestradiol in healthy women aged 17 to 40 years who received the treatments for up to 26 cycles. For evaluating the primary efficacy of "Yasmin® Plus" in maintaining folate status, a randomized, single-center European study was conducted in 172 healthy women aged 18 to 40 years to compare the pharmacodynamic effects of "Yasmin®" + 0.451 mg calcium levomefolate versus co-administration of "Yasmin®" with folic acid over 24 weeks of treatment, followed by a 20-week open-label study of "Yasmin®" use.

Adverse reactions observed during use for both indications were similar and are presented with frequencies based on combined data sets. The most common adverse reactions (≥ 2%) were: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressive mood, irritability, mood alteration, mood changes and affective lability) (2.3%), abdominal pain/discomfort/tenderness (2.2%).

Adverse Reactions (≥1%) Leading to Discontinuation from Clinical Trials

Clinical trials assessing contraceptive efficacy. Of 2837 women, 6.7% discontinued the trials due to adverse reactions, the most common being headache/migraine (1.5%).

Clinical trials assessing efficacy of folate supplementation. No adverse reactions led to discontinuation from the trials.

Serious Adverse Reactions

Clinical trials assessing contraceptive efficacy: depression, pulmonary embolism, toxic skin eruption, uterine leiomyoma.

Clinical trial assessing efficacy of folate supplementation: no serious adverse reactions were reported.

Post-Marketing Experience

The following adverse reactions have been identified during post-marketing use of "Yasmin®". Because these reports are voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular system disorders: Venous and arterial thromboembolic events (including pulmonary embolism, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein thrombosis, myocardial infarction, and stroke), arterial hypertension.

Hepatobiliary disorders: Gallbladder disease.

Immune system disorders: Hypersensitivity.

Nutrition and metabolism disorders: Hyperkalemia.

Skin and subcutaneous tissue disorders: Chloasma.

Shelf Life.

36 months.

Storage Conditions.

Store in a place inaccessible to children at a temperature not exceeding 25°C.

Packaging.

28 film-coated tablets per blister with calendar scale, 1 or 3 blisters per cardboard pack.

Prescription Category.

Prescription only.

Manufacturer.

Bayer AG.

Manufacturer's Name and Address.

Müllerstrasse 178, 13353, Berlin, Germany / Mullerstrasse 178, 13353, Berlin, Germany.