Yarina®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT YARYNA® (YARYNA®)

Composition:

Active substances: ethinylestradiol, drosperinone;

One coated tablet contains ethinylestradiol 0.03 mg and drosperinone 3 mg;

Excipients: lactose monohydrate, maize starch, pregelatinized maize starch, povidone, magnesium stearate, hydroxypropylmethylcellulose, macrogol 6000, talc, titanium dioxide (E 171), yellow iron oxide (E 172).

Pharmaceutical form. Coated tablets.

Main physico-chemical properties: coated tablets, light yellow in color, round and biconvex in shape, marked "DO" inside a hexagon on one side.

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

Fixed combinations of progestogens and estrogens. Drosperinone and ethinylestradiol.

ATC code G03A A12.

Pharmacological Properties

Pharmacodynamics.

The Pearl Index for contraceptive failures for the drug is 0.09 (upper two-sided 95% confidence interval (CI) – 0.32).

The overall Pearl Index (contraceptive failures + user errors) for the drug is 0.57 (upper two-sided 95% CI – 0.90).

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

The medicinal product Yarina® is a combined oral contraceptive containing ethinylestradiol and the progestogen drospirenone. At therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It has no estrogenic, glucocorticoid, or antiglucocorticoid activity. Thus, drospirenone has a pharmacological profile similar to that of natural progesterone.

According to clinical study data, the moderate antimineralocorticoid properties of Yarina® result in a moderate antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentration, amounting to 38 ng/mL, is reached approximately 1–2 hours after single oral administration. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, drospirenone serum concentration decreases with a mean terminal half-life of about 31 hours. Drospirenone binds to serum albumin, but does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of total drospirenone concentration is present in serum as free steroid. The increase in SHBG levels induced by ethinylestradiol does not affect the binding of drospirenone to serum proteins. The mean apparent volume of distribution of drospirenone is 3.7±1.21 L/kg.

Metabolism. After oral administration, drospirenone is extensively metabolized. The main metabolites in plasma are the acid form of drospirenone, formed by opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, formed by hydration followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Elimination. The metabolic clearance of drospirenone from serum is 1.5±0.2 mL/min/kg. Only a negligible amount of drospirenone is excreted unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of approximately 1.2:1.4. The elimination half-life of metabolites in urine and feces is about 40 hours.

Steady-state concentration. During the treatment cycle, maximum steady-state concentration of drospirenone in serum, approximately 70 ng/mL, is reached after about 8 days of treatment. Serum concentration of drospirenone increased about threefold due to the relationship between terminal half-life and dosing interval.

Special patient populations

Effect of renal impairment. At steady state during drospirenone therapy, similar serum concentrations of drospirenone were observed in women with mild renal impairment (creatinine clearance 50–80 mL/min) and in women with normal renal function. In women with moderate renal impairment (creatinine clearance 30–50 mL/min), serum concentrations of drospirenone were on average 37% higher than in women with normal renal function. Drospirenone therapy was well tolerated in women with mild to moderate renal impairment. Drospirenone therapy showed no clinically significant effect on serum potassium concentrations.

Effect of hepatic impairment. In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared to volunteers with normal liver function. The observed deviation in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences regarding serum potassium concentrations. Even in the presence of diabetes mellitus and concomitant therapy with spironolactone (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnic origin. No clinically significant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between Japanese women and Europeans.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Following a 30 µg dose, peak plasma concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass metabolism, which is subject to individual variability.

Absolute bioavailability is approximately 45%.

Distribution. The expected volume of distribution of ethinylestradiol is approximately 5 L/kg, and protein binding to plasma proteins is about 98%. Ethinylestradiol induces hepatic synthesis of SHBG and corticosteroid-binding globulins. With administration of 30 µg ethinylestradiol, plasma concentration of SHBG increases from 70 to about 350 nmol/L.

Ethinylestradiol is excreted in small amounts in breast milk (0.02% of the dose).

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first pass through the liver. Ethinylestradiol is primarily metabolized via aromatic hydroxylation, forming a large number of hydroxylated and ethylated metabolites, which are present as free metabolites and conjugates with glucuronides and sulfates. Metabolic plasma clearance of ethinylestradiol is about 5 mL/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and a mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Metabolites of ethinylestradiol are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is about 1 day. The elimination half-life of metabolites is 20 hours.

Steady-state concentration. Steady-state concentration is achieved during the second half of the treatment cycle, and the plasma level of ethinylestradiol increases approximately 1.4–2.1 times.

Preclinical safety data.

In laboratory animals, effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological activity. In particular, reproductive toxicity studies in animals showed species-specific embryotoxic and fetotoxic effects. Exposure exceeding that in Yarina® users was associated with effects on sexual differentiation in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Safety precautions").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the conditions listed below are present. If any of these conditions occur for the first time during CHC use, the medication should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE).
  • Current venous thromboembolism, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • Known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • Major surgery with prolonged immobilization (see section "Special precautions");
  • High risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE).
  • Current or past arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • Current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to the presence of a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function tests return to normal range.
• Severe or acute renal insufficiency.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant tumors (e.g., of genital organs or breasts).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medication.
• Suspected or confirmed pregnancy.

Concomitant use of the medicinal product Yarina® with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Special safety measures.

This medicinal product may be hazardous to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Information on concomitantly administered medicinal products should be reviewed to identify potential interactions.

• Effect of other medicinal products on Yarina®

Interactions are possible with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, resulting in changes in menstrual bleeding patterns and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of treatment initiation. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to COCs. The barrier method should be used throughout the treatment period with the enzyme-inducing agent and for an additional 28 days after discontinuation of the drug. If treatment is initiated during the period of taking the last tablets from the COC pack, the next pack of COCs should be started immediately after the previous one, without the usual tablet-free interval.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another appropriate non-hormonal contraceptive method.

The following interactions have been reported according to published data.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; medicinal products used in HIV infection: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal products containing St. John's wort (Hypericum perforatum).

Substances with variable effects on COC clearance:

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the medical use of the medicinal product for treatment of HIV/HCV should be reviewed to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances decreasing COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both components.

In a multiple-dose study of the combination drospirenone (3 mg/day)/ethinylestradiol (0.002 mg/day) and the strong CYP3A4 inhibitor ketoconazole administered concomitantly for 10 days, the AUC(0-24h) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively.

Etoricoxib at doses of 60 to 120 mg/day demonstrated a 1.4- to 1.6-fold increase in ethinylestradiol plasma concentrations, respectively, when administered concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Yarina® on other medicinal products

Oral contraceptives may affect the metabolism of certain active substances. Consequently, plasma and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as probe substrates, clinically significant interactions of drospirenone at a dose of 3 mg with other active substances metabolized by cytochrome P450 are unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

During clinical trials involving patients receiving medicinal products for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN) were observed. This occurred more frequently in women taking medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, increased ALT levels were also observed in women taking ethinylestradiol-containing medicinal products, such as CHCs, during treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Contraindications").

Therefore, women using Yarina® should temporarily switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the aforementioned combination of medicinal products. Yarina® may be resumed 2 weeks after completion of therapy with the specified combination.

In patients with normal renal function, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Yarina® with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first treatment cycle (see also section "Special precautions").

Other forms of interaction

Laboratory tests. Use of contraceptive steroids may influence the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma concentrations of transport proteins such as corticosteroid-binding globulin; plasma concentrations of lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. These changes are usually within normal ranges.

Drospirenone increases plasma renin and aldosterone activity, induced by its moderate anti-mineralocorticoid activity.

Special precautions.

The decision to prescribe the medicinal product Yasmin® should be made taking into account individual risk factors currently present in a woman, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with the use of Yasmin® compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Warning

• If any of the conditions or risk factors listed below are present, the need for using Yasmin® should be discussed with the woman.
• In case of exacerbation or at the first signs of any of the listed conditions or risk factors, women are advised to consult a physician to determine whether discontinuation of Yasmin® is necessary.
• Combined hormonal contraceptives (CHCs) should be discontinued if VTE or arterial thromboembolism (ATE) is suspected or confirmed. If anticoagulant therapy is initiated, an alternative effective contraception should be provided due to the teratogenic effect of anticoagulants (coumarins).
• Circulatory disorders.

Risk of venous thromboembolism (VTE)

The use of any CHCs increases the risk of venous thromboembolism (VTE) in women using them compared to women who do not use them. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. The use of other medicinal products, such as Yasmin®, may double the risk. The decision to use products other than those with the lowest risk of VTE should be made only after discussion with the woman. It is essential to ensure that she understands the risk of VTE associated with the use of Yasmin®, the impact of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming CHC use after a break of 4 weeks or longer.

Among 2 out of 10,000 women who do not use CHCs and are not pregnant, VTE develops within one year. However, in individual women, the risk may be significantly higher depending on existing risk factors (see below).

It has been established¹ that among 10,000 women using CHCs containing drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of 6 per 10,000 women using CHCs containing levonorgestrel.

In both cases, the annual number of VTE events was lower than typically expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

¹ These estimates are based on all available epidemiological data, taking into account relative risks associated with the use of different CHCs compared to CHCs containing levonorgestrel.

² On average, 5–7 cases per 10,000 woman-years, based on the relative risk calculation for CHCs containing levonorgestrel compared to non-users of CHCs (approximately 2.3–3.6 cases).

Very rarely, thrombosis in other blood vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, cerebral vessels, or retinal vessels, has been reported in women using CHCs.

Risk factors for VTE

The risk of venous thromboembolic complications in women using CHCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Yasmin® is contraindicated in women with multiple risk factors that may increase the risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor; therefore, the overall risk of VTE should be considered. If the benefit-risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1.

Risk factors for VTE

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the development and progression of venous thrombosis.

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially within 6 weeks after delivery (for information on pregnancy and lactation, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

Women should be advised to seek immediate medical attention and inform their physician that they are taking COCs if any of the symptoms listed below occur.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or along a vein in the leg; pain or tenderness in the leg, which may only be felt when standing or walking; warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include: sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; syncope or dizziness; rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as more common or less severe conditions (e.g., respiratory tract infections).

Other manifestations of vascular occlusion may include sudden pain, swelling, acute abdomen, and mild cyanosis of a limb.

In occlusion of ocular vessels, initial symptoms may include blurred vision without pain, which may progress to vision loss. Sometimes, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies indicate that use of any COCs 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 ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular complications increases in women with risk factors (see Table 2). Use of Yarina® is contraindicated in women who have one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the risk increase may be greater than the sum of risks associated with each individual factor, so the overall risk should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2.

Risk factors for ATE

Signs of ATE

Women should be advised to seek immediate medical attention and inform their physician that they are taking COCs if any of the following symptoms occur.

Symptoms of cerebrovascular disorders may include: sudden numbness of the face, weakness or numbness of the extremities, especially unilateral; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension disturbances; sudden visual impairment in one or both eyes; sudden, severe or prolonged headache without apparent cause; loss of consciousness or fainting with or without seizures.

Transient nature of symptoms may indicate transient ischemic attack (TIA).

Symptoms of myocardial infarction may include: pain, discomfort, pressure or heaviness in the chest, arm or below the sternum; discomfort radiating to the back, jaw, throat, arm, or stomach; feeling of fullness, indigestion or suffocation; excessive sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or dyspnea; rapid or irregular heartbeat.

Tumors

Results of some epidemiological studies suggest an additional increased risk of cervical cancer with long-term use of COCs (> 5 years), although this statement remains controversial, since it has not been definitively established to what extent study results account for concomitant risk factors such as sexual behavior and other factors such as human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer in women currently or recently using COCs is negligible relative to the overall risk of breast cancer. Results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors. There is a trend that breast cancer diagnosed in women who have ever taken COCs is clinically less severe than in those who have never used COCs.

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

Use of COCs at high doses (50 mcg ethinyl estradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these data apply to low-dose COCs as well.

Other conditions

The progestin component of the medicinal product Yarina® is an aldosterone antagonist with potassium-sparing properties. In most cases, increased potassium levels are not expected during use. During clinical trials, slight but not clinically significant increases in serum potassium levels were observed in some patients with mild to moderate renal insufficiency who were simultaneously taking potassium-sparing medicinal products during treatment with drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first treatment cycle in patients with renal insufficiency. These patients are also advised to maintain serum potassium levels not exceeding the upper limit of normal before starting treatment, especially when taking potassium-sparing medicinal products concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Women with hypertriglyceridemia or a family history of this condition are at increased risk of developing pancreatitis when using COCs.

Although slight increases in blood pressure have been reported in many women taking COCs, clinically significant hypertension is observed only in rare cases. Immediate discontinuation of COCs is required only in these rare cases. In case of persistent hypertension or inability to control blood pressure with antihypertensive agents, women taking COCs should discontinue their use. If appropriate, COC use may be resumed after achieving normotension with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and with COC use, but their relationship to estrogen/progestin use has not been definitively established: cholestatic jaundice and/or pruritus, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Metabolism of steroid hormones may be impaired in patients with liver dysfunction. Acute or chronic liver disorders may require discontinuation of COCs until liver function tests return to normal and a causal relationship with COCs is excluded.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or cholestatic pruritus previously experienced during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating the need to modify therapeutic regimens in diabetic women taking low-dose COCs (< 0.05 mg ethinyl estradiol). However, women with diabetes should be carefully monitored during COC use, especially at the beginning of treatment.

Exacerbations of epilepsy, Crohn's disease, and ulcerative colitis have also been observed during COC use.

Depressed mood and depression are well-known adverse effects that may occur during use of hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult a physician if mood changes or symptoms of depression occur, including soon after starting treatment.

Chloasma may occasionally occur, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during COC use.

One tablet of the medicinal product contains 46 mg of lactose. In the presence of rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, or when on a lactose-free diet, this lactose content should be taken into account.

Consultations/Medical examination

Before initiating or resuming use of the medicinal product Yarina®, a complete medical and family history should be taken, a full medical examination performed, and pregnancy excluded. Blood pressure should be measured and a medical examination conducted, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Yarina® compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

Patients are advised to carefully read the package leaflet and follow the recommendations provided therein.

The frequency and nature of examinations should be based on current medical practice guidelines, taking into account individual characteristics of each woman.

Patients should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted diseases.

Reduced efficacy

The efficacy of COCs may be reduced in case of missed tablet intake (see section "Dosage and administration"), gastrointestinal disorders (see section "Dosage and administration"), or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Cycle disturbances

Irregular bleeding (spotting or breakthrough bleeding) may occur during COC use, especially during the first few months. If such bleeding persists after three menstrual cycles, it should be considered significant.

If irregular bleeding persists or appears after a period of regular bleeding, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures taken, including evaluation to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to the instructions in the section "Dosage and administration," pregnancy is unlikely. However, if COCs have been taken irregularly before the absence of the first withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is contraindicated during pregnancy. If pregnancy occurs during use of Yarina®, treatment must be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor do they indicate teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological properties"). Based on these animal studies, adverse effects due to the hormonal activity of the active substances cannot be excluded. However, overall experience with COC use during pregnancy does not indicate an adverse effect in humans.

Available data on use of the medicinal product during pregnancy are too limited to draw conclusions regarding any negative impact of Yarina® on pregnancy outcome, fetal or neonatal health. Currently, there are no relevant epidemiological data.

When resuming use of Yarina®, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration," "Special precautions for use").

Breastfeeding. COCs may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Therefore, COCs are not recommended during breastfeeding. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the infant.

Effect on ability to drive and use machines.

No studies on the effect on the ability to drive or operate machinery have been conducted. There have been no reports of effects on the ability to drive or operate machinery in women taking combined oral contraceptives.

Method of Administration and Dosage

Orally.

Dosing

The tablets should be taken regularly at approximately the same time each day, swallowed with a small amount of liquid if necessary, in the order indicated on the blister pack. The medication is taken as 1 tablet daily for 21 consecutive days. After this, a 7-day tablet-free interval should be observed, during which withdrawal bleeding usually occurs. The next pack should be started after completion of this 7-day break. Withdrawal bleeding typically begins on the 2nd or 3rd day after taking the last tablet and may continue until the start of the next pack.

How to Start Using the Medicinal Product Yarina®

• No previous use of hormonal contraceptives (previous month)

Tablet intake should begin on the first day of the natural cycle (i.e., the first day of menstrual bleeding).

• Switching from combined oral contraceptives (COCs), vaginal ring, or transdermal patch

It is recommended to take the first tablet of Yarina® the day after the last active tablet (i.e., the tablet containing the active ingredient) of the previous COC. However, it should not be later than the day after the tablet-free interval or the interval for hormone-free tablets of the previous COC. When switching from a vaginal ring or transdermal patch, start taking Yarina® on the day of removal of the device, but no later than the day when the next application of these products would have been required.

• Switching from a progestogen-only method ("mini-pill", injection, implant) or intrauterine system containing progestogen

Yarina® can be started at any time after discontinuation of the "mini-pill" (in the case of an implant or intrauterine system – on the day of removal; in the case of an injection – instead of the next scheduled injection). However, in all cases, it is recommended to use an additional barrier method of contraception during the first 7 days of taking the medication.

• After first-trimester abortion

The medication can be started immediately. In this case, there is no need to use additional contraceptive methods.

• After childbirth or second-trimester abortion

It is recommended to start taking Yarina® on days 21–28 after childbirth or second-trimester abortion. If starting later, an additional barrier method of contraception should be used during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, possible pregnancy should be ruled out before starting the medication, or the woman should wait for the onset of the first menstrual period.

For breastfeeding women, see section "Use during pregnancy or breastfeeding".

What to Do if a Tablet is Missed

If the delay in taking any tablet does not exceed 12 hours, the contraceptive effect of the medication is not reduced. The missed tablet should be taken as soon as possible. The next tablet should be taken at the usual time.

If the delay in taking a tablet exceeds 12 hours, contraceptive protection may be reduced. In this case, two main principles should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamus-pituitary-ovarian system is achieved by continuous tablet intake for 7 days.

Accordingly, the following practical recommendations should be observed:

• Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. Additionally, use a barrier method of contraception (e.g., condom) for the next 7 days. If unprotected intercourse occurred in the previous 7 days, consider the possibility of pregnancy. The more tablets missed and the closer the missed dose is to the tablet-free interval, the higher the risk of pregnancy.

• Week 2

Take the last missed tablet as soon as remembered, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. If tablets were taken correctly for the 7 days prior to the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use a barrier method of contraception for 7 days.

• Week 3

The risk of reduced effectiveness increases as the 7-day tablet-free interval approaches. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided. If one of the regimens below is followed and tablets were taken correctly during the 7 days before the missed dose, no additional contraceptive methods are needed. If this is not the case, follow the first option below and use additional barrier methods for the next 7 days.

1. Take the last missed tablet as soon as remembered, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. Start the next pack immediately after finishing the current one, i.e., there should be no tablet-free interval between the two packs. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking tablets from the current pack. In this case, the medication-free interval should not exceed 7 days, including the days of missed tablets; then start the next pack.

If withdrawal bleeding does not occur during the first planned tablet-free interval after missing tablets, pregnancy should be considered.

Recommendations in Case of Gastrointestinal Disorders

In case of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the medication may occur; in such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the medication, take a new (replacement) tablet as soon as possible. The next tablet should be taken, if possible, within 12 hours, according to the usual dosing schedule. If more than 12 hours have passed, follow the recommendations provided above under "What to Do if a Tablet is Missed". If a woman does not wish to change her tablet-taking schedule, she should take additional tablet(s) from the next pack.

How to Delay Withdrawal Bleeding

To delay withdrawal bleeding, continue taking tablets from a new pack without a break. The duration of intake may be extended at will, up to the end of the second pack. Breakthrough bleeding or spotting may occur during this time. Usually, the use of Yarina® resumes after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. Note that the shorter the interval, the more likely it is that withdrawal bleeding will not occur and that breakthrough bleeding or spotting may occur during the intake of tablets from the second pack (similar to when delaying withdrawal bleeding).

Additional Information for Special Patient Groups

Elderly patients. The drug is not indicated after menopause.

Patients with hepatic impairment. Yarina® is contraindicated in women with severe hepatic impairment (see sections "Contraindications" and "Pharmacological Properties").

Patients with renal impairment. Yarina® is contraindicated in women with severe renal impairment or acute renal failure (see sections "Contraindications" and "Pharmacological Properties").

Children.

Yarina® is indicated only after the onset of menarche. Based on epidemiological data collected from over 2000 adolescents under 18 years of age, there is no evidence of differences in safety and efficacy in this patient group compared to women aged 18 years and older.

Overdose.

There are no clinical data on overdose with Yarina® tablets. Based on general experience with COCs, overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur even in girls before menarche in cases of accidental or unintentional intake of the medication. There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

For serious adverse reactions in women using COCs, see also section "Special precautions for use". The adverse reactions listed below were observed during the use of the medicinal product Yarina® (see Table 3).

Table 3.

Adverse reactions observed during the use of the medicinal product Yarina®.

Description of individual adverse reactions

An increased risk of venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism, has been observed in women using combined oral contraceptives (COCs), as further described in the section "Special warnings and precautions for use".

The following serious adverse reactions have been observed in women using COCs and have also been described in the section "Special warnings and precautions for use":

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumours;
• development or exacerbation of conditions whose relationship with COC use has not been definitively established: Crohn’s disease, non-specific ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uraemic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function parameters return to normal;

Adverse reactions observed in patients using COCs include emotional lability, depression; loss of libido; venous and arterial thromboembolic events, including occlusion of deep peripheral veins, thrombosis and pulmonary vascular embolism, myocardial infarction, stroke (including haemorrhagic stroke, ischaemic stroke, transient ischaemic attack); erythema.

Other adverse reactions associated with combined oral contraceptives are also listed in the sections "Contraindications" and "Special warnings and precautions for use" (including hearing loss associated with otosclerosis, hypertriglyceridaemia and increased risk of pancreatitis, gallstone formation, changes in glucose tolerance or effects on peripheral insulin resistance, jaundice and/or pruritus associated with cholestasis, hypersensitivity reactions including rash, urticaria).

The incidence of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases of breast cancer among women currently or recently using COCs is small in relation to the overall risk of breast cancer. The relationship with COC use is not known. See also sections "Contraindications" and "Special warnings and precautions for use".

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging.

21 film-coated tablets in a blister with a calendar strip, in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

Batch release authorization:

Bayer AG / Bayer AG

Manufacturer's address.

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