Yarina^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Contact Information

Bayer AG (Germany)

ATC Code

G03AA12 (Drospirenone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Dosage Form

Yarina®

Film-coated tablets, 30 mcg+3 mg: 21 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex, with a hexagon engraved on one side containing the letters “DO”.

Excipients: lactose monohydrate – 48.17 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone K25 – 4 mg, magnesium stearate – 0.8 mg.

Shell composition: hypromellose 5 cP – 1.0112 mg, macrogol 6000 – 0.2024 mg, talc – 0.2024 mg, titanium dioxide – 0.5565 mg, yellow iron oxide – 0.0275 mg.

21 pcs. – blisters (1) with a carrying pouch – cardboard packs with first-opening control.
21 pcs. – blisters (3) with a carrying pouch – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Contraceptive combined drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

Yarina^® is a low-dose monophasic oral combined estrogen-gestagen contraceptive drug.

The contraceptive effect of combined oral contraceptive drugs (COCs) is based on the interaction of various factors, the most important of which are suppression of ovulation, increased viscosity of cervical secretion, and changes in the endometrium.

When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for one year) for Yarina^® is less than 1. If tablets are missed or used incorrectly, the Pearl index may increase.

In women taking COCs, the menstrual cycle becomes more regular, painful menstrual-like bleeding is less common, and the intensity and duration of bleeding are reduced, thereby lowering the risk of iron deficiency anemia. There is also evidence of a reduced risk of endometrial and ovarian cancer when taking COCs.

Drospirenone, which is part of Yarina^®, has antimineralocorticoid activity and can prevent weight gain and the appearance of other symptoms (such as edema) associated with estrogen-dependent fluid retention. Drospirenone has a positive effect on premenstrual syndrome. In combination with ethinylestradiol, Drospirenone demonstrates a favorable effect on the lipid profile, characterized by an increase in HDL. Drospirenone also has antiandrogenic activity and helps reduce acne, oily skin, and seborrhea. These features of drospirenone should be considered when choosing a contraceptive for women with hormone-dependent fluid retention, as well as for women with acne and seborrhea.

Drospirenone does not possess androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. All this, combined with antimineralocorticoid and antiandrogenic action, gives drospirenone a biochemical and pharmacological profile similar to natural progesterone.

Pharmacokinetics

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed from the gastrointestinal tract. After a single dose, the C_max of drospirenone in plasma is reached in 1-2 hours and is 38 ng/ml. Food intake does not affect bioavailability, which ranges from 76 to 85%.

Distribution

Drospirenone binds to plasma albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3-5% of the total plasma concentration is present in free form, 95-97% of the substance is non-specifically bound to albumin. Ethinylestradiol-induced increase in SHBG does not affect the binding of drospirenone to plasma proteins. The mean apparent V_d is 3.7±1.2 L/kg.

Steady-state concentration. SHBG concentration does not affect the pharmacokinetic parameters of drospirenone. With daily oral administration, the plasma concentration of drospirenone increases 2-3 times, C_ss is reached after 8 days of drug administration.

Metabolism

After oral administration, Drospirenone is completely metabolized. Most metabolites in plasma are represented by acidic forms of drospirenone. Drospirenone is also a substrate for oxidative metabolism catalyzed by the CYP3A4 isoenzyme. The metabolic clearance rate of drospirenone from plasma is 1.5±0.2 ml/min/kg.

Excretion

The plasma concentration of drospirenone decreases in two phases. In the second, terminal, phase T_1/2 is about 31 hours. Drospirenone is excreted unchanged in trace amounts. Its metabolites are excreted via the gastrointestinal tract and kidneys in a ratio of approximately 1.2:1.4. The T_1/2 of drospirenone metabolites is approximately 40 hours.

Pharmacokinetics in special patient groups

Renal impairment. Studies have shown that the plasma concentration of drospirenone in women with mild renal impairment (creatinine clearance – 50-80 ml/min) at steady state and in women with normal renal function (creatinine clearance – greater than 80 ml/min) are comparable. However, in women with moderate renal impairment (creatinine clearance – 30-50 ml/min), the mean plasma concentration of drospirenone was 37% higher than in patients with normal renal function. No change in plasma potassium concentration was observed with drospirenone use. The pharmacokinetics of drospirenone has not been studied in patients with severe renal impairment.

Hepatic impairment. In women with moderate hepatic impairment (Child-Pugh class B), the AUC is comparable to that in healthy women with similar C_max values in the absorption and distribution phase. The T_1/2 of drospirenone in patients with moderate hepatic impairment was 1.8 times higher than in healthy volunteers. In patients with moderate hepatic impairment, a decrease in drospirenone clearance of approximately 50% was noted compared to healthy women, with no differences in plasma potassium concentration in the studied groups. When diabetes mellitus was detected and spironolactone was used concomitantly (both conditions are considered factors predisposing to hyperkalemia), no increase in plasma potassium concentration was found. Thus, it can be concluded that the tolerability of drospirenone in women with mild to moderate hepatic impairment is good (Child-Pugh class B). The pharmacokinetics of drospirenone has not been studied in patients with severe hepatic impairment.

Ethinylestradiol

Absorption

After oral administration of the drug, Ethinylestradiol is rapidly and completely absorbed from the gastrointestinal tract.

C_max in plasma is reached in 1-2 hours and is 100 pg/ml. Ethinylestradiol undergoes first-pass effect through the liver, resulting in an oral bioavailability of about 45% with high interindividual variability – from 20 to 65%. Concurrent food intake in some cases is accompanied by a 25% decrease in the bioavailability of ethinylestradiol.

Distribution

Ethinylestradiol is non-specifically but strongly bound to plasma albumin (about 98%) and induces an increase in plasma SHBG concentration. The estimated V_d is 5 L/kg.

Steady-state concentration. Steady state is reached in the second half of the drug administration cycle, when the plasma concentration of ethinylestradiol increases by 40-110% compared to a single dose.

Metabolism

Ethinylestradiol undergoes significant primary metabolism in the intestine and liver. Ethinylestradiol and its oxidative metabolites are primarily conjugated with glucuronides or sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.

Excretion

The decrease in plasma ethinylestradiol concentration is biphasic; the first phase is characterized by a half-life of about 1 hour, the second – 20 hours. Ethinylestradiol is almost not excreted unchanged. Ethinylestradiol metabolites are excreted by the kidneys and through the intestine in a 4:6 ratio. The T_1/2 of metabolites is approximately 24 hours.

Pharmacokinetics in special patient groups

Ethnicity. No effect of ethnicity (study conducted on cohorts of Caucasian and Japanese women) on the pharmacokinetic parameters of drospirenone and ethinylestradiol was established.

Indications

• Contraception.

ICD codes

Dosage Regimen

How and when to take the tablets

The calendar pack of Yarina^® contains 21 tablets. Each tablet in the pack is labeled with the day of the week it should be taken. The tablets should be taken orally every day for 21 days in the order indicated on the package, at approximately the same time, with a small amount of water. The intake of tablets from the next pack starts after a 7-day break, during which menstrual-like bleeding (withdrawal bleeding) usually occurs. As a rule, it begins on the 2nd-3rd day after taking the last tablet and may not end before starting the tablets from the new pack. After the 7-day break, it is necessary to start taking tablets from the new pack even if the menstrual-like bleeding has not stopped yet. This means that starting the tablets from the new pack must be on the same day of the week, and that each month the withdrawal bleeding will occur on approximately the same day of the week.

Starting Yarina^®

If no hormonal contraceptive was used in the previous month

Yarina^® should be started on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding). The tablet labeled with the corresponding day of the week should be taken. Then the tablets should be taken in order. Starting on the 2nd-5th day of the menstrual cycle is allowed, but in this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking tablets from the first pack.

When switching from other combined contraceptive drugs (COC, contraceptive vaginal ring, or contraceptive transdermal patch)

It is preferable to start taking Yarina^® the day after taking the last active tablet from the previous pack, but in no case later than the next day after the usual 7-day break (for drugs containing 21 tablets) or after taking the last inactive tablet (for drugs containing 28 tablets per pack). Yarina^® should be started after the usual break in taking active tablets when switching from contraceptive drugs with an extended regimen of use. Yarina^® should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch applied.

When switching from contraceptives containing only gestagens (“mini-pills”, injectable forms, implant), or from an intrauterine therapeutic system releasing gestagen

You can switch from “mini-pills” to Yarina^® on any day (without a break), from an implant or intrauterine contraceptive with gestagen – on the day of its removal, from an injectable form – on the day when the next injection is due. In all cases, during the first 7 days of taking Yarina^® tablets, it is necessary to additionally use a barrier method of contraception (for example, a condom).

After abortion (including spontaneous) in the first trimester of pregnancy

The drug can be started immediately. If this condition is met, no additional contraceptive measures are required.

After childbirth (in the absence of breastfeeding) or termination of pregnancy (including spontaneous) in the second trimester

The drug should be started on the 21st-28th day after childbirth (in the absence of breastfeeding) or termination of pregnancy in the second trimester. If the drug is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the tablets. If sexual intercourse occurred before starting Yarina^®, pregnancy must be ruled out.

Taking missed tablets

If the delay in taking the drug is less than 12 hours, contraceptive protection is not reduced. The woman should take the tablet as soon as possible, the next tablet is taken at the usual time.

If the delay in taking the drug is more than 12 hours, contraceptive protection is reduced. The more tablets are missed, and the closer the miss is to the 7-day break in taking the tablets, the greater the likelihood of pregnancy.

It must be remembered

• The drug intake should never be interrupted for more than 7 days.
• 7 days of continuous tablet intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking the tablet exceeds 12 hours (the interval since taking the last tablet is more than 36 hours), depending on the week when the tablet was missed, the following recommendations must be followed

First week of drug intake

It is necessary to take the last missed tablet as soon as possible, as soon as the woman remembers (even if this means taking 2 tablets at the same time). The next tablet is taken at the usual time. During the next 7 days, an additional barrier method of contraception (for example, a condom) must be used. If sexual intercourse occurred within 7 days before missing the tablet, the possibility of pregnancy must be considered.

Second week of drug intake

It is necessary to take the last missed tablet as soon as possible, as soon as the woman remembers (even if this means taking 2 tablets at the same time). The next tablet is taken at the usual time. Provided that the woman has taken the tablets correctly during the previous 7 days, there is no need to use additional contraceptive measures. Otherwise, and also if 2 or more tablets are missed, it is necessary to additionally use barrier methods of contraception (for example, a condom) for the next 7 days.

Third week of drug intake

The risk of reduced contraceptive reliability is inevitable due to the upcoming break in taking the tablets. In this case, the following algorithms must be followed

• If during the 7 days preceding the first missed tablet, all tablets were taken correctly, there is no need to use additional methods of contraception. When taking missed tablets, follow points 1 or 2;
• If during the 7 days preceding the first missed tablet, the tablets were taken incorrectly, then during the next 7 days it is necessary to additionally use a barrier method of contraception (for example, a condom) and in this case, one should be guided by point 1 for taking missed tablets.

1. It is necessary to take the missed tablet as soon as possible, as soon as the woman remembers (even if this means taking 2 tablets at the same time). The next tablets are taken at the usual time until the tablets from the current pack are finished. The intake of tablets from the next pack should be started immediately without the usual 7-day break. Withdrawal bleeding is unlikely until the tablets from the second pack are finished, but spotting and/or breakthrough bleeding may be noted on the days of taking the drug.
2. You can also interrupt taking the tablets from the current pack, take a break for 7 or fewer days (including the days of missing tablets), and then start taking tablets from a new pack.

If a woman missed taking tablets, and then during the break in taking she does not have withdrawal bleeding, pregnancy must be ruled out.

Action plan in case of violation of the tablet intake regimen

It is allowed to take no more than 2 tablets in one day.

Recommendations for gastrointestinal disorders

In case of severe gastrointestinal disorders, the absorption of the drug may be incomplete, so additional methods of contraception should be used.

If vomiting or diarrhea occurs within 3-4 hours after taking the tablets, depending on the week of drug intake, one should be guided by the recommendations for missed tablets indicated above. If the woman does not want to change her usual regimen and shift the start of menstruation to another day of the week, an additional tablet should be taken from another pack.

Discontinuation of Yarina^®

Yarina^® can be discontinued at any time. If the woman is not planning a pregnancy, she should take care of other methods of contraception. If pregnancy is planned, one should simply stop taking Yarina^® and wait for natural menstrual bleeding.

Delaying the onset of menstrual-like bleeding

To delay the onset of menstrual-like bleeding, it is necessary to continue further intake of tablets from a new pack of Yarina^® without a 7-day break. The tablets from the new pack can be taken for as long as necessary, including until the tablets in the pack run out. While taking the drug from the second pack, spotting vaginal bleeding and/or breakthrough uterine bleeding may be noted. Resumption of Yarina^® intake from the next pack should be after the usual 7-day break.

Changing the start day of the menstrual cycle

To shift the day of the onset of withdrawal bleeding to another day of the week, a woman should shorten (but not lengthen) the nearest 7-day tablet-free interval by as many days as she wishes. For example, if the cycle usually starts on Friday, and in the future the woman wants it to start on Tuesday (3 days earlier), the intake of tablets from the next pack must be started 3 days earlier than usual. The shorter the tablet-free interval, the higher the likelihood that withdrawal bleeding will not occur, and spotting and/or breakthrough bleeding will be observed during the intake of tablets from the second pack.

Use in specific patient groups

Adolescent girls. The drug Yarina^® is indicated only after menarche. Available data do not suggest a dose adjustment in this patient group.

Elderly patients. Not applicable. The drug Yarina^® is not indicated after the onset of menopause.

Liver function impairment. The drug Yarina^® is contraindicated in women with severe liver diseases until liver function tests return to normal (see also sections “Contraindications” and “Pharmacokinetics”).

Renal function impairment. The drug Yarina^® is contraindicated in women with severe renal failure or acute renal failure (see also sections “Contraindications” and “Pharmacokinetics”).

Adverse Reactions

Serious adverse events when taking combined oral contraceptives are also described in the section “Special Precautions”.

The following adverse reactions were observed during the use of the drug Yarina^®.

Description of selected adverse reactions

Women taking combined oral contraceptives have an increased risk of developing arterial and venous thrombotic and thromboembolic disorders, including myocardial infarction, stroke, transient ischemic attacks, deep vein thrombosis, and pulmonary embolism, described in more detail in the section “Special Precautions”.

The following serious adverse reactions have been reported in women using combined oral contraceptives. These adverse reactions are described in the section “Special Precautions”

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Increased blood pressure;
• Liver tumors;
• Development or worsening of conditions for which the association with the use of combined oral contraceptives is not indisputable: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes during pregnancy, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• Chloasma;
• Acute or chronic liver function impairment, which may require discontinuation of combined oral contraceptives until liver function tests normalize;
• In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

The frequency of diagnosis of breast cancer in women using oral contraceptives is very slightly increased. Breast cancer is rarely observed in women under 40 years of age, and the excess frequency is insignificant relative to the overall risk of breast cancer. A causal relationship between the occurrence of breast cancer and the use of combined oral contraceptives has not been established. For additional information, see sections “Contraindications” and “Special Precautions”.

Interaction

Interaction of other drugs (enzyme inducers) with oral contraceptives may lead to breakthrough bleeding and/or a decrease in contraceptive effect (see section “Drug Interactions”).

Contraindications

The drug Yarina^® is contraindicated in the presence of any of the conditions/diseases/risk factors listed below. If any of these conditions/diseases develop for the first time while taking the drug, the use of the drug should be discontinued immediately.

• Thromboses (venous and arterial) and thromboembolisms (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders – currently or in history;
• Conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) currently or in history;
• Identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of a high risk of venous or arterial thrombosis (see section “Special Precautions”);
• Migraine with focal neurological symptoms currently or in history;
• Diabetes mellitus with vascular complications;
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Hepatic failure and severe liver diseases (until liver function tests return to normal);
• Liver tumors (benign or malignant) currently or in history;
• Severe or acute renal failure;
• Identified hormone-dependent malignant diseases (including of the genital organs or breasts) or suspicion thereof;
• Vaginal bleeding of unknown origin;
• Pregnancy or suspected pregnancy;
• Breastfeeding period;
• Concomitant use with direct-acting antiviral drugs containing ombitasvir, paritaprevir, dasabuvir, or a combination of these substances (see section “Drug Interactions”);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the drug contains lactose monohydrate);
• Hypersensitivity to any of the components of the drug.

With caution

The potential risk and expected benefit of using combined oral contraceptives should be carefully weighed in each individual case in the presence of the following diseases/conditions and risk factors

• Risk factors for the development of thrombosis and thromboembolism (smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, valvular heart disease, hereditary predisposition to thrombosis (thrombosis, myocardial infarction, or cerebrovascular accident at the age of less than 50 years in any of the immediate family members);
• Other diseases in which peripheral circulation disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis);
• Hereditary angioedema;
• Hypertriglyceridemia;
• History of mild to moderate liver diseases with normal liver function tests;
• Diseases that first appeared or worsened during pregnancy or during previous use of sex hormones (for example, jaundice and/or pruritus associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

If pregnancy is detected during the use of the drug Yarina^®, the drug should be discontinued immediately. Extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy, or a teratogenic effect when sex hormones were taken inadvertently in early pregnancy.

At the same time, data on the outcomes of using the drug Yarina^® during pregnancy are limited, which does not allow any conclusions to be drawn about the negative impact of the drug on pregnancy, the health of the newborn and the fetus. Currently, there are no significant epidemiological data.

The use of the drug may reduce the amount of breast milk and change its composition, therefore, the use of the drug is contraindicated until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites may be excreted in breast milk and affect the child’s health.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure and severe liver diseases (until liver function tests return to normal); liver tumors (benign or malignant) currently or in history.

The drug should be prescribed with caution in case of a history of mild to moderate liver diseases with normal liver function tests.

Use in Renal Impairment

Contraindicated in acute renal failure and severe renal failure.

Pediatric Use

The drug is indicated only after menarche. Available data do not suggest a dose adjustment in this patient group.

Geriatric Use

Not applicable. The drug Yarina^® is not indicated after the onset of menopause.

Special Precautions

If any of the conditions, diseases and risk factors listed below are currently present, the potential risk and expected benefit of using the drug Yarina^® should be carefully weighed in each individual case and discussed with the woman before she decides to start taking the drug. In case of worsening, intensification, or first manifestation of any of these conditions, diseases, or risk factors, the woman should consult her doctor, who may decide on the need to discontinue the drug.

Cardiovascular diseases

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

The risk of developing VTE is highest in the first year of taking combined oral contraceptives. An increased risk is present after initial use of combined oral contraceptives or resumption of use of the same or another combined oral contraceptive (after a break in drug use of 4 weeks or more). Data from a large-scale prospective study involving 3 patient groups show that this increased risk is present predominantly during the first 3 months.

The overall risk of VTE in women taking low-dose combined oral contraceptives (<0.05 mg ethinyl estradiol) is 2-3 times higher than in non-pregnant patients who do not take combined oral contraceptives, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth.

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

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

Very rarely, thrombosis of other blood vessels, such as hepatic, mesenteric, renal, cerebral veins and arteries, or retinal vessels, occurs with the use of combined oral contraceptives.

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

Symptoms of pulmonary embolism: difficult or rapid breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep inspiration; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions/diseases (e.g., respiratory tract infections).

ATE can lead to stroke, vascular occlusion, or myocardial infarction.

Symptoms of stroke: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden one- or two-sided loss of vision; sudden gait disturbance, dizziness, loss of balance or coordination; sudden, severe, or prolonged headache for no apparent reason; loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion: sudden pain, swelling, and slight bluish discoloration of the limbs, “acute abdomen” symptom complex.

Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone, with radiation to the back, jaw, left upper limb, epigastric region; cold sweat, nausea, vomiting, or dizziness, severe weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.

ATE can be life-threatening or fatal.

In women with a combination of several risk factors or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the total value of the existing risk factors increases. In this case, the use of the drug Yarina^® is contraindicated (see section “Contraindications”).

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

• With age;
• In smokers (with an increase in the number of cigarettes smoked or increasing age, the risk increases, especially in women over 35 years of age);

In the presence of

• Obesity (BMI more than 30 kg/m²);
• Family history (e.g., venous or arterial thromboembolism ever in close relatives or parents under the age of 50). In case of a hereditary or acquired predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking the drug Yarina^®;
• Prolonged immobilization, major surgical intervention, any surgery on the lower limbs, or major trauma. In these cases, the use of the drug Yarina^® must be discontinued (in case of planned surgery at least 4 weeks before it) and not resumed until 2 weeks after the end of immobilization. Temporary immobilization (e.g., air travel lasting more than 4 hours) may also be a risk factor for the development of venous thromboembolism, especially in the presence of other risk factors;
• Dyslipoproteinemia;
• Arterial hypertension;
• Migraine;
• Valvular heart diseases;
• Atrial fibrillation.

The use of any combined hormonal contraceptives increases the risk of developing VTE. The use of drugs containing levonorgestrel, norgestimate, or norethisterone carries the lowest risk of developing VTE. The use of other drugs, such as Yarina^®, may lead to a twofold increase in risk. The decision to use a combined oral contraceptive with a higher risk of VTE can only be made after consulting the patient, ensuring that she fully understands the risk of VTE associated with the use of the drug Yarina^®, the effect of the drug on her existing risk factors, and that the risk of VTE is highest during the first year of drug use.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

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

Peripheral circulation disorders may also be noted in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis), and sickle cell anemia.

An increase in the frequency and severity of migraine during the use of combined oral contraceptives (which may precede cerebrovascular disorders) is a reason for immediate discontinuation of these drugs.

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

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

Tumors

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing cervical cancer with long-term use of combined oral contraceptives. However, the association with the use of combined oral contraceptives has not been proven. The possibility of a connection between these data with cervical disease screening or with sexual behavior characteristics (less frequent use of barrier contraceptive methods) is discussed.

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking combined oral contraceptives (relative risk 1.24). The increased risk gradually disappears within 10 years after discontinuation of these drugs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking or recently taking combined oral contraceptives is insignificant relative to the overall risk of this disease. Its association with the use of combined oral contraceptives has not been proven. The observed increase in risk may also be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using combined oral contraceptives, the biological effect of sex hormones, or a combination of both factors. In women who have ever used combined oral contraceptives, earlier stages of breast cancer are detected than in women who have never used them.

In rare cases, the use of COCs has been associated with the development of benign, and in extremely rare cases, malignant liver tumors, which in some instances have led to life-threatening intra-abdominal bleeding. In the event of severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding, this should be considered in the differential diagnosis. Malignant tumors can be life-threatening or fatal.

Other Conditions

The progestin component in Yarina^® is an aldosterone antagonist with potassium-sparing properties. In most cases, no increase in plasma potassium concentration should be observed. In clinical studies, some patients with mild to moderate renal impairment and concomitant use of potassium-sparing drugs showed a slight increase in plasma potassium concentration during drospirenone intake. Therefore, plasma potassium concentration should be monitored during the first treatment cycle in women with renal impairment and an initial potassium concentration at the upper limit of normal, especially with the concomitant use of potassium-sparing drugs (see the “Drug Interactions” section).

Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of pancreatitis while taking COCs. Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. However, if a persistent, clinically significant increase in blood pressure develops during the use of the drug, these drugs should be discontinued and treatment for arterial hypertension initiated. The drug may be continued if normal blood pressure values are achieved with antihypertensive therapy.

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

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

Acute or chronic liver function disorders may require discontinuation of the drug until liver function tests return to normal. A recurrence of cholestatic jaundice that first occurred during a previous pregnancy or prior use of sex hormones requires discontinuation of the drug.

Although COCs can affect insulin resistance and glucose tolerance, adjustment of the dosage of hypoglycemic drugs is generally not required in patients with diabetes using low-dose COCs (<0.05 mg ethinyl estradiol). Nevertheless, women with diabetes should be carefully monitored during COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women prone to chloasma during the use of Yarina^® should avoid prolonged sun exposure and ultraviolet radiation.

Laboratory Tests

The use of Yarina^® may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, and adrenal function, the concentration of transport proteins in plasma, parameters of carbohydrate metabolism, and parameters of blood coagulation and fibrinolysis. The changes usually remain within the normal range. Drospirenone increases plasma renin activity and aldosterone concentration, which is associated with its antimineralocorticoid effect.

Reduced Efficacy

The efficacy of Yarina^® may be reduced in the following cases: missed tablets, gastrointestinal disorders, or as a result of drug interactions.

Frequency and Severity of Menstrual-like Bleeding

During the use of Yarina^®, irregular (acyclical) vaginal bleeding (“spotting” and/or “breakthrough” uterine bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular menstrual-like bleeding should be performed after an adaptation period of approximately 3 treatment cycles. If irregular menstrual-like bleeding recurs or develops after previous regular cycles, a thorough examination should be conducted to rule out malignant neoplasms or pregnancy.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If Yarina^® was taken as recommended, it is unlikely that the woman is pregnant. However, if the drug was used irregularly and two consecutive menstrual-like bleedings are absent, the drug should not be continued until pregnancy is ruled out.

Medical Examinations

Before starting or resuming the use of Yarina^®, it is necessary to review the woman’s personal and family history, conduct a thorough general medical and gynecological examination, and rule out pregnancy. The scope of examinations and the frequency of check-ups should be based on existing standards of medical practice, taking into account the individual characteristics of each patient. Typically, blood pressure, heart rate, and BMI are measured; the condition of the breasts, abdomen, and pelvic organs, including a cytological examination of the cervical epithelium (Pap test), is checked. Routine check-ups should usually be performed at least once every 6 months.

It must be borne in mind that Yarina^® does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Effect on the Ability to Drive and Operate Machinery

Not studied.

No cases of adverse effects on the ability to drive and operate machinery have been identified with the use of the drug.

Conditions Requiring Medical Consultation

• Any changes in health, especially the occurrence of conditions listed in the “Contraindications” section and the “Use with Caution” subsection;
• A localized lump in the breast;
• Concomitant use of other medications (see also the “Drug Interactions” section);
• If prolonged immobilization is expected (e.g., a cast on a lower limb), hospitalization or surgery is planned (at least 4 weeks before the planned surgery);
• Unusually heavy vaginal bleeding;
• A tablet was missed in the first week of taking the pack and there was sexual intercourse 7 or fewer days before;
• Absence of the next menstrual-like bleeding twice in a row or suspicion of pregnancy (do not start taking tablets from the next pack before consulting a doctor).

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

Overdose

No serious adverse effects from overdose have been reported.

Based on the overall experience with COCs, symptoms that may occur with overdose include: nausea, vomiting, and withdrawal bleeding. The latter may occur in girls who have not reached menarche if the drug is taken accidentally.

Treatment consists of symptomatic therapy. There is no specific antidote.

Drug Interactions

Effect of Other Drugs on Yarina^®

Interaction with drugs that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, leading in turn to breakthrough uterine bleeding and/or reduced contraceptive efficacy.

Induction of hepatic microsomal enzymes may be observed within a few days of treatment. Maximum induction of hepatic microsomal enzymes is usually observed within a few weeks. After discontinuation of the drug, induction of hepatic microsomal enzymes may persist for up to 4 weeks.

Short-term Therapy

Women receiving treatment with such drugs in addition to Yarina^® are advised to use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method should be used throughout the period of concomitant drug use and for 28 days after their discontinuation. If therapy with the inducer drug needs to be continued after finishing the tablets from the current Yarina^® pack, a new pack of Yarina^® should be started without the usual tablet-free interval.

Long-term Therapy

Women on long-term therapy with drugs that induce hepatic microsomal enzymes are advised to use another reliable non-hormonal method of contraception.

Agents that increase the clearance of Yarina^® (weakening efficacy by enzyme induction) phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

Agents with variable effects on the clearance of Yarina^® when co-administered with Yarina^®, many HIV protease inhibitors or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogen or progestin. In some cases, this effect may be clinically significant.

Agents that decrease the clearance of COCs (enzyme inhibitors) strong and moderate inhibitors of CYP3A4, such as azole antifungals (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolide antibiotics (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase plasma concentrations of estrogen or progestin, or both.

Etoricoxib at doses of 60 and 120 mg/day has been shown to increase the plasma concentration of ethinyl estradiol by 1.4 and 1.6 times, respectively, when co-administered with COCs containing 0.035 mg ethinyl estradiol.

Effect of Yarina^® on Other Drugs

COCs may affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations.

In vitro, Drospirenone can weakly or moderately inhibit the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Based on in vivo interaction studies in female volunteers taking omeprazole, simvastatin, or midazolam as marker substrates, it can be concluded that a clinically significant effect of 3 mg drospirenone on drug metabolism mediated by cytochrome P450 enzymes is unlikely. In vitro, Ethinyl estradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, as well as an irreversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, the administration of a hormonal contraceptive containing Ethinyl estradiol did not lead to any increase or led only to a slight increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam), while plasma concentrations of CYP1A2 substrates may increase slightly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

Pharmacodynamic Interaction

Concomitant use of ethinyl estradiol-containing drugs and direct-acting antiviral drugs containing ombitasvir, paritaprevir, dasabuvir, or their combination has been shown to be associated with an increase in ALT levels more than 20 times the upper limit of normal in healthy women and women infected with hepatitis C virus (see the “Contraindications” section).

Other Forms of Interaction

In patients with normal renal function, concomitant use of drospirenone and ACE inhibitors or NSAIDs does not have a significant effect on plasma potassium concentration. However, concomitant use of Yarina^® with aldosterone antagonists or potassium-sparing diuretics has not been studied. When co-administered with these drugs, plasma potassium concentration should be monitored during the first treatment cycle (see the “Special Instructions” section).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.