Yarina film-coated tablets blister pack No. 21

Instructions for use Yarina film-coated tablets blister pack No. 21

Composition

active ingredients: ethinylestradiol, drosperinone;

1 film-coated tablet contains ethinylestradiol 0.03 mg and drospirenone 3 mg;

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

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets, light yellow in color, round and biconvex in shape, embossed with “DO” in a hexagon on one side.

Pharmacotherapeutic group

Sex gland hormones and drugs used in genital pathology. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATX code G03A A12.

Pharmacological properties

Pharmacodynamics

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

The overall Pearl Index (contraceptive failures + patient 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 various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

The drug Yarina® is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It does not have estrogenic, glucocorticoid and antiglucocorticoid activity. Therefore, drospirenone has a similar pharmacological profile to natural progesterone.

According to clinical studies, the moderate antimineralocorticoid properties of Yarina® lead to a moderate antimineralocorticoid effect.

Pharmacokinetics

Drospirenone

Absorption: Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentrations of 38 ng/ml are reached approximately 1–2 hours after a single oral dose. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution: After oral administration, serum drospirenone concentrations decline with a mean terminal half-life of approximately 31 hours. Drospirenone is bound to serum albumin but not to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 3–5% of the total drospirenone concentration is present in serum as free steroid. The increase in SSGB induced by ethinylestradiol does not affect serum protein binding of drospirenone. 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, which is formed as a result of the opening of the lactone ring, as well as 4,5-dihydro-drospirenone-3-sulfate, which is formed by hydration with subsequent sulfation. Drospirenone is also the subject of oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone can weakly or moderately inhibit the 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 small amount of drospirenone is excreted unchanged. The metabolites of drospirenone are excreted in the feces and urine in a ratio of approximately 1.2:1.4. The half-life of metabolites in urine and feces is about 40 hours.

Steady-state concentration: During a treatment cycle, the maximum steady-state serum concentration of drospirenone of approximately 70 ng/ml is reached after approximately 8 days of treatment. The serum concentration of drospirenone increased approximately 3-fold due to the ratio of the terminal half-life to the dosing interval.

Special categories of patients

Effects on 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 difference in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentrations. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that can induce hyperkalemia), no increase in serum potassium concentrations above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in subjects with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnicity: No clinically significant difference in the pharmacokinetics of drospirenone or ethinyl estradiol was observed between Japanese and Caucasian women.

Ethinylestradiol

Absorption: Ethinylestradiol is rapidly and completely absorbed after oral administration. After administration of 30 mcg, peak serum concentrations of 100 pg/ml are reached within 1-2 hours. Ethinylestradiol is subject to extensive first-pass metabolism, which varies between individuals.

Absolute bioavailability is about 45%.

Distribution. The expected volume of distribution of ethinylestradiol is approximately 5 l/kg and plasma protein binding is approximately 98%. Ethinylestradiol induces hepatic synthesis of GH and corticosteroid-binding globulin. With 30 μg of ethinylestradiol, plasma GH concentrations increase from 70 to approximately 350 nmol/l.

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

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during the first pass through the liver. Ethinylestradiol is mainly metabolized by aromatic hydroxylation with the formation of a large number of hydroxylated and ethylated metabolites, which are present as free metabolites and conjugates with glucuronides and sulfates. The metabolic plasma clearance of ethinylestradiol is about 5 ml/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, and based on the mechanism of action, an inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

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

Steady-state concentration: Steady-state concentration is reached during the second half of the therapy cycle and serum ethinylestradiol levels increase approximately 1.4-2.1-fold.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, studies on reproductive toxicity in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of Yarina®, effects on sexual differentiation were observed in some animal species.

Indication

Oral contraception.

Contraindication

Combined hormonal contraceptives (CHCs) should not be used if any of the following conditions are present. If any of these conditions appear for the first time during CHC use, the drug should be discontinued immediately.

Presence or risk of venous thromboembolism (VTE): current or history of venous thromboembolism, particularly as a result of anticoagulant therapy [e.g. deep vein thrombosis (DVT) or pulmonary embolism (PE)]; known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;

major surgical interventions with prolonged immobilization (see section "Special instructions for use");

high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

Presence or risk of arterial thromboembolism (ATE): current or history of arterial thromboembolism (e.g. myocardial infarction) or presence of prodromal symptoms (e.g. angina); current or history of cerebrovascular accident, presence of prodromal symptoms [e.g. transient ischemic attack (TIA)]; known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and presence of phospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); history of migraine with focal neurological symptoms;

Current or history of severe liver disease if liver function tests have not returned to normal. Severe renal failure or acute renal failure. Current or history of liver tumors (benign or malignant). Known or suspected malignant tumors (e.g., genital or breast) that are sex hormone dependent. Vaginal bleeding of unknown etiology. Hypersensitivity to the active substances or to any of the excipients. Suspected or confirmed pregnancy.

The drug Yarina is contraindicated with the simultaneous use of drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

The information for the concomitant medicinal product should be consulted to identify potential interactions.

The effect of other medicines on the drug Yarina®

Interactions are possible with drugs that induce microsomal enzymes. This will lead to an increase in the clearance of sex hormones, which in turn causes changes in the pattern of menstrual bleeding and/or loss of contraceptive effectiveness.

Therapy

Enzyme induction can be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method should be used throughout the entire period of treatment with the drug and for 28 days after stopping its use. If therapy is started during the last COC tablet-free period, the next COC tablet-free period should be started immediately after the previous one without the usual tablet-free interval.

Long-term treatment

For women on long-term therapy with active substances that induce liver enzymes, a barrier or other appropriate non-hormonal method of contraception is recommended.

The following interactions have been reported based on published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example:

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

Active substances with variable effects on COC clearance:

When used concomitantly with COCs, a large number of 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 estrogen or progestins. The cumulative effect of such changes may be clinically significant in some cases.

Therefore, the prescribing information for the concomitant HIV/HCV medicinal product should be consulted for potential interactions and any other recommendations. In case of any doubt, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that reduce COC clearance (enzyme inhibitors)

The clinical significance of the potential interaction with enzyme inhibitors remains unclear.

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

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

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinyl estradiol by 1.4- to 1.6-fold, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.

The effect of Yarina® on other medicines

Oral contraceptives may affect the metabolism of some active substances. Accordingly, 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 marker substrates, it was found that a clinically significant interaction of drospirenone at a dose of 3 mg with other active substances induced by cytochrome P450 is unlikely.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a mild (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin increases the risk of alanine aminotransferase (ALT) elevations (see sections 4.3 and 4.4).

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 this combination of drugs. Yarina® can be resumed 2 weeks after completing therapy with this combination.

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

Other forms of interaction

Laboratory tests. The use of contraceptive steroids may affect the results of some laboratory tests, such as biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, and parameters of carbohydrate metabolism, coagulation and fibrinolysis. These changes are usually within normal limits.

Drospirenone increases plasma renin and aldosterone activity, which is induced by its moderate antimineralocorticoid activity.

Application features

The decision to prescribe Yarina® should take into account the individual woman's current risk factors, including risk factors for venous thromboembolism (VTE), and the risk of VTE associated with Yarina® compared with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Instructions").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Yarina® should be discussed with the woman. In the event of exacerbation or at the first appearance of any of the listed conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue Yarina®. In the event of suspected or confirmed VTE or ATE, CHC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins). Circulatory disorders.

Risk factors for developing VTE

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

The use of Yarina® is contraindicated in women with multiple risk factors that may increase the risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing VTE should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1. Risk factors for VTE development

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

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 (deep vein thrombosis and pulmonary embolism)

Women should be advised to contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or areas along a vein in the leg; pain or increased sensitivity in the leg that may only be felt when standing or walking; a feeling of heat 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; fainting or dizziness; and a fast or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific or 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 slight blueness of the limb.

In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and which can progress to loss of vision. Sometimes the loss of vision develops almost instantly.

Risk of developing arterial thromboembolism (ATE)

Epidemiological studies have shown that the use of any CHC is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular complications (transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for developing ATE

When using CHCs, the risk of arterial thromboembolic complications or cerebrovascular complications increases in women with risk factors (see Table 2). The use of Yarina® is contraindicated if women 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 increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 2. Risk factors for the development of ATE

Symptoms of ATE

Women should be advised to contact their doctor immediately if they experience the symptoms listed below and to inform them that they are using CHCs.

Symptoms of a cerebrovascular accident may include: sudden numbness of the face, weakness or numbness of the limbs, especially on one side; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden loss of vision in one or both eyes; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizures.

The transient nature of the symptoms may indicate a transient ischemic attack (TIA).

Symptoms of a myocardial infarction may include: pain, discomfort, a feeling of squeezing or heaviness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; a feeling of fullness in the stomach, indigestion or shortness of breath; increased sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or shortness of breath; fast or irregular heartbeat.

The results of some epidemiological studies indicate an additional increase in the risk of developing cervical cancer with long-term use of COCs (> 5 years), but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior, and other factors, such as human papillomavirus infection.

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of breast cancer in women who use COCs. This increased risk gradually disappears within 10 years after stopping COCs. Since breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women who are current or recent users of COCs is small in relation to the overall risk of breast cancer. The 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 women who use COCs, the biological action of COCs, or a combination of both. There is a trend for breast cancer detected in women who have ever used COCs to be clinically less severe than in women who have never used COCs.

In isolated 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 bleeding. In case of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis when using COCs.

High-dose COCs (50 mcg ethinylestradiol) reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings can also be extended to low-dose COCs.

Other states

The progestin component of Yarina® is an aldosterone antagonist with potassium-sparing properties. In most cases of use, an increase in potassium levels is not expected. In clinical studies, in some patients with mild to moderate renal insufficiency and concomitant use of potassium-sparing drugs, serum potassium levels increased slightly, but not significantly, during the use of drospirenone. Therefore, monitoring of potassium levels is recommended during the first treatment cycle in patients with renal insufficiency. These patients are also recommended to maintain serum potassium levels not above the upper limit of normal before starting the drug, especially when concomitantly using potassium-sparing drugs (see section “Interaction with other medicinal products and other forms of interaction”).

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

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant increases in blood pressure have been observed in isolated cases. Immediate discontinuation of COCs is only necessary in these isolated cases. In the case of persistent hypertension or failure to control blood pressure with antihypertensive drugs, women taking COCs should discontinue their use. If appropriate, COC use can be resumed after achieving normotensive status with antihypertensive therapy.

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

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

The metabolism of steroid hormones may be impaired in patients with impaired liver function. Acute or chronic disorders of liver function may require discontinuation of COC use until liver function tests have returned to normal and a causal relationship to COC use has been excluded.

If cholestatic jaundice and/or itching associated with cholestasis recurs, which previously occurred during pregnancy or previous use of sex hormones, COC use should be discontinued.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest that diabetic women taking low-dose COCs (<0.05 mg ethinylestradiol) should be monitored closely during COC use, especially at the beginning of treatment.

Depressed mood and depression are well-known side effects that can occur with hormonal contraceptives (see section 4.8). Depression can be a serious condition and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including shortly after starting treatment.

Chloasma may occasionally occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while using COCs.

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

Elevated ALT levels

In clinical trials in patients treated for hepatitis C with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using ethinylestradiol-containing medicinal products such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

Consultations/medical examination

Before initiating or reinstituting Yarina®, a complete medical history (including family history) and a complete physical examination are recommended, and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and the specifics of use (see section 4.4). The woman should be informed about venous and arterial thrombosis, including the risk associated with Yarina® compared with other CHCs, the symptoms of VTE and ATE, known risk factors, and the actions to be taken if thrombosis is suspected.

Patients are advised to carefully read the instructions for medical use of the medicinal product and follow the recommendations contained therein.

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

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

Decreased efficiency

The effectiveness of COCs may be reduced in the event of missed tablets (see section "Method of administration and dosage"), gastrointestinal disorders (see section "Method of administration and dosage") or concomitant use of other medicines (see section "Interaction with other medicines and other types of interactions").

Cycle disruption

Irregular bleeding (spotting or breakthrough bleeding) may occur when taking COCs, especially during the first few months. If such bleeding continues after 3 menstrual cycles, it should be considered serious.

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

Some women may not have a withdrawal bleed during the tablet-free interval. If COCs are taken according to the instructions in the section "Method of administration and dosage", pregnancy is unlikely. However, if COC use has been irregular until the first withdrawal bleed is absent or if withdrawal bleeds are absent for two cycles, pregnancy should be ruled out before COC use is resumed.

The ability to influence the speed of reaction when driving a vehicle or other