Vibin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIBIN (VIBIN)

Composition:

Active substances: ethinylestradiol, drospirenone;

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

Excipients:

Active tablets:

Tablet core: lactose monohydrate, maize starch, pregelatinized maize starch, crospovidone (type A and B), povidone K30, polysorbate 80, magnesium stearate;
Coating: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, yellow iron oxide (E 172).

Placebo tablets:

Tablet core: lactose monohydrate, povidone K30, magnesium stearate;
Coating: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Active tablets: flat, round, yellow film-coated tablets.

Placebo tablets: flat, round, white film-coated tablets.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

The Pearl Index for contraceptive failures of 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 several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

Vibin 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. Therefore, drospirenone has a pharmacological profile similar to that of natural progesterone.

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

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentration of approximately 38 ng/mL is reached about 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 concentrations decline 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-dihydrodrospirenone-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. 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, the maximum steady-state concentration of drospirenone in serum of approximately 70 ng/mL is reached after about 8 days of treatment. Serum concentration of drospirenone increased about threefold due to the relationship between the terminal half-life and the 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. This observed difference 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), serum potassium concentration did not exceed the upper limit of normal. It can be concluded that drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child–Pugh class B).

Ethnicity. 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 administration of 30 µg, peak serum concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass effect, which depends on individual differences. Absolute bioavailability is approximately 45%.

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

A small amount of ethinylestradiol is excreted in breast milk (0.02% of dose).

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first-pass through the liver. Ethinylestradiol is mainly metabolized via aromatic hydroxylation, forming a large number of hydroxylated and ethylated metabolites, 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 based on its mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Ethinylestradiol metabolites 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 serum levels of ethinylestradiol increase approximately 1.4–2.1 times.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. In particular, animal studies on reproductive toxicity showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of Vibin, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a risk to the aquatic environment (see section "Special 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 patients receiving 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 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 presence of multiple risk factors (see section "Special precautions") or 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 limits.
• Severe renal insufficiency or acute renal failure.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant tumors (e.g., of the genital organs).
• Current or past breast cancer that may be hormone-sensitive (see section "Special precautions", subsection "Malignant neoplasms").
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
• Suspected or confirmed pregnancy.

Concomitant use of Vybinn 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 pose a risk 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 regarding concomitantly administered medicinal products should be reviewed to identify potential interactions.

Pharmacodynamic interactions

In clinical trials involving patients receiving treatment for hepatitis C virus (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevated alanine aminotransferase (ALT) levels exceeding 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Additionally, ALT elevations 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 Vybinn must temporarily switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with these drug combinations. Use of Vybinn may be resumed 2 weeks after completion of therapy with the aforementioned combination.

In patients with normal renal function, concomitant use of drospirenone and 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 Vybinn 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").

• Effect of other medicinal products on Vybinn

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 occur within a few days of starting treatment. Maximum enzyme induction is generally observed after several weeks. After discontinuation of the inducing agent, 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 additional contraceptive method alongside COCs. The barrier method should be used throughout the entire duration of treatment with the enzyme-inducing agent and for an additional 28 days after discontinuation of the agent. If therapy is initiated during the period of taking the last tablets in the COC pack, the next pack of COC tablets 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 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; 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).

Active substances with variable effects on COC clearance

When used concomitantly with COCs, numerous combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may either 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 additional 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.

Active substances that reduce 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, 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 when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Vybinn 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 marker substrates, clinically significant interaction of drospirenone at a dose of 3 mg with other active substances metabolized by cytochrome P450 is 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.

Other forms of interaction

Laboratory tests. Use of contraceptive steroids may affect 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, coagulation, and fibrinolysis parameters. Such changes are usually within normal limits.

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

Use characteristics.

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

Warning

• If any of the conditions or risk factors listed below are present, the appropriateness of using the medicinal product Vebin 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 and determine the need to discontinue use of the medicinal product Vebin.
• In case of suspected or confirmed VTE or ATE, use of CHCs should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effect of anticoagulants (coumarins).
• Circulatory disorders.

Risk of venous thromboembolism (VTE)

Use of any CHCs increases the risk of developing venous thromboembolism (VTE) in women who use them compared to those who do not. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Use of other medicinal products, such as Vebin, may double the risk. The decision to use medicinal products other than those with the lowest risk of VTE should only be made after discussion with the woman. It is necessary to ensure that she understands the risk of VTE associated with use of the medicinal product Vebin, the extent of influence of her existing 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 10,000 women who do not use CHCs and are not pregnant, 2 will develop VTE within a year. However, in each individual woman, the risk may be significantly higher depending on her 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 1 year. This compares with a rate of 6–2 in women using CHCs containing levonorgestrel.

In both cases, the number of VTE cases per year was lower than usually expected during pregnancy or in the postpartum period.

VTE can lead to fatal outcomes in 1–2% of cases.

Number of VTE cases per 10,000 women per year

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

² Average of 5–7 cases per 10,000 woman-years, based on calculation of relative risk of using CHCs containing levonorgestrel compared to women not using CHCs (approximately 2.3–3.6 cases).

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

Factors increasing the risk of VTE

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

Use of the medicinal product Vebin 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

Factors increasing the risk of 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 the first 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 a leg and/or foot, or swelling along a vein in the leg;
• Pain or tenderness in the leg, which may only be felt when standing or walking;
• A feeling of 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 hemoptysis;
• Sudden chest pain;
• Near-syncope or dizziness;
• Rapid or irregular heartbeat.

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

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

Ocular vascular occlusion may initially present with painless blurred vision, which may progress to vision loss. In some cases, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies indicate that the 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 may 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). The use of VIBIN 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 increase in risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be considered. If the benefit-risk balance is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for ATE

Arterial Thromboembolism (ATE) Symptoms

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 cerebrovascular disorders may include:

• sudden numbness of the face, weakness or numbness of limbs, especially on one side;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, speech or comprehension disturbances;
• sudden vision impairment in one or both eyes;
• sudden, severe or prolonged headache without a known cause;
• loss of consciousness or fainting with or without seizures.

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

Symptoms of myocardial infarction may include:

• pain, discomfort, tightness or heaviness in the chest, arm or below the sternum;
• discomfort radiating to the back, jaw, throat, arm or stomach;
• sensation of stomach fullness, indigestion or heartburn;
• excessive sweating, nausea, vomiting or dizziness;
• unusual weakness, anxiety or shortness of breath;
• rapid or irregular heartbeat.

Malignant Neoplasms

Results of some epidemiological studies suggest an additional increased risk of cervical cancer with long-term use of COCs (>5 years), although this remains controversial as it is not fully established whether study results adequately account for confounding risk factors such as sexual behavior and other factors such as human papillomavirus infection.

Breast Cancer (Warnings issued by the FDA Center for Drug Evaluation and Research (CDER))

Drospirenone/ethinyl estradiol is contraindicated in women who currently have or have had breast cancer, as breast cancer may be hormonally sensitive (see section "Contraindications").

Epidemiological studies have not shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not show an association between ever use (current or past use) of COCs and the risk of breast cancer. However, some studies report a slight increase in breast cancer risk among women who are currently or recently (within <6 months since last use) using COCs, and among those who have previously used COCs (see section "Adverse Reactions", subsection "Post-marketing Data").

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer in women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among women currently or recently using 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 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 used COCs tends to be less clinically advanced 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 cases of severe epigastric pain, hepatomegaly or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in differential diagnosis during COC use.

High-dose COCs (50 mcg ethinyl estradiol) reduce 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 VIBIN is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected during use. In clinical trials, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal insufficiency who were concurrently using potassium-sparing medications during treatment with drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first treatment cycle in patients with renal insufficiency. These patients should also be advised to maintain serum potassium levels not exceeding the upper limit of normal before starting VIBIN, especially when using potassium-sparing medications concurrently (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 pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension occurs only rarely. Immediate discontinuation of COCs is required only in these rare cases. In cases of persistent hypertension or inability to control blood pressure with antihypertensive therapy, women taking COCs should discontinue their use. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and during COC use, but their relationship to estrogen/progestin use has not been definitively established: 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.

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 pruritus associated with cholestasis that previously occurred 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 alter 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 reported during COC use.

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

One active tablet (yellow) of the medicinal product contains 62 mg of lactose. One placebo tablet (white) contains 89.5 mg of lactose. In case of rare hereditary conditions of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, or when on a lactose-free diet, this amount of lactose should be taken into account.

Consultations/Medical Examination

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

Patients should be advised to carefully read the package leaflet and follow the recommendations provided.

The frequency and nature of follow-up examinations should be based on established medical practice guidelines, taking into account individual patient characteristics.

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 tablets (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 reappears after a period of regular bleeding, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures taken, including evaluation to exclude tumors 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 were 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 VIBIN, 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 is there evidence of 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 a harmful effect in humans.

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

When resuming use of VIBIN, 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.

Ability to Affect Reaction Speed When Driving or Operating Machinery

No studies have been conducted on the effect on the ability to drive or operate machinery. 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.

Each blister contains 28 tablets (21 active yellow tablets and 7 placebo white tablets). Tablets should be taken regularly at approximately the same time each day, swallowing with a small amount of liquid if necessary, in the order indicated on the blister. Take 1 tablet daily for 28 consecutive days (take yellow tablets for the first 21 days, followed by white tablets for the last 7 days). The first tablet of each subsequent pack should be taken the day following ingestion of the last tablet from the previous pack.

Due to the different composition of the tablets, treatment must start with the first tablet located in the top left corner, and tablets should be taken daily in sequence. To ensure correct order, follow the direction of the arrows on the blister.

Preparation for using the weekly calendar sticker

To facilitate tracking regular tablet intake, a weekly calendar sticker indicating the 7 days of the week is included in the package.

Select a self-adhesive calendar strip starting with the day of the week on which tablet intake begins. For example, if treatment starts on Wednesday, use the self-adhesive strip beginning with the label "Wed." ("Wednesday").

Attach the weekly sticker horizontally over the "space for sticker" marking so that the first day aligns above the tablet marked "Start." Each day of the week will then correspond parallel to the row of tablets in the blister pack, allowing the woman to see which day of the week she is taking each tablet. Tablets must be taken in the order indicated on the blister pack until all 28 tablets have been consumed.

Withdrawal bleeding usually begins on day 2–3 after starting the white placebo tablets (last row) and may continue until the start of the next pack.

After taking the last white tablet, begin the next blister pack immediately and apply the next weekly calendar sticker, regardless of whether withdrawal bleeding has stopped. This ensures that each new calendar strip is started on the same day of the week and that withdrawal bleeding occurs on the same days each month.

Starting treatment with VIBIN

• Previous use of hormonal contraceptives (last month)

Begin taking tablets 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 VIBIN tablet the day after the last active tablet (containing active ingredients) of the previous COC. However, it must be no later than the day after the tablet-free interval or hormone-free period of the previous contraceptive. When switching from a vaginal ring or transdermal patch, start VIBIN on the day of device removal, but no later than the day the next application would have been due.

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

VIBIN may be started on any day after stopping the "mini-pill" (on the day of removal in the case of an implant or intrauterine system, or 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 VIBIN.

• After first-trimester abortion

VIBIN may be started immediately. In this case, no additional contraceptive methods are required.

• After childbirth or second-trimester abortion

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

Missed tablets from the last row of the blister are placebo tablets and may be disregarded. However, they should be omitted to avoid unintentionally prolonging the placebo phase.

The following advice applies only to missed active tablets (rows 1–3 of the blister):

If a tablet is missed by less than 12 hours, contraceptive protection is not reduced. Take the missed tablet as soon as remembered. Take the next tablet at the usual time.

If a tablet is missed by more than 12 hours, contraceptive protection may be reduced. In this case, follow these two main rules:

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

Accordingly, follow these practical recommendations:

• Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at once. Then continue taking tablets at the usual time. Additionally, use a barrier method of contraception (e.g., condom) for the next 7 days. If 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 once. Then continue taking tablets at the usual time. If tablets were taken correctly in the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, use a barrier method for 7 days.

• Week 3

The risk of reduced effectiveness increases as the 7-day tablet-free interval approaches. However, following one of the regimens below can prevent reduced contraceptive protection. If one of the following options is followed, no additional contraceptive methods are required, provided tablets were taken correctly for 7 days before the missed dose. If not, 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 once. Then continue taking tablets at the usual time until all active tablets are finished.

Discard the 7 tablets in the last row (placebo tablets). Immediately start tablets from the next pack. Withdrawal bleeding is unlikely before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.

2. Alternatively, stop taking active tablets from the current pack. Take the placebo tablets from the last row for 7 days, including the days when doses were missed; then start the next pack.

If withdrawal bleeding does not occur during the first scheduled tablet-free interval after a missed tablet, pregnancy should be considered.

Recommendations in case of gastrointestinal disturbances

In cases of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the drug may occur; in such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, take another (replacement) tablet as soon as possible. The next tablet should, if possible, be taken within 12 hours according to the usual schedule. If more than 12 hours have passed, follow the advice given above in the section "How to use and dosage", subsection "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.

Delaying withdrawal bleeding

To delay withdrawal bleeding, continue taking VIBIN tablets from a new pack without taking the placebo tablets from the current pack. This period may be extended up to the end of the second pack, if desired. Breakthrough bleeding or spotting may occur. Usually, VIBIN treatment resumes after the placebo tablet phase.

To shift the timing of withdrawal bleeding to another day of the week, shorten the placebo tablet phase by the desired number of days. Note that the shorter the interval, the more likely it is that withdrawal bleeding will be absent and breakthrough bleeding or spotting may occur during intake of tablets from the second pack (as also occurs when delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients. Do not use the drug after menopause.

Patients with hepatic impairment. VIBIN is contraindicated in women with severe hepatic impairment (see sections "Pharmacological properties" and "Contraindications").

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

Children.

VIBIN is indicated only after 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 currently no clinical data on overdose with VIBIN tablets. Based on general experience with COCs, overdose may cause nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche in cases of accidental or unintentional ingestion. There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

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

Table 3

Adverse reactions observed during the use of the medicinal product Vebin

Description of individual adverse reactions

Women taking COCs have been observed to have an increased risk of developing venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism, which are described in more detail in the section "Special warnings and precautions for use".

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

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• development or exacerbation of conditions whose relationship with COC use has not been definitively established: Crohn's disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function tests return to normal;
• in women with a hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

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

Other adverse reactions associated with the class of combined oral contraceptives are also indicated in the sections "Contraindications" and "Special warnings and precautions for use" (including hearing loss associated with otosclerosis, hypertriglyceridemia 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 and 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 the number of diagnosed cases of breast cancer among women currently using or who have recently used COCs is small relative to the overall risk of breast cancer. The relationship to COC use is unknown. (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").

Post-marketing data (Warning issued by the Center for Drug Evaluation and Research (CDER) FDA)

In five studies comparing the risk of breast cancer between current users (current or past use) of COCs and women who have never used COCs, no association was reported between any use of COCs and the risk of breast cancer, with effect estimates ranging from 0.90 to 1.12.

In three studies, the risk of breast cancer was compared between women currently using or who had recently used COCs (<6 months since last use) and those who had never used them. One of these studies reported no association between the risk of breast cancer and COC use. Two other studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies also found an increased risk of breast cancer with long-term use, with relative risks ranging from 1.03 for less than one year of COC use to approximately 1.4 for more than 8–10 years of COC use.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

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

Packaging

28 tablets per blister pack (21 active yellow tablets and 7 placebo white tablets).

1 blister pack in a cardboard box with a weekly calendar-sticker.

Prescription status

Prescription only.

Manufacturer

Laboratorios Leon Farma S.A., Spain.

Manufacturer's address and place of business

Calle La Vallina s/n, Poligono Industrial Navatejera, Villaquilambre, 24193, Spain.