Vibin mini

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

Composition:

Active substances: ethinylestradiol, drospirenone;

1 film-coated tablet contains ethinylestradiol 0.02 mg and drospirenone 3 mg;

Excipients:

Active tablets:

lactose monohydrate, pregelatinized corn starch, povidone K30, sodium croscarmellose, polysorbate 80, magnesium stearate

Coating Opadry II85F34610 Pink: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc, yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)

Placebo tablet: anhydrous lactose, povidone K30, magnesium stearate, partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

Placebo tablets: flat, round, film-coated, white 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 0.11 (upper two-sided 95% confidence interval (CI) – 0.6).

The overall Pearl Index (contraceptive failures + patient errors) for the drug is 0.31 (upper two-sided 95% CI – 0.91).

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

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

Pharmacokinetics

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Maximum serum concentration, amounting to 38 ng/mL, is 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, drospirenone serum concentration declines with a mean terminal half-life of approximately 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 in serum exists as free steroid. The increase in SHBG levels induced by ethinylestradiol does not affect drospirenone binding to serum proteins. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.21 L/kg.

Metabolism. Following 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 via 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.

Excretion. 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 approximately 40 hours.

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

Special patient populations

Effect of renal impairment. At steady state during drospirenone therapy, serum drospirenone concentrations were similar 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 drospirenone concentrations 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 concentration.

Effect of hepatic impairment. In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in individuals with moderate hepatic impairment compared to volunteers with normal liver function. This observed alteration in drospirenone clearance in individuals with moderate hepatic impairment did not result in any significant differences in serum potassium concentration. 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 (ULN). 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 a 33 µg dose, maximum plasma concentration of 100 pg/mL is reached within 1–2 hours. Absolute bioavailability, due to presystemic conjugation and first-pass metabolism, is approximately 60%. Concomitant food intake reduced ethinylestradiol bioavailability by approximately 25% in some subjects, while no changes were observed in others.

Distribution. Ethinylestradiol levels in serum decline in a biphasic manner, with the terminal disposition phase characterized by a half-life of approximately 24 hours. Ethinylestradiol binds extensively, but non-specifically, to serum albumin (approximately 98.5%) and induces increased serum concentrations of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). Apparent volume of distribution has been determined to be approximately 5 L/kg.

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first-pass through the liver. The primary metabolic pathway is aromatic hydroxylation, resulting in a large number of hydroxylated and methylated metabolites, which exist as free metabolites and conjugates with glucuronides and sulfates. Metabolic plasma clearance of ethinylestradiol is approximately 5 mL/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and also, based on mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Excretion. 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 approximately 1 day.

Steady-state concentration. Steady-state concentration is achieved during the second half of the treatment cycle, and plasma levels of ethinylestradiol increase approximately 2.0–2.3-fold.

Preclinical safety data

In laboratory animals, effects of drospirenone and ethinylestradiol were limited to those associated with their known pharmacological actions. In particular, animal studies on reproductive toxicity revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of Vibin Mini, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Special precautions for safety").

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 occurs for the first time while taking CHCs, the drug 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 the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • Current or past arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • Current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to the presence of a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function tests have returned to normal limits.
• Severe or acute renal impairment.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormonally-dependent malignancies (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 the medicinal product Vebin mini 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 precautions.

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

Pharmacodynamic interactions

In clinical studies involving patients receiving treatment for hepatitis C virus (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increases in alanine aminotransferase (ALT) levels above 5 times the upper limit of normal (ULN) were observed significantly more frequently in women taking medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increases the risk of elevated ALT levels (see sections "Contraindications" and "Special precautions").

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

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

Therapy

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

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another method of contraception in addition to COCs. The barrier method should be used throughout the entire duration of treatment with the enzyme-inducing medicinal product and for an additional 28 days after discontinuation of the drug. If treatment 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 method of contraception.

The following interactions have been reported based on published data.

Substances increasing COC clearance (reducing COC efficacy via enzyme induction), e.g.:

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

Substances with variable effects on COC clearance

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) antivirals, 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 medicinal product used for HIV/HCV treatment should be reviewed to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances decreasing COC clearance (enzyme inhibitors)

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

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

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

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

• Effect of Vebin mini on other medicinal products

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

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as probe substrates, clinically significant 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 parameters, and coagulation and fibrinolysis parameters. These changes are usually within normal ranges.

Drospirenone increases plasma renin and aldosterone activity due to its moderate anti-mineralocorticoid activity.

Special precautions for use

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

Warning

• If any of the conditions or risk factors listed below are present, the need for use of Vybim mini 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 whether discontinuation of Vybim mini is necessary.
• In suspected or confirmed VTE or ATE, 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)

The use of any CHCs increases the risk of VTE in women using them compared to women who do not use them. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. The use of other medicinal products, such as Vybim mini, 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 the use of Vybim mini, the extent to which her individual risk factors contribute, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming CHC use after a break of 4 weeks or longer.

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

It has been established[1] that among 10,000 women using CHCs containing drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of 6[2] among women using CHCs containing levonorgestrel.

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

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

Epidemiological studies have shown that the risk of VTE with oral contraceptives containing drospirenone is higher than with oral contraceptives containing levonorgestrel (so-called second-generation preparations) and may be similar to the risk with oral contraceptives containing desogestrel/gestodene (so-called third-generation oral contraceptives).

Epidemiological studies have also linked the use of COCs with an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attack).

Very rarely, thrombosis in other blood vessels, for example in the hepatic arteries and veins, kidneys, mesenteric vessels, cerebral vessels, or retinal vessels, has been reported in women using CHCs.

Risk factors for VTE

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

The use of Vybim mini 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 the risks associated with each individual factor, therefore the overall risk of 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

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

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

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

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

Symptoms of DVT may include:

• unilateral swelling of the leg and/or foot or along a vein in the leg;
• pain or tenderness in the leg, which may occur only when standing or walking;
• a feeling of warmth in the affected leg; redness or change in skin color of the leg.

Symptoms of PE may include:

• sudden unexplained shortness of breath or rapid breathing;
• sudden cough, possibly with hemoptysis;
• sudden chest pain;
• 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 severe conditions (e.g., respiratory tract infections).

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

In occlusion of ocular vessels, initial symptoms may include painless blurred vision, which may progress to vision loss. In some cases, vision loss may occur almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological data 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

The risk of arterial thromboembolic or cerebrovascular complications increases in women using COCs who have risk factors (see Table 2). The use of Vybinn mini 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. COCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 2

Risk factors for ATE

ATE Symptoms

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

Symptoms of cerebrovascular disorders may include:

• sudden numbness of the face, weakness or numbness of the extremities, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, speech disturbances or difficulty understanding speech;
• sudden visual disturbances 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 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, including human papillomavirus infection.

Breast cancer (warnings issued by the FDA Center for Drug Evaluation and Research [CDER])

Ethinylestradiol and drospirenone are contraindicated in women who currently have or have had breast cancer, as breast cancer may be hormone-sensitive (see section "Contraindications").

Epidemiological studies have not demonstrated a consistent association between COC use and the risk of breast cancer. Overall, studies do not show an association between ever use (current or past) of COCs and breast cancer risk. However, some studies have observed a slight increase in breast cancer risk among women who are currently using or have recently used COCs (<6 months since last use) compared to those who have never 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 additional number of breast cancer cases diagnosed in women who are currently or recently used COCs is small in relation to the overall risk of breast cancer. These study results 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 tendency for breast cancers diagnosed in women who have ever used COCs 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 taking COCs, which in some cases led to life-threatening intra-abdominal hemorrhage. In case of complaints of severe epigastric pain, hepatomegaly or signs of intra-abdominal bleeding, the possibility of a COC-related liver tumor should be considered in differential diagnosis.

Use of COCs at high doses (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings also apply to low-dose COCs.

Other conditions

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

Women with hypertriglyceridemia or a family history of this condition are at increased risk of 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 necessary 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 cholestatic pruritus previously observed during pregnancy or prior use of sex hormones.

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

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

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 reactions 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 they experience mood changes or symptoms of depression, including shortly after starting treatment.

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

The medicinal product contains less than 23 mg of sodium per tablet, i.e., it is practically sodium-free.

Consultations/Medical examination

Before initiating or resuming use of the medicinal product Vybinn Mini, a complete medical and family history should be obtained, a full medical examination should be performed, and pregnancy should be ruled out. 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 Vybinn Mini compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

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

The frequency and nature of 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 infections.

Reduced efficacy

The efficacy of COCs may be reduced if active tablets are missed (see section "Dosage and administration"), in case of gastrointestinal disturbances (see section "Dosage and administration") during intake of active tablets, or when other medicinal products are used concomitantly (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 clinically 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 undertaken, including evaluation to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to the instructions in the section "Dosage and administration", pregnancy is unlikely. However, if COCs have been taken irregularly prior to 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 Vybinn Mini, treatment should be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor do they indicate teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological properties"). Based on these animal studies, adverse effects due to the hormonal action of the active substances cannot be excluded. However, overall clinical 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 Vybinn Mini on pregnancy outcome or fetal and neonatal health. Currently, there are no relevant epidemiological data available.

When resuming use of Vybinn Mini, the increased risk of VTE in the postpartum period should be taken into account (see sections "Special precautions for use" and "Dosage and administration").

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 influence reaction speed when driving or operating machinery.

No studies have been conducted on the effect of the medicinal product 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 pink tablets and 7 placebo tablets of white color). 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. The medicinal product is taken as one tablet daily for 28 consecutive days (during the first 21 days, the pink tablets should be taken, followed by the white tablets during the last 7 days). The next pack should be started the day following the last tablet of the previous pack.

Due to the different composition of the tablets, treatment must begin with the first tablet in the upper left corner and proceed daily. Follow the direction of the arrows on the blister to ensure correct sequence.

Preparation for using the weekly calendar sticker

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

A self-adhesive calendar strip should be selected, the labeling of which starts with the day of the week when tablet intake begins. For example, if tablet intake starts on Wednesday, a self-adhesive strip starting with the label “Wed.” (“Wednesday”) should be used.

The weekly sticker should be applied horizontally over the label “space for sticker” so that the first day aligns with the tablet marked “Start.” Each day of the week will then correspond parallel to the row of tablets in the blister pack. This allows one to see on which day of the week the woman takes a tablet. Tablets must be taken in the order indicated on the blister pack until all 28 tablets have been consumed.

Withdrawal bleeding usually occurs on the 2--3rd day after starting the white placebo tablets (last row) and may not end before starting tablets from the next pack.

After taking the last white tablet, the woman should immediately start taking tablets from a new pack and use the next seven-day calendar sticker, regardless of whether withdrawal bleeding has ended or not. This means that the woman will start each weekly calendar strip on the same day of the week, and withdrawal bleeding will occur on the same days each month.

How to start using the medicinal product Vebin Mini

• No previous hormonal contraceptives were used (previous month).

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

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

It is recommended to take the first tablet of Vebin Mini the day after the last active tablet (tablet containing active ingredient) was taken, but no later than the day after the tablet-free interval or the hormone-free period of the previous COC. If using a vaginal ring or transdermal patch, start taking Vebin Mini on the day of removal of the device, but no later than the day when the next application of these products would have been due.

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

The intake of Vebin Mini can be started on any day after discontinuing the “mini-pill” (in the case of an implant or intrauterine system – on the day of removal; in the case of an injection – instead of the next scheduled injection). However, in all cases, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the medicinal product.

• After first-trimester abortion

The medicinal product may be started immediately. In this case, there is no need to use additional contraceptive methods.

• After childbirth or second-trimester abortion

It is recommended to start taking Vebin Mini on day 21–28 after childbirth or second-trimester abortion. If tablet intake is started later, it is recommended to additionally use a barrier method of contraception during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, possible pregnancy should be ruled out before starting the medicinal product, or wait for the onset of the first menstruation.

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 therefore can be disregarded. However, their intake should be discontinued to avoid unintentionally prolonging the placebo tablet phase.

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

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

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

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

Accordingly, in everyday practice, the following recommendations should be followed:

• Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. Additionally, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer the gap in medication intake, the higher the risk of pregnancy.

• Week 2

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

• Week 3

The risk of reduced effectiveness increases as the 7-day tablet-free interval approaches. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided. If one of the options below is followed, additional contraceptive methods are not required, provided tablets were taken correctly for 7 days before the missed dose. If this is not the case, it is recommended to follow the first option below and use additional precautionary methods for the next 7 days.

1. Take the last missed tablet as soon as the woman remembers, even if two tablets have to be taken at the same time. Then continue taking tablets at the usual time until all active tablets are finished. The 7 tablets in the last row (placebo tablets) should be discarded. Start taking tablets from the next pack immediately. Withdrawal bleeding is unlikely to occur before finishing tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking active tablets from the current pack. In this case, take placebo tablets from the last row for 7 days, including the days when doses were missed; then start tablets from the next pack.

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

Recommendations in case of gastrointestinal disturbances

In case of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the medicinal product may occur, and additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the medicinal product, another (replacement) tablet should be taken as soon as possible. The next tablet, if possible, should be taken within 12 hours according to the usual dosing schedule. If more than 12 hours have passed, the recommendations given above in the section “How to use and dosage” under “What to do if a tablet is missed” apply. If the woman does not wish to change her tablet-taking schedule, she should take additional tablet(s) from the next pack.

How to delay withdrawal bleeding

To delay withdrawal bleeding, continue taking Vebin Mini tablets from a new pack without taking the placebo tablets from the current pack. The duration of intake may be extended, if desired, until the tablets from the second pack are finished. Breakthrough bleeding or spotting may occur during this time. Usually, Vebin Mini is resumed after the placebo tablet phase.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the placebo tablet phase by the desired number of days. It should be noted that the shorter the interval, the more frequently absence of withdrawal bleeding 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. The product is not indicated after menopause.

Patients with hepatic impairment. Vebin Mini is contraindicated in women with severe hepatic impairment (see sections “Pharmacological properties” and “Contraindications”).

Patients with renal impairment. Vebin Mini is contraindicated in women with severe renal impairment or acute renal failure (see sections “Pharmacological properties” and “Contraindications”).

Children.

Vebin Mini is indicated only after menarche.

Overdose.

There are currently no clinical data on overdose with Vebin Mini tablets. Based on general experience with COCs, overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche in cases of accidental or unintentional intake of the medicinal product. 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 Vybimini (see Table 3).

Table 3

Adverse reactions observed during the use of the medicinal product Vybimini

Description of individual adverse reactions

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

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

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

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

Other adverse reactions associated with combined oral contraceptives are also listed in the sections "Contraindications" and "Special warnings and precautions for use" (including hearing loss associated with otosclerosis, hypertriglyceridaemia and increased risk of pancreatitis, gallstone formation, changes in glucose tolerance or effects on peripheral insulin resistance, jaundice and/or pruritus associated with cholestasis, hypersensitivity reactions including rash 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 diagnosed cases among current or recent users of COCs is small relative to the overall risk of breast cancer. The relationship to COC use is not known. See also sections "Contraindications" and "Special warnings and precautions for use".

Interactions

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

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 or past users of COCs and women who have never used COCs, no association was reported between any use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

In three studies comparing the risk of breast cancer between women who were current or recent users of COCs (<6 months since last use) and women who had never used COCs, one study reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 for current or recent use. Both of these studies also found an increased risk with longer duration of 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 suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

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

Packaging

28 tablets in a blister pack (21 active pink tablets and 7 white placebo 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.

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[1] These figures are based on all available epidemiological data, taking into account relative risks associated with the use of various COCs compared to COCs containing levonorgestrel.

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