Vidora micro

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

Composition:

Active substances: drospirenone, ethinylestradiol;

1 blister contains 28 tablets (21 pink active tablets and 7 white placebo tablets);

1 film-coated tablet, pink in color, contains drospirenone 3.0 mg and ethinylestradiol 0.02 mg;

Excipients: lactose monohydrate, pregelatinized starch, povidone K-30, sodium croscarmellose, polysorbate 80, magnesium stearate, Opadry® II pink (polyethylene glycol, polyvinyl alcohol, titanium dioxide (E 171), talc, yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)).

1 film-coated tablet, white in color (placebo), contains:

Excipients: anhydrous lactose, povidone K-30, magnesium stearate, Opadry® II white (polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), macrogol 3350, talc (E 553b)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

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

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Drospirenone and ethinylestradiol. ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

Pearl Index of contraceptive failures: 0.41 (upper two-sided 95% confidence interval: 0.85).

Overall Pearl Index (contraceptive failures + patient errors): 0.80 (upper two-sided 95% confidence interval: 1.30).

The contraceptive effect of VIdora micro is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

In a three-cycle clinical study comparing the combination of drospirenone 3 mg/ethinyl estradiol 0.02 mg administered in a 24-day regimen versus a 21-day regimen, the 24-day regimen was associated with greater suppression of follicular development. After intentional dosing errors during the third treatment cycle, ovarian activity, including ovulation, was observed in the majority of women in the 21-day regimen group compared to those in the 24-day regimen group. Ovarian activity returned to pre-treatment levels within the cycle after therapy in 91.8% of women in the 24-day regimen group.

VIdora micro is a combined oral contraceptive containing ethinyl estradiol 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 VIdora micro result in a moderate antimineralocorticoid effect.

Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the efficacy and safety of VIdora micro in women with moderate acne vulgaris. After 6 months of therapy, compared to placebo, the drug demonstrated a statistically significant reduction of 15.6% (49.3% vs. 33.7%) in the number of inflammatory lesions, 18.5% (40.6% vs. 22.1%) in the number of non-inflammatory lesions, and 16.5% (44.6% vs. 28.1%) in the total number of acne lesions. Additionally, a higher percentage of subjects, 11.8% (18.6% vs. 6.8%), had "clear" or "almost clear" skin as assessed by the Investigator's Static Global Assessment (ISGA) scale.

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 single oral administration. Bioavailability is 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 and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin. Only 3–5% of its total amount in serum is unbound. Ethinyl estradiol-induced elevation of SHBG does not affect the protein binding of drospirenone. The mean volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.

Metabolism. Drospirenone is extensively metabolized after oral administration. The main metabolites in plasma are the acid forms 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. The metabolic clearance rate of drospirenone from serum is approximately 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted unchanged only in very small amounts. Metabolites are excreted in urine and feces in a ratio of 1.2 to 1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

Steady state. During the treatment cycle, the maximum steady-state concentration of drospirenone in serum, approximately 70 ng/mL, is reached after 8 days of administration. Drospirenone levels in blood accumulate 3-fold as a result of the relationship between the terminal half-life and the dosing interval.

Special patient groups

Women with impaired renal function

Steady-state serum concentration of drospirenone in women with mild renal impairment (creatinine clearance 50–80 mL/min) was comparable to that in women with normal renal function (creatinine clearance >80 mL/min). Serum drospirenone levels were on average 37% higher in women with moderate renal impairment (creatinine clearance 30–50 mL/min) compared to women with normal renal function. Administration of drospirenone demonstrated good tolerability in all patient groups. It has been demonstrated that drospirenone intake does not have a clinically significant effect on serum potassium concentration.

Women with impaired hepatic function

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. The observed alteration in drospirenone clearance in individuals with moderate hepatic impairment did not result in any obvious differences in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant administration of spironolactone (two factors that may provoke hyperkalemia), serum potassium concentration did not exceed the upper limit of normal. Therefore, drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnic groups. No clinically significant differences in the pharmacokinetics of drospirenone or ethinyl estradiol were observed between Japanese women and Europeans.

Ethinyl estradiol

Absorption. After oral administration, ethinyl estradiol is rapidly and completely absorbed. Maximum serum concentration of 33 pg/mL is reached within 1–2 hours after single oral administration. Absolute bioavailability, due to presystemic conjugation and first-pass metabolism in the liver, is approximately 60%. Concomitant food intake reduces the bioavailability of ethinyl estradiol by approximately 25% in the subjects studied, with unchanged bioavailability in the remainder.

Distribution. Serum levels of ethinyl estradiol decline in a biphasic manner, with a terminal half-life of approximately 24 hours. Ethinyl estradiol binds strongly but non-specifically to serum albumins (approximately 98.5%) and induces an increase in SHBG and corticosteroid-binding globulin concentrations in serum. The apparent volume of distribution is approximately 5 L/kg.

Metabolism. Ethinyl estradiol is extensively metabolized in the gastrointestinal tract and during first-pass metabolism in the liver. Ethinyl estradiol is metabolized primarily by hydroxylation of the aromatic ring, forming a wide spectrum of hydroxylated and methylated metabolites present in free form and as glucuronide and sulfate conjugates. Metabolic clearance of ethinyl estradiol is approximately 5 mL/min/kg.

In vitro, ethinyl estradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinyl estradiol is almost not excreted unchanged. Ethinyl estradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is nearly 1 day.

Steady state. Steady state is achieved in the second half of the treatment cycle, when serum ethinyl estradiol concentration increases by 2.0–2.3 times.

Preclinical safety data

In laboratory animals, effects of drospirenone and ethinyl estradiol were limited to those associated with known pharmacological actions. In particular, reproductive toxicity studies in animals revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in animals receiving VIdora micro, effects on sexual differentiation were observed in certain animal species.

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 drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • Current VTE, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • known hereditary or acquired predisposition to VTE, 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 VTE due to multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • current ATE or history of ATE (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • current cerebrovascular disease or history of cerebrovascular disease, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to ATE, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of ATE due to multiple risk factors (see section "Special precautions") or due to a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past history of severe liver disease until liver function tests have returned to normal limits.
• Current or past history of hormone-sensitive breast cancer (see section "Special precautions", subsection "Malignant neoplasms").
• Severe or acute renal failure.
• Current or past history of hepatic tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of the genital organs).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the drug.

The medicinal product Viodora micro is contraindicated when used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Information regarding any concurrently administered medicinal product should be reviewed to identify potential interactions.

• Effect of other medicinal products on Viodora micro

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

Therapy

Enzyme induction may be observed within a few days of treatment initiation. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing 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 contraceptive method in addition to combined oral contraceptives (COCs). The barrier method should be used throughout the treatment period and for an additional 28 days after discontinuation of the enzyme-inducing agent. If treatment is initiated during the period of taking the last tablets in the COC pack, the next pack of COCs should be started immediately after the previous one, without the usual tablet-free interval.

Long-term treatment

For women undergoing long-term therapy with enzyme-inducing substances, a barrier method or another appropriate non-hormonal contraceptive method is recommended.

The following interactions have been documented according to published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

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

Active substances with variable effects on COC clearance:

Concomitant use of COCs with 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 regarding the medical use of the medicinal product for HIV/HCV treatment taken concomitantly should be reviewed to identify potential interactions and 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.

Active substances that decrease COC clearance (enzyme inhibitors)

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

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

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

Etoricoxib at doses of 60 to 120 mg/day demonstrated a 1.4- to 1.6-fold increase in plasma concentrations of ethinylestradiol when used concomitantly with a CHC containing 0.035 mg ethinylestradiol.

• Effect of Viodora micro on other medicinal products

COCs 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 substrate markers, 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, thereby causing mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

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

Therefore, women using the medicinal product Viodora micro must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the specified combination of medicinal products. Use of Viodora micro may be resumed 2 weeks after completion of therapy with the specified combination.

Other forms of interaction

In patients with normal renal function, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Viodora micro 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").

Laboratory tests

Use of contraceptive steroids may influence the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma concentrations of transport proteins such as corticosteroid-binding globulin; plasma concentrations of lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Such changes are usually within normal limits. Drospirenone increases plasma renin and aldosterone activity, induced by its moderate antimineralocorticoid activity.

Special precautions for use.

The decision to prescribe VIdora micro should be made taking into account a woman's current individual risk factors, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with taking VIdora micro compared to other combined oral contraceptives (COCs) (see sections "Contraindications" and "Special precautions for use").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using VIdora micro should be discussed with the woman.

Women should be advised to consult a physician in case of exacerbation or first signs of any of the conditions or risk factors listed below, and to determine whether discontinuation of VIdora micro is necessary.

If suspected or confirmed VTE or arterial thromboembolism (ATE) occurs, COCs should be discontinued immediately. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (coumarins).

• Circulatory disorders

Risk of VTE

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

Among 10,000 women who do not use COCs and are not pregnant, approximately 2 will develop VTE within one year. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

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

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

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

1 These figures are based on data from epidemiological studies, taking into account relative risks associated with different COCs compared to COCs containing levonorgestrel.

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

Factors increasing the risk of VTE

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

The use of VIdora micro 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 carefully considered. If the benefit-risk balance is unfavorable, COCs 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 or breastfeeding, see section "Use in pregnancy or breastfeeding").

Symptoms of VTE (DVT and PE)

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; warmth in the affected leg; redness or discoloration of the skin on the leg.

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

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

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

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

Risk of ATE

Epidemiological studies indicate that use of any COCs is associated with an increased risk of ATE (myocardial infarction) or cerebrovascular events (transient ischemic attack (TIA), stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The use of Vidor micro 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 ratio is unfavorable, COCs should not be prescribed (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 any of the symptoms listed below occur.

Symptoms of cerebrovascular disorders may include: sudden numbness of the face, weakness or numbness of the limbs, especially on one side of the body; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension disturbances; sudden worsening of vision 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, pressure or heaviness in the chest, arm, or below the sternum; discomfort radiating to the back, jaw, throat, arm, or stomach; a feeling of stomach fullness, indigestion, or gas; excessive sweating, nausea, vomiting, or dizziness; extreme 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, including human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer among women currently using COCs. This increased risk gradually disappears within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among women currently or recently using COCs is minimal relative 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 cancer 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 instances have 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 associated with COC use should be considered in differential diagnosis.

High-dose COCs (50 mcg ethinylestradiol) have been shown to reduce the risk of endometrial and ovarian cancers. It remains to be confirmed whether these findings apply to low-dose COCs as well.

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

Drospirenone/ethinylestradiol is 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 shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not demonstrate an association between current or past use of COCs and the risk of breast cancer. However, some studies have reported 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 previously used COCs (see section "Adverse Reactions," subsection "Post-marketing data").

Other conditions

The progestin component of the drug Vadora micro is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected during use. During clinical trials, slight but not clinically significant increases in serum potassium levels were observed in some patients with mild to moderate renal 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 should also be advised to maintain serum potassium levels within the upper limit of normal before initiating treatment, especially when concurrently using potassium-sparing medications (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 achieving normotension with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, although a definitive causal relationship with estrogen/progestin use has not been established: cholestasis 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.

Acute or chronic liver function 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 that previously occurred during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest a need to alter the therapeutic regimen 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 endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have also been observed during COC use.

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

One light pink tablet contains 46 mg of lactose; one white tablet contains 22 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.

Consultations/Medical examination

Before initiating or resuming use of Vadora micro, a complete medical and family history should be obtained, a full medical examination performed, and pregnancy excluded. Blood pressure should be measured and a medical examination conducted, considering contraindications (see section "Contraindications") and special precautions (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with Vadora micro compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

Patients are 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 infections.

Reduced efficacy

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

Cycle disturbances

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

If irregular vaginal bleeding persists or appears 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 COC intake has been irregular 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 drug is contraindicated during pregnancy.

If pregnancy occurs during use of Vadora micro, 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 a teratogenic effect from inadvertent COC use during pregnancy.

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

Available data on the use of the drug during pregnancy are too limited to draw conclusions regarding any negative impact of Vadora micro on pregnancy outcome, fetal or neonatal health. To date, there are no relevant epidemiological data.

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

Breastfeeding period. 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.

Fertility. Vadora micro is indicated for the prevention of pregnancy. Information on the return of fertility is provided in section "Pharmacological properties."

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect of Vadora micro on reaction speed during driving or operating machinery have been conducted. No effects on the ability to drive or operate machinery have been reported in women using COCs.

Method of Administration and Dosage

Route of administration: Oral.

Dosing

How to use VIdora micro

Tablets should be taken daily according to the order indicated on the blister pack, approximately at the same time each day, swallowing with a small amount of liquid if necessary. Tablets should be taken continuously. Take 1 tablet daily for 28 consecutive days. The next pack should be started the day after finishing the previous pack. Withdrawal bleeding usually begins on days 2–3 after starting the placebo tablets (last row) and may not stop before starting tablets from the next pack.

Starting VIdora micro

• No previous use of hormonal contraceptives (in the past month)

Start taking tablets on day 1 of the natural cycle (i.e., the first day of menstrual bleeding).

• Switching from another combined oral contraceptive (COC), vaginal ring, or transdermal patch

It is recommended to start taking VIdora micro the day after taking the last active (hormone-containing) tablet of the previous COC, but no later than the day after the tablet-free or placebo tablet period of the previous COC. If using a contraceptive vaginal ring or transdermal patch, start taking VIdora micro on the day of removal, but no later than the day when the next application of these products would be due.

• Switching from a progestogen-only method ("mini-pill", injections, implants) or a progesterone-releasing intrauterine system

VIdora micro can be started at any time after stopping the "mini-pill" (in the case of an implant or intrauterine system — on the day of removal; in the case of injections — 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 VIdora micro.

• After a first-trimester abortion

VIdora micro can be started immediately. In such cases, additional contraceptive methods are not required.

• After childbirth or second-trimester abortion

It is recommended to start taking VIdora micro on days 21–28 after childbirth or second-trimester abortion. If starting 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 medication, or wait for the onset of the first menstrual period.

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

What to do if a tablet is missed

A missed placebo tablet from the last (4th) row can be disregarded. However, such tablets should be removed from the pack to avoid unintentional prolongation of the placebo phase. The instructions below apply only to missed active tablets containing active ingredients.

If the delay in taking a tablet does not exceed 24 hours, contraceptive protection 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 the missed tablet exceeds 24 hours, contraceptive protection may be reduced. In such cases, two main principles should be followed:

1. The recommended hormone-free interval is 4 days; the tablet-free interval must never exceed 7 days;
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous tablet intake for 7 days.

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

• Days 1–7

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

• Days 8–14

Take the last missed tablet as soon as possible, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, no additional contraceptive methods are needed. Otherwise, or if more than one tablet was missed, additional contraceptive methods are recommended for 7 days.

• Days 15–24

The risk of reduced effectiveness increases as the placebo tablet phase approaches. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided, provided tablets were taken correctly for 7 days before the missed dose. If this is not the case, follow the first option below and use additional contraceptive methods for the next 7 days.

1. Take the last missed tablet as soon as possible, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time until the end of the active tablets. The 4 placebo tablets in the last row should be disregarded. Start taking tablets from the next pack immediately after the last active tablet. Withdrawal bleeding is unlikely to occur before finishing all active 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. Then take the placebo tablets from the last row for 4 days, including the days of missed tablets; resume taking tablets from the next pack.

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

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disturbances (e.g., 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 an active tablet, a new (replacement) tablet should be taken as soon as possible. The next tablet should be taken, if possible, within 24 hours, according to the usual dosing schedule. If more than 24 hours have passed, the recommendations provided above under "Method of Administration and Dosage", subsection "What to do if a tablet is missed", should be followed. If a woman does not wish to change her tablet-taking schedule, she should take an additional tablet(s) from the next pack.

How to delay withdrawal bleeding

To delay the onset of withdrawal bleeding, continue taking VIdora micro tablets from a new pack without taking the placebo tablets from the current pack. If desired, this period can be extended up to the end of the active tablets in the second pack. Breakthrough bleeding or spotting may occur during this time. Usually, VIdora micro is resumed after taking the placebo tablets.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the placebo tablet-free interval by the number of days desired. 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 (similar to delayed menstruation or withdrawal bleeding).

Children

The drug is indicated for use only after regular menstruation has been established and only under medical supervision.

Overdose

There are no clinical data on overdose with VIdora micro 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 drug intake. There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

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

Table 3 presents adverse reactions according to MedDRA system organ classes. Frequencies are based on clinical data. The most appropriate MedDRA terms have been used to describe specific reactions and their synonyms and related conditions.

Table 3

Frequency of adverse reactions reported during clinical trials of Viodara micro as an oral contraceptive and for the treatment of mild acne, according to MedDRA system organ classes and preferred terms.

*irregular bleeding usually resolves with continued therapy

Description of individual adverse reactions

In women taking COCs, an increased risk of venous or arterial thrombotic and thromboembolic events has been observed, including myocardial infarction, stroke, transient ischemic attack (TIA), venous thrombosis, and pulmonary embolism, as described in detail in the section "Special precautions for use".

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

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• development or exacerbation of diseases for which the association 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 COCs until liver function parameters return to normal;
• in women with hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

The frequency 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 who are currently or 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 precautions for use".

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions of other medicinal products (enzyme inducers) with 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.)

Five studies comparing the risk of breast cancer between women who had ever used (currently or previously) COCs and those who had never used COCs reported no association between COC use and 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 taking or who recently used COCs (<6 months since last use) and those who had never used COCs. One of these studies reported no association between the risk of breast cancer and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with long-term use, with relative risk 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 during post-marketing surveillance is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store out of reach and sight of children, at temperatures not exceeding 25 °C.

Packaging.

28 tablets per blister pack (21 pink tablets and 7 white tablets), 1 or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Laboratorios Leon Farma, S.A.

Manufacturer's address and place of business.

C/La Valina s/n, Polígono Industrial Navatejera, Villacilambre, 24193 León, Spain