Vidora

INSTRUCTIONS for medical use of the medicinal product Vidorra (Vidora)

Composition:

Active substances: drospirenone, ethinylestradiol;

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

1 film-coated yellow tablet contains drospirenone 3.0 mg and ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate, maize starch, pregelatinized starch, crospovidone Plasdone XL-10, crospovidone Plasdone XL, povidone K-30, polysorbate 80, magnesium stearate, Opadry® yellow (polyethylene glycol, polyvinyl alcohol, titanium dioxide (E 171), talc, yellow iron oxide (E 172)).

1 film-coated white tablet (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: yellow, round, film-coated tablets. Placebo tablets: white, round, film-coated tablets.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Drospirenone and ethinylestradiol. ATC code G03AA12.

Pharmacological properties.

Pharmacodynamics.

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

The overall Pearl Index (contraceptive failures + patient errors) for the drug is 0.57 (upper two-sided 95% CI – 0.90).

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

Vidora is a COC 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 study data, the moderate antimineralocorticoid properties of Vidora result in a moderate antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentration, reaching approximately 38 ng/mL, is achieved within about 1–2 hours after single oral administration. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, drospirenone serum 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 the 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.

Elimination. The 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, the maximum steady-state concentration of drospirenone in serum, approximately 70 ng/mL, is reached after about 8 days of treatment. Serum drospirenone concentration increased 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 subjects with moderate hepatic impairment compared to healthy volunteers. This observed alteration in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant administration of spironolactone (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper normal limit was observed. Therefore, drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnicity. No clinically significant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between Japanese women and Europeans.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Following administration of 30 µg, peak plasma concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass effect, which depends on individual variations.

Absolute bioavailability is approximately 45%.

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

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

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

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day. The elimination half-life of metabolites is 20 hours.

Steady-state concentration. Steady-state concentration is reached during the second half of the treatment cycle; plasma ethinylestradiol levels increase approximately 1.4–2.1-fold.

Preclinical safety data

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. In particular, studies on reproductive toxicity in animals revealed species-specific embryotoxic and fetotoxic effects. Exposure exceeding that in animals treated with Vidora resulted in effects on sexual differentiation 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 occur for the first time during use of CHCs, 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 or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to ATE, such as hyperhomocysteinemia and antiphospholipid antibodies (antibodies to cardiolipin, 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 presence of a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function tests return to normal range.
• Current or past hormone-sensitive breast cancer (see section "Special precautions", subsection "Malignant neoplasms").
• Severe or acute renal insufficiency.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., genital organs).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients.
• Suspected or confirmed pregnancy.

Vidora 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").

Special safety measures.

This medicinal product may pose a hazard 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.

Carefully review information on any concomitantly administered medicinal product to identify potential interactions.

• Effect of other medicinal products on Vidora

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 pattern 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 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 contraceptive method in addition to COCs. The barrier method should be used throughout the duration of treatment with the enzyme-inducing drug and for an additional 28 days after discontinuation. 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

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 reported according to published data.

Active substances that increase COC clearance (reducing COC efficacy via enzyme induction), e.g.:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; drugs 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:

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 increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the medical use of the HIV/HCV medicinal product taken concomitantly 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.

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 administered concomitantly with a COC containing 0.035 mg ethinylestradiol.

• Effect of Vidora on other medicinal products

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

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as marker substrates, clinically significant interaction of drospirenone at a dose of 3 mg with other active substances metabolized by cytochrome P450 is unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

During clinical trials involving patients receiving antiviral treatments for hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased alanine aminotransferase (ALT) levels exceeding 5 times the upper limit of normal (ULN) were observed. This occurred significantly more frequently in women using ethinylestradiol-containing medicinal products, 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 Vidora must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the specified combination of medicinal products. Vidora 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 nonsteroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Vidora 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").

Other forms of interaction

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. Usually, such changes remain within normal ranges.

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

Special precautions for use

The decision to prescribe Vidorra should be made taking into account the woman's individual risk factors currently present, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with taking Vidorra 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 need for Vidorra use should be discussed with the woman.
• In case of exacerbation or first signs of any of the listed conditions or risk factors, women are advised to consult a physician and determine whether discontinuation of Vidorra is necessary.
• If suspected or confirmed venous or arterial thromboembolism (VTE or ATE) occurs, COCs should be discontinued immediately. If anticoagulant therapy is initiated, an alternative adequate contraceptive method should be provided due to the teratogenic effects of anticoagulants (e.g., coumarins).
• Circulatory disorders.

Risk of VTE development

Use of any COC increases the risk of VTE in women who take them compared to women who do not. COCs containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Use of other medicinal products, such as Vidorra, may result in a doubling of VTE risk. The decision to prescribe such 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 taking Vidorra, 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 take COCs and are not pregnant, approximately 2 will develop VTE within one year. However, in individual women, the risk may be significantly higher depending on existing risk factors (see below).

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

In both cases, the annual number of VTE events was lower than 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 estimates are based on all available epidemiological data, taking into account relative risks associated with different COCs compared to COCs containing levonorgestrel.

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

Very rarely, thrombosis in other blood vessels—such as hepatic, renal, mesenteric, cerebral, or retinal veins and arteries—has been reported in women using COCs.

Risk factors for VTE development

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

Use of Vidorra is contraindicated in women with multiple risk factors that may increase the risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor; therefore, the overall risk of VTE should be considered. If the benefit-risk balance is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1

Risk factors for VTE development

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 thromboembolic events during pregnancy, especially within the 6 weeks following delivery (for information on pregnancy and breastfeeding, see section "Use during 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 a COC 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; sensation of warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include: sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with hemoptysis; sudden chest pain; 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 painless blurred vision, which may progress to vision loss. In some cases, vision loss occurs almost instantaneously.

Risk of ATE

Epidemiological studies indicate that the use of any COC is associated with an increased risk of arterial thromboembolism (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 VIdora 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 using 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; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension disturbances; sudden visual impairment in one or both eyes; sudden, severe or prolonged headache without a known cause; loss of consciousness or fainting, with or without seizures.

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

Symptoms of myocardial infarction may include: chest 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 acid reflux; 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 to what extent study results account for confounding risk factors such as sexual behavior and 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 COC use. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs is small relative to the overall baseline risk of breast cancer. These studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors. There is a trend that breast cancers diagnosed in women who have ever used COCs are clinically less advanced than in those who have never used COCs.

Benign, and in rare cases malignant, liver tumors have been observed in women using COCs, which in some cases led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor associated with COC use should be considered in differential diagnosis.

Use of COCs at high doses (50 mcg ethinyl estradiol) reduces the risk of endometrial and ovarian cancer. 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) of the FDA).

Drospirenone/ethinyl estradiol is contraindicated in women with current or past history of breast cancer, as breast cancer may be hormonally sensitive (see section "Contraindications").

Epidemiological studies have not consistently demonstrated an association between use of combined oral contraceptives (COCs) and risk of breast cancer. Studies do not show a clear link between current or past use of COCs and risk of breast cancer. However, some studies report 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 used COCs in the past (see section "Adverse Reactions", subsection "Post-marketing data").

Other Conditions

The progestin component of Vidorah 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 not clinically significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment who were concurrently using 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 below the upper limit of normal before initiating Vidorah, 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 normotension is achieved with antihypertensive therapy.

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

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 ruled out.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or cholestatic pruritus previously experienced 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 ethinyl estradiol). 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.

Depressed mood and depression are well-known adverse effects that may occur during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult a physician if they experience mood changes or symptoms of depression, including shortly after starting treatment.

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

One tablet contains 46 mg of lactose. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, this amount of lactose should be taken into account, especially if on a lactose-free diet.

Consultations/Medical Examinations

Before initiating or resuming use of Vidorah, a complete medical and family history should be taken, a full medical examination performed, and pregnancy excluded. Blood pressure should be measured and a medical evaluation 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 Vidorah compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

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

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

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

Reduced Efficacy

The efficacy of COCs may be reduced in case of missed 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 reappears after a period of regular bleeding, non-hormonal causes should be considered and appropriate diagnostic measures undertaken, including evaluation to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

Some women may not experience withdrawal bleeding during the tablet-free interval. If COCs have been taken according to instructions in section "Dosage and Administration", pregnancy is unlikely. However, if COC use 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 ruled out before continuing COC use.

Use during Pregnancy or Breastfeeding

Pregnancy. The drug is contraindicated during pregnancy. If pregnancy occurs during treatment with Vidorah, 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 before pregnancy, nor evidence of teratogenic effects from unintentional COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological Properties"). Based on 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 harmful effects in humans.

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

When resuming use of Vidorah, the increased risk of VTE during the postpartum period should be considered (see sections "Special Precautions for Use" and "Dosage and Administration").

Breastfeeding Period. COCs may affect breastfeeding by reducing the quantity and altering 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, which may affect the infant.

Ability to influence the speed of reactions when driving or operating machinery.

No studies have been conducted on the effect of this drug on the ability to drive or operate machinery. No effect on the ability to drive or operate machinery has been observed in women using COCs.

Method of Administration and Dosage

Orally.

Dosing

Tablets should be taken regularly at approximately the same time each day, swallowed with a small amount of liquid if necessary, following the order indicated on the blister pack. The medication is taken as one tablet daily for 21 consecutive days. After this, a new pack should be started following a 7-day tablet-free interval, during which withdrawal bleeding usually occurs. This bleeding typically begins on the 2nd or 3rd day after the last tablet and may continue until the start of the next pack.

Starting treatment with Viodora

• No previous use of hormonal contraceptives (previous month)

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

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

It is recommended to take the first Viodora tablet the day after the last active tablet (containing the active ingredient), but no later than the day after the tablet-free interval. When switching from a vaginal ring or transdermal patch, start Viodora on the day of device removal, but no later than the day the next application would have been due.

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

Viodora may be started at any time after discontinuation of 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 use an additional barrier method of contraception for the first 7 days of taking Viodora.

• After first-trimester abortion

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

• After childbirth or second-trimester abortion

It is recommended to start taking Viodora between days 21 and 28 after childbirth or second-trimester abortion. If starting later, an additional barrier method of contraception should be used for the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting Viodora, or the woman should wait until the onset of the first menstruation.

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

Missed tablet intake

If the delay in taking any tablet does not exceed 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as remembered. The next tablet should be taken at the usual time.

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

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

Accordingly, the following practical recommendations should be followed:

• Week 1

Take the most recently missed tablet as soon as possible, even if this means taking two tablets at the same time. 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 more tablets missed and the closer the missed dose is to the tablet-free interval, the higher the risk of pregnancy.

• Week 2

Take the most recently missed tablet as soon as remembered, even if two tablets must be taken at the same time. Continue taking tablets at the usual time. If tablets were taken correctly during the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use a barrier method of contraception for 7 days.

• Week 3

The risk of reduced efficacy increases as the 7-day tablet-free interval approaches. However, following one of the regimens below can help avoid reduced contraceptive protection. If one of the following options is followed, no additional contraceptive methods are required, provided tablets were taken correctly during the 7 days before the missed dose. If not, follow the first option below and use additional barrier methods for the next 7 days.

1. Take the most recently missed tablet as soon as remembered, even if two tablets must be taken at the same time. Continue taking tablets at the usual time. Start the next pack immediately after finishing the current one—there should be no tablet-free interval between packs. Withdrawal bleeding is unlikely before the end of the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking tablets from the current pack. In this case, the tablet-free interval (including days of missed tablets) should not exceed 7 days; then start the next pack.

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

Gastrointestinal disturbances

In case of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the drug may occur; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, take another (replacement) tablet as soon as possible. The next tablet should be taken, if possible, within 12 hours according to the usual dosing schedule. If more than 12 hours have passed, follow the advice provided above under "Missed tablet intake". If a woman does not wish to alter her tablet-taking schedule, she should take additional tablet(s) from the next pack.

Delaying withdrawal bleeding

To delay withdrawal bleeding, continue taking Viodora tablets from a new pack without a break. This can be continued until the tablets from the second pack are finished. Breakthrough bleeding or spotting may occur. Usually, Viodora treatment is resumed after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, shorten the tablet-free interval by the desired number of days. Note that the shorter the interval, the more likely it is that withdrawal bleeding will not occur and that breakthrough bleeding or spotting may occur during intake of tablets from the second pack (similar to delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients

Viodora is not indicated after menopause.

Patients with hepatic impairment

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

Patients with renal impairment

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

Children

Viodora is indicated only after the onset of the first menstruation. Based on epidemiological data from over 2000 adolescents under 18 years of age, there is no evidence of differences in safety and efficacy in this patient group compared to women aged 18 years and older.

Overdose

There are no clinical data on overdose with Viodora tablets. Based on general experience with COCs, overdose may cause nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche in cases of accidental or unintentional 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". The adverse reactions listed below were observed during the use of the drug VIdora (see Table 3).

Table 3

Adverse reactions observed during the use of the drug VIdora.

Description of individual adverse reactions

An increased risk of developing venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischaemic attack (TIA), venous thrombosis, and pulmonary embolism, 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 an 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, haemolytic-uraemic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function parameters return to normal;

Adverse reactions observed in patients using COCs include: emotional lability, depression; loss of 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, TIA); erythema.

Other adverse reactions associated with the COC class are also mentioned in the sections "Contraindications" and "Special warnings and precautions for use" (e.g., 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 additional number of breast cancer cases diagnosed in women who are currently or recently used COCs is small relative to the overall risk of breast cancer. A causal relationship with 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 interaction").

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 in the past) COCs and those who had never used COCs reported no association between COC use and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

In three studies, the risk of breast cancer was compared between women who were current or recent users of COCs (<6 months since last use) and those who had never used COCs. One of these studies reported no association between breast cancer risk 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 also 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 use.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of a medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store out of the reach of children at a temperature not exceeding 25 °C.

Packaging.

28 tablets per blister pack (21 yellow 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 Vallina s/n, Polígono Industrial Navatedjera, Villacilambre, 24193 León, Spain.