Darilia

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

Composition:

Active substances: drospirenone, ethinylestradiol;

1 active tablet contains 3 mg of crystalline drospirenone 100% and 0.02 mg of micronized ethinylestradiol 100%;

Excipients: lactose monohydrate, corn starch, pregelatinized starch, polyvinyl alcohol copolymer and polyethylene glycol, magnesium stearate;

film coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol (macrogol), talc, lecithin (soy);

1 placebo tablet contains:

Active substances: absent;

Excipients: microcrystalline cellulose, lactose, pregelatinized starch, magnesium stearate, anhydrous colloidal silicon dioxide;

film coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol (macrogol), talc, indigotine (E 132), quinoline yellow (E 104), iron oxide black (E 172), yellow sunset FCF (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Active tablets: white or almost white, round, biconvex film-coated tablets, approximately 6 mm in diameter; one side of the tablet is marked with the imprint "G73";

Placebo tablets: green, round, biconvex film-coated tablets, approximately 6 mm in diameter.

Pharmacotherapeutic group. Sex hormones and modulators of the genital system. Hormonal contraceptives for systemic use. 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 Darillia is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in the endometrium.

Darillia, film-coated tablets, is a combined oral contraceptive containing ethinylestradiol and the progestin drospirenone. At therapeutic doses,
drospirenone exhibits antiandrogenic and weak antimineralocorticoid properties. It lacks any estrogenic, glucocorticoid, or antiglucocorticoid activity. This gives drospirenone a pharmacological profile very similar to the natural hormone progesterone. The weak antimineralocorticoid properties of the drug result in a mild antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone (3 mg)

Absorption. After oral administration, drospirenone is rapidly and almost completely absorbed. The maximum serum concentration of the active substance – 38 ng/mL – is reached within 1–2 hours after a single dose. Bioavailability ranges from 76% to 85%. Food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, serum concentrations of drospirenone decline with a terminal half-life of 31 hours. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of the total serum concentration of the active substance represents free hormone. Ethinylestradiol-induced increases in SHBG do not affect the protein binding of drospirenone in serum. The expected mean volume of distribution is 3.7 ± 1.2 L/kg.

Biological transformation. After oral administration, drospirenone undergoes extensive metabolism. Most plasma metabolites are represented by acid forms of drospirenone formed by opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, formed via reduction and subsequent 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 in serum is 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted only in trace amounts unchanged. Metabolites of drospirenone are excreted in feces and urine in a ratio of approximately 1.2:1.4; the elimination half-life of metabolites is approximately 40 hours.

Steady-state concentration. During one cycle of use, the maximum steady-state concentration of drospirenone in serum (approximately 70 ng/mL) is reached after 8 days. Serum concentrations of drospirenone increase about threefold as a result of the relationship (or proportion) between the terminal half-life and the dosing interval.

Special patient populations:

• Renal impairment: Steady-state serum levels of drospirenone in women with mild renal impairment (creatinine clearance 50–80 mL/min) were comparable to those in women with normal renal function (>80 mL/min). Serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr 30–50 mL/min) compared to women with normal renal function. Therapy with drospirenone was well tolerated in women with either mild or moderate renal impairment and had no clinically significant effect on serum potassium concentration.
• Hepatic impairment: It is known that in volunteers with moderate hepatic impairment, the clearance of a single oral dose was reduced by approximately 50% compared to healthy volunteers. This reduction in drospirenone clearance in volunteers with moderate renal impairment does not lead to any significant changes in serum potassium concentration. Even in patients with diabetes and concomitant treatment with spironolactone (two factors that may predispose to hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in patients with mild to moderate hepatic impairment (Child-Pugh class B).

Ethinylestradiol (0.02 mg)

Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentration after a single dose is reached within 1–2 hours and is approximately 33 pg/mL. Absolute bioavailability varies and is approximately 60%. Concomitant food intake reduced the bioavailability of ethinylestradiol by approximately 25% in the examined patients, while no changes were observed in the remainder.

Distribution. Serum concentrations of ethinylestradiol decline in a biphasic manner, with a terminal half-life of approximately 24 hours. Ethinylestradiol binds well, but non-specifically, to serum albumin (approximately 98.5%) and induces an increase in serum concentrations of SHBG and corticosteroid-binding globulin (CBG). The expected volume of distribution is approximately 5 L/kg.

Biological transformation. Ethinylestradiol undergoes extensive presystemic metabolism in the small intestine and liver. Primarily, ethinylestradiol is metabolized via aromatic hydroxylation, resulting in a wide spectrum of hydroxylated and methylated metabolites, present as free metabolites and conjugates with glucuronides and sulfates. The metabolic clearance rate of ethinylestradiol metabolites is approximately 5 mL/min/kg.

In vitro studies have shown that ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and also, based on its mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinylestradiol is practically not excreted unchanged. Metabolites of ethinylestradiol are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day.

Steady-state concentration. Steady-state conditions are achieved during the second half of the cycle, with serum concentrations of ethinylestradiol increasing approximately 2–2.3-fold.

Ethnic groups

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

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. Specifically, studies on reproductive toxicity in animals revealed species-specific embryotoxic and fetotoxic effects. Exposure to drospirenone and ethinylestradiol at levels exceeding therapeutic doses resulted in effects on sexual differentiation in rat embryos, but not in monkeys.

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

DARILIA is contraindicated in women with the presence or development of the following conditions:

• Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition";

• Hypersensitivity to peanuts or soy;

• Presence or risk of venous thromboembolism (VTE):

  • Venous thromboembolism – current VTE, including cases requiring anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));

• Known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;

• Major surgical intervention with prolonged immobilization (see section "Special precautions");

• High risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions");

• Presence or risk of arterial thromboembolism (ATE):

  • Current or past arterial thromboembolism (e.g., myocardial infarction), or prodromal conditions (e.g., angina pectoris);
  • Cerebrovascular disorders – current or past stroke, or presence of prodromal conditions (e.g., transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to the presence of any of the following serious risk factors:

• Diabetes mellitus with vascular complications;

• Severe arterial hypertension;

• Severe dyslipoproteinemia;

• Current or past severe hepatic disease until liver function tests return to normal range;

• Severe renal insufficiency or acute renal failure;

• Current or past hepatic tumors (benign or malignant);

• Known or suspected hormone-dependent malignancies (e.g., of genital organs or breasts);

• Current or past hormone-dependent breast cancer (see section "Special precautions");

• Vaginal bleeding of unknown etiology.

DARILIA is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with 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.

The information on any concomitantly administered medicinal product should be reviewed to identify potential interactions.

Pharmacodynamic interactions

During clinical studies 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 more frequently in women using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, when treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, elevated ALT levels were also observed in women taking ethinylestradiol-containing products such as CHCs (see section "Contraindications"). Therefore, before initiating treatment with these combinations of medicinal products, users of DARILIA must switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods). Use of DARILIA may be resumed 2 weeks after completion of treatment with these medicinal product combinations.

Pharmacokinetic interactions

Effect of other medicinal products on DARILIA

Interactions are possible with medicinal products that induce microsomal enzymes. This leads to increased clearance of sex hormones, which in turn may cause changes in menstrual bleeding patterns and/or loss of contraceptive efficacy.

Therapy

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

Short-term therapy

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

If therapy with an enzyme-inducing agent is initiated during the period of taking the last tablets in the current pack, the next pack of active CHC tablets should be started immediately after finishing the active tablets in the previous pack, omitting the placebo tablets.

Long-term therapy

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another appropriate non-hormonal contraceptive method.

The following interactions have been documented according to published data.

Substances increasing CHC clearance (reducing CHC efficacy via enzyme induction), e.g.: barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; HIV medications: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing the herbal extract St. John’s wort (Hypericum perforatum).

Substances with variable effects on CHC clearance

When used concomitantly with CHCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including HCV antiviral combinations, 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 concomitantly administered HIV/HCV treatment should be reviewed to identify potential interactions and any additional recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances decreasing CHC clearance (enzyme inhibitors)

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

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

In a study using multiple doses of drospirenone (3 mg daily)/ethinylestradiol (0.02 mg daily) co-administered with the potent CYP3A4 inhibitor ketoconazole for 10 days, AUC (0–24 hours) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively.

Concomitant use of etoricoxib at doses of 60 mg to 120 mg daily with combined hormonal contraceptives containing 0.035 mg ethinylestradiol resulted in a 1.4–1.6-fold increase in plasma ethinylestradiol concentrations, respectively.

Effect of DARILIA on other medicinal products

CHCs may affect the metabolism of certain other drugs, thereby altering plasma and tissue concentrations of active substances—either increasing (e.g., cyclosporine) or decreasing (e.g., lamotrigine).

Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as marker substrates, clinically significant interactions between 3 mg drospirenone and other active substances metabolized by cytochrome P450 are unlikely.

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

Other forms of interaction

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 DARILIA 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 liver function biochemical parameters, thyroid, adrenal, and renal function, as well as plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism parameters, coagulation, and fibrinolysis. Changes are usually within normal ranges.

Drospirenone increases plasma renin and aldosterone activity due to its moderate antimineralocorticoid activity.

Special precautions for use.

The decision to prescribe Dariliah should be made taking into account the woman's individual risk factors at the time, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with Dariliah compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Warnings" below).

Warnings

• If any of the conditions or risk factors listed below are present, the need for using Dariliah should be discussed with the woman.
• Women should be advised to consult a physician if they experience an exacerbation or the first signs of any of the listed conditions or risk factors, and to determine whether discontinuation of Dariliah is necessary.
• Combined hormonal contraceptives (CHCs) should be discontinued if VTE or arterial thromboembolism (ATE) is suspected or confirmed. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (coumarins).

Cardiovascular disorders

Risk of venous thromboembolism (VTE).

The use of any CHC increases the risk of venous thromboembolism (VTE) in women who use them compared to women who do not. CHCs containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Use of other CHCs, such as Dariliah, may double the risk. The decision to use a contraceptive not belonging to the group with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure she understands the VTE risk associated with Dariliah, the impact of her individual risk factors, and that the risk of VTE is highest during the first year of use. Some data suggest that the risk of VTE may increase when restarting CHC use after a break of 4 weeks or more.

Among women who do not use CHCs and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, in any individual woman, the risk level may be significantly higher depending on her underlying risk factors (see below).

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

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

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

Number of VTE cases per 10,000 women per year

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

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

Rarely, thrombosis in other vascular sites, such as hepatic, mesenteric, renal veins, retinal veins, and arteries, has been reported in women using CHCs.

Risk factors for VTE development.

The risk of developing venous thromboembolic complications while using CHCs may be substantially increased in women with additional risk factors, particularly when multiple risk factors are present (see Table 1).

Dariliah is contraindicated in women with multiple risk factors that place them in a high-risk category for venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor; therefore, the overall VTE risk should be considered. CHCs should not be prescribed if the benefit-risk balance is unfavorable (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 thromboembolism during pregnancy, especially within the first 6 weeks after delivery (see section "Use during pregnancy or breastfeeding").

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

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot, or swelling along a vein in the leg;
• Pain or increased tenderness in the leg, which may only be felt while standing or walking;
• A sensation of warmth in the affected leg;
• Redness or change in skin color of the leg.

Symptoms of pulmonary embolism (PE) may include:

• Sudden onset of unexplained shortness of breath or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis (coughing up blood);
• Sudden chest pain;
• Near-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 serious conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include: sudden pain, swelling, and mild cyanosis of a limb.

Ocular vascular occlusion may present with painless blurred vision that may progress to vision loss. In some cases, vision loss develops almost immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have shown that the use of any COCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack, stroke). Arterial thromboembolic events can 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). Darilía is contraindicated if a woman has one serious or multiple risk factors 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 of ATE should be considered. COCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 2

Risk factors for ATE.

ATE Symptoms

If any of the symptoms listed below occur, women should seek immediate medical attention and inform the physician that they are taking COCs.

Symptoms of cerebrovascular disorders may include:

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

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

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, squeezing or stretching sensation in the chest, arm or behind the breastbone;
• discomfort radiating to the back, jaw, throat, arm or stomach;
• sensation of stomach fullness, indigestion or suffocation;
• excessive sweating, nausea, vomiting or dizziness;
• extreme weakness, restlessness or shortness of breath;
• rapid or irregular heartbeat.

Tumors

Some epidemiological studies suggest an additional increased risk of cervical cancer with prolonged use of oral contraceptives (OCs) (> 5 years), although this claim remains controversial, as it has not been definitively established to what extent study results account for confounding risk factors such as sexual behavior and other factors, for example, human papillomavirus (HPV) infection.

The drug Darilía is contraindicated in women with current or past history of hormone-dependent breast cancer (see section "Contraindications").

Epidemiological studies have not demonstrated a consistent association between the use of combined oral contraceptives (COCs) and the risk of developing breast cancer. Studies do not show a link between current or past use of COCs and the risk of developing breast cancer. However, some studies report a slight increase in the risk of breast cancer among women who are currently using or have recently used COCs (< 6 months since last use) and among those who have used COCs for a prolonged period (see section "Adverse Reactions").

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using COCs. In some cases, these tumors have led to life-threatening intra-abdominal hemorrhage. In the differential diagnosis, if severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding occur, the possibility of liver tumor should be considered in women taking COCs.

High-dose COCs (0.05 mg ethinylestradiol) reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether these data also apply to low-dose COCs.

Other conditions

Depressed mood and depression are common adverse reactions during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be informed about the need to consult a physician if mood changes or symptoms of depression occur, even shortly after starting treatment.

The progestogenic component of Darilía is an aldosterone antagonist with potassium-sparing properties. In most cases, increased serum potassium levels are not expected during use. Nevertheless, in a clinical study, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment and concomitant use of potassium-sparing drugs during treatment with drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first cycle of treatment in patients with renal insufficiency. These patients are also advised to maintain serum potassium levels not exceeding the upper limit of normal before starting treatment, especially when concomitantly using potassium-sparing drugs (see section "Interaction with other medicinal products and other forms of interaction").

Women with hypertriglyceridemia or a family history of this disorder may belong to a risk group for developing pancreatitis when using COCs.

Although slight increases in blood pressure have been reported in many women using COCs, clinically significant hypertension is rare. Only in these rare cases is immediate discontinuation of COCs justified.

In cases of persistent arterial hypertension or inability to control blood pressure with antihypertensive drugs, women with diagnosed arterial hypertension who are using COCs should discontinue their use. If appropriate, COC use may be resumed after achieving normotension with antihypertensive therapy.

The occurrence or exacerbation of the following conditions has been reported during pregnancy and with use of COCs, but their relationship to COC use has not been definitively established: cholestasis-related 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 hereditary or acquired angioedema.

Acute or chronic liver function disorders may require discontinuation of COCs until liver function tests return to normal.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus previously caused by cholestasis during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating the need to modify the therapeutic regimen for women with diabetes who are taking low-dose COCs (containing < 0.05 mg ethinylestradiol). However, women with diabetes should be under careful and regular medical supervision, especially at the beginning of COC use.

Cases of worsening of endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have also been observed during COC use. Chloasma may sometimes occur, particularly in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid prolonged exposure to direct sunlight or ultraviolet radiation during COC use.

Excipients

1 active tablet contains 48.53 mg of lactose monohydrate; 1 placebo tablet contains 37.26 mg of lactose.

This medicinal product should not be used in patients with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption, or in those on a lactose-free diet.

1 active tablet contains 0.07 mg of soy lecithin; therefore, this medicinal product should not be used in patients hypersensitive to peanuts or soy.

Placebo tablets contain the colorant Sunset Yellow (E 110), which may cause allergic reactions.

Medical examination/consultation

Before starting or resuming use of Darilía, a complete medical history (including family history) should be obtained, a medical examination performed, and pregnancy excluded. Blood pressure should be measured and a physical examination conducted, taking into account contraindications (see section "Contraindications") and special precautions for use (see section "Special precautions for use"). It is important to inform women about the risk of venous and arterial thrombosis, including the risk associated with Darilía compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis. Patients are advised to carefully read the package leaflet and follow the recommendations provided.

The frequency and nature of medical check-ups should be based on established medical practice guidelines, taking into account individual characteristics of each woman.

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

Reduced efficacy

The effectiveness of COCs may be reduced, for example, in case of missed active tablets (see section "Dosage and administration"), gastrointestinal disturbances during active tablet intake (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 months of treatment. Therefore, evaluation of any irregular bleeding should only be performed after an adaptation period of three menstrual cycles.

If irregular bleeding persists or occurs after several normal cycles, non-hormonal causes should be considered and appropriate diagnostic measures performed (if necessary, curettage) to exclude malignant neoplasms or pregnancy.

In some women, withdrawal bleeding may not occur during placebo tablet intake. If COCs have been taken according to instructions (see section "Dosage and administration"), pregnancy is unlikely. However, if contraceptive use has been irregular or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

Use during pregnancy or breastfeeding

Pregnancy

Darilía is not indicated during pregnancy.

If pregnancy occurs during treatment with Darilía, the drug should be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children born to women who used oral contraceptives prior to pregnancy, nor a teratogenic effect from inadvertent use of oral contraceptives during pregnancy.

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

Data on the use of Darilía during pregnancy are too limited to draw conclusions regarding any negative impact of Darilía on pregnancy outcome, fetal or neonatal health. Currently, there are no relevant epidemiological data. When resuming use of Darilía, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration", "Special precautions for use").

Breastfeeding period

COCs may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Therefore, COCs are generally not recommended while a woman is fully 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

Darilía is indicated for prevention of pregnancy. Information on fertility recovery can be found in the section "Pharmacological properties".

Ability to influence reaction rate while driving or operating machinery

No studies on the effect on the ability to drive or operate machinery have been conducted. Women taking combined oral contraceptives have not reported effects on the ability to drive or operate machinery.

Method of Administration and Dosage

Each blister pack contains 28 tablets (24+4): 24 white or almost white tablets (active tablets) and 4 green tablets (placebo tablets – inactive).

How to take Darilya (24+4)

Tablets should be taken daily at approximately the same time, with a small amount of liquid if needed, following the order indicated on the blister pack. There should be no breaks between taking tablets. One tablet should be taken daily for 28 consecutive days. The next pack should be started immediately after taking the last tablet from the previous pack. Menstrual-like bleeding usually occurs on days 2–3 after starting the placebo tablets (green tablets in the last row) and does not necessarily end before starting tablets from a new pack.

How to start taking Darilya (24+4)

If hormonal contraceptives were not previously used (previous period, last month). Tablet intake should begin on the first day of the menstrual cycle (i.e., the first day of menstrual bleeding).

Switching from another combined hormonal contraceptive (combined oral contraceptive (COC) tablet, vaginal ring, or transdermal patch). It is recommended to take the first Darilya tablet the day after taking the last active tablet (tablet containing active ingredient) of the previous combined hormonal contraceptive (CHC), but no later than the day after the tablet-free interval or the hormone-free period of the previous COC. When switching from a vaginal ring or transdermal patch, tablet intake should preferably begin on the day of removal of the previous method, but no later than the day scheduled for the next application of the vaginal ring or transdermal patch.

Switching from a progestogen-only method (mini-pill, injections, implants) or an intrauterine system containing progestogen (IUS). A woman may start taking Darilya on any day of mini-pill intake (in the case of an implant or intrauterine system – on the day of removal; in the case of an injection – instead of the next scheduled injection). However, in all cases, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the drug.

After first-trimester abortion. Drug use should begin immediately on the same day as the procedure. In this case, there is no need to use additional contraceptive methods.

After childbirth or second-trimester abortion. If the woman is breastfeeding – see section "Use during pregnancy or breastfeeding".

Women should be advised to start taking Darilya between days 21–28 after childbirth or second-trimester abortion. If a woman starts taking tablets later, she should be advised to additionally use a barrier method of contraception during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be excluded before starting COC use, or the woman should wait for her first menstrual period.

Missed tablet intake

A missed green placebo tablet from the 4th row of the blister can be disregarded. However, it should be discarded to avoid accidental prolongation of the placebo phase. The instructions below apply only to missed active white tablets.

If the delay in taking any missed tablet does not exceed 24 hours, contraceptive efficacy is not reduced. The missed tablet should be taken as soon as remembered. The next tablet from this pack should be taken at the usual time.

If the delay in taking any missed tablet exceeds 24 hours, contraceptive protection may be reduced. In such a case, two main rules should be followed:

1. The recommended hormone-free interval is 4 days; drug intake should not be interrupted for more than 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved with continuous tablet intake for 7 days.

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

Days 1–7

The woman should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. After that, she should continue taking tablets at the usual time. Additionally, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred within the previous 7 days, the possibility of pregnancy should be considered. The greater the number of tablets missed and the closer the missed dose is to the placebo phase, the higher the risk of pregnancy.

Days 8–14

The woman should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. After that, she should continue taking tablets at the usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, there is no need to use additional contraceptive methods. Otherwise, or if more than one tablet is missed, additional contraceptive methods (e.g., barrier method) should be used for 7 days.

Days 15–24

The risk of reduced contraceptive effect is significant due to the approaching placebo phase. However, if the dosing schedule is followed, a reduction in contraceptive protection can be avoided. If one of the following options is followed, there is no need to use additional contraceptive methods, provided tablets were taken correctly for 7 days before the missed dose. Otherwise, it is recommended to follow the first of the options listed below and use additional contraceptive methods for the next 7 days.

1. The woman should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. After that, she should continue taking tablets at the usual time until the active tablets are finished, but the 4 green placebo tablets should not be taken; instead, she should immediately start taking tablets from the next blister pack. It is unlikely that menstrual-like bleeding will occur before finishing tablets from the second pack, although spotting or breakthrough bleeding may occur during tablet intake.
2. The woman may also be advised to stop taking active tablets from the current blister pack. Instead of active tablets, she should take the green placebo tablets from the last row for 4 days, including the days of missed tablets, and then start taking tablets from the next blister pack.

If a woman has missed tablets and does not experience menstrual-like bleeding during the first placebo tablet period, pregnancy should be considered.

Recommendations in case of gastrointestinal disturbances

In case of severe gastrointestinal disturbances (e.g., vomiting, diarrhea), incomplete absorption of the drug is possible. 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 (from another pack) should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual intake time. If more than 24 hours have passed, the rules for tablet intake described in the section "Missed tablet intake" should be followed. If the woman does not wish to change her usual dosing schedule, she should take additional tablet(s) from another pack.

How to shift the timing of withdrawal bleeding

To delay the onset of menstruation, the woman should skip the placebo tablets and start taking active Darilya tablets from a new pack. The duration of intake may be extended up to the end of the second pack if desired. Breakthrough bleeding or spotting may occur during this time. Regular use of Darilya resumes after completing the placebo tablet phase.

To shift menstruation to another day of the week, it is recommended to shorten the placebo phase by the desired number of days. It should be noted that the shorter the break, the higher the likelihood of absence of menstrual-like bleeding and the greater the risk of breakthrough bleeding or spotting during the tablet intake period from the next pack (as in the case of delaying menstruation).

Preparation for use of the weekly calendar sticker

To help the patient track tablet intake, a weekly calendar sticker indicating the 7 days of the week is included in the package.

A woman should choose the adhesive strip of the calendar that starts with the day of the week on which she begins taking tablets. For example, if she starts taking tablets on Wednesday, she should select the sticker-strip starting with the label "Wed." ("Wednesday").

Attach the symbol "ð" on the strip to the corresponding symbol on the blister pack and affix the strip to the blister at the area outlined by a line. Each day of the week will thus be aligned parallel to the row of tablets in the blister pack. This allows a woman to see on which day of the week she is taking a tablet. Tablets must be taken in the order indicated on the blister pack until all 28 tablets have been consumed.

During the 4 days when a woman takes the green placebo tablets, a menstruation-like bleeding should occur. This usually begins on the 2nd or 3rd day after taking the last white active Darilium tablet.

After a woman has taken the last green tablet, she must begin taking tablets from a new blister pack and apply the next weekly calendar sticker-strip, regardless of whether withdrawal bleeding has stopped or not.

This means that a woman will start each weekly calendar strip on the same day of the week, and withdrawal bleeding will occur on the same days each month.

Children.

The drug is indicated for use by prescription only after establishment of regular menstruation.

Overdose.

There is no experience of overdose with Darilium to date.

Based on general data regarding oral contraceptives, the following symptoms may occur in case of overdose of active tablets: nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in girls before menarche if the drug is taken accidentally. There is no specific antidote; treatment should be symptomatic.

Adverse reactions

The most serious adverse effects associated with the use of COCs are described in the section "Special precautions".

The following adverse reactions have been reported with the concomitant use of drospirenone and ethinylestradiol.

The table below lists adverse reactions by MedDRA System Organ Classes (MedDRA SOCs).

Frequencies are based on data from clinical studies. The most appropriate MedDRA term is used to describe a specific reaction and its synonyms and related conditions.

* Irregular menstruation usually resolves with continued use of the drug.

Description of individual adverse reactions

Women taking COCs have been observed to have an increased risk of developing arterial or venous thrombotic/thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism. More detailed information is provided in the section "Special precautions".

The following serious adverse reactions have been reported in women using oral contraceptives (see section "Special precautions"):

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• occurrence or worsening of conditions whose relationship with COC use has not been definitively established: Crohn's disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic liver function disorders, which may require discontinuation of COC use until liver function parameters normalize;
• exogenous estrogens may induce or exacerbate symptoms of angioneurotic edema.

In five studies comparing the risk of breast cancer in women who had ever used COCs (currently or in the past) versus those who had never used COCs, no association was found between COC use (ever) and the risk of developing breast cancer, with effect estimates ranging from 0.90–1.12.

In three studies comparing the risk of breast cancer in women who currently or recently used COCs (< months since last use) versus those who had never used COCs, one of these studies found no association between breast cancer risk and COC use. The other two studies found a relative risk increase of 1.19–1.33 in women who currently or recently used COCs. Both studies found an increased risk of breast cancer in women using COCs for prolonged periods, with relative risks ranging from 1.03 with COC use for less than one year to approximately 1.4 with COC use for more than 8–10 years.

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 types of interactions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions during the post-marketing period is very important. It allows continuous monitoring of the benefit-risk balance of medicinal products. Healthcare professionals should report suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in the original packaging to protect from light. Keep out of reach of children.

Packaging. 28 (24+4) tablets in a blister; 1 (1(24+4)) or 3 (3(24+4)) blisters per cardboard pack. Each cardboard pack contains a flat cardboard case for storing the blister and a weekly calendar sticker.

Prescription category. Prescription only.

Manufacturer. JSC "Gedeon Richter", Hungary.

Manufacturer's address and location of its business operations.

H-1103 Budapest, 19-21 Demréti Street, Hungary.