Delsia

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

Composition:

Active substances: ethinylestradiol, drospirenone;

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

Excipients: lactose monohydrate; maize starch; colloidal anhydrous silicon dioxide; hypromellose 2910; purified talc; magnesium stearate;

Oparid II Yellow 31F82689 (hypromellose 2910; lactose monohydrate; titanium dioxide (E 171); macrogol; talc; iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets with "647" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Systemic hormonal contraceptives.

Fixed combinations of progestogens and estrogens. Drospirenone and ethinylestradiol.

ATC code G03A A12.

Pharmacological Properties

Pharmacodynamics

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

The overall Pearl Index (contraceptive failures + patient-related 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.

The medicinal product Delsia 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 clinical study data, the moderate antimineralocorticoid properties of Delsia result in a moderate antimineralocorticoid effect.

Pharmacokinetics

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Maximum serum concentration, reaching 38 ng/mL, is achieved approximately 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 total drospirenone concentration exists in serum 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-dihydro-drospirenone-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, maximum steady-state concentration of drospirenone in serum, reaching approximately 70 ng/mL, is achieved 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, similar serum concentrations of drospirenone were observed in women with mild renal impairment (creatinine clearance 50–80 mL/min) and in women with normal renal function. In women with moderate renal impairment (creatinine clearance 30–50 mL/min), serum concentrations of drospirenone were on average 37% higher than in women with normal renal function. Drospirenone therapy was well tolerated in women with mild to moderate renal impairment. Drospirenone therapy showed no clinically significant effect on serum potassium 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 volunteers with normal liver function. This observed alteration in drospirenone clearance in subjects with moderate hepatic impairment did not result in any significant differences in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that may provoke hyperkalemia), serum potassium concentration did not exceed the upper limit of normal (ULN). It can be concluded that drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

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

Ethinylestradiol

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

Absolute bioavailability is approximately 45%.

Distribution. The expected volume of distribution of ethinylestradiol is approximately 5 L/kg, and protein binding to plasma proteins is approximately 98%. Ethinylestradiol induces hepatic synthesis of SHBG and corticosteroid-binding globulins. When 30 µg of ethinylestradiol is administered, plasma SHBG concentration increases from 70 to approximately 350 nmol/L.

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

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

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is 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, and serum levels of ethinylestradiol increase by approximately 1.4–2.1 times.

Preclinical safety data

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological activity. In particular, studies assessing reproductive toxicity in animals showed species-specific embryotoxic and fetotoxic effects. With exposure exceeding that in users of the medicinal product Delsia, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Safety precautions").

Clinical characteristics

Indications

Oral contraception.

Contraindications

Combined hormonal contraceptives (CHCs) must not be used if any of the conditions listed below are present. If any of these conditions occur for the first time during CHC use, the drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • Current venous thromboembolism, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • Known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • Major surgery with prolonged immobilization (see section "Special precautions");
  • High risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • Current or past arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • Current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function tests return to normal limits.
• Severe renal insufficiency or acute renal failure.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignancies (e.g., of the genital organs or breasts).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the drug.
• Suspected or confirmed pregnancy.

Concomitant use of Delcuffe with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions

This medicinal product may be hazardous to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction

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

• Effect of other medicinal products on Delcuffe

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

Therapy

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

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another 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 its 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

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

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

Active substances with variable effects on COC clearance

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, 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 medicinal product for treatment of HIV/HCV 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 drospirenone (3 mg/day)/ethinylestradiol (0.002 mg/day) co-administered with the strong CYP3A4 inhibitor ketoconazole 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 1.4–1.6-fold increase in ethinylestradiol plasma concentrations when administered concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Delcuffe 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, leading to mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

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

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

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 Delcuffe 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 affect the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma concentrations of transport proteins such as corticosteroid-binding globulin; plasma concentrations of lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Usually, such changes remain within normal ranges.

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

Special Warnings

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

Warning

• If any of the conditions or risk factors listed below are present, the appropriateness of using Delsia should be discussed with the woman.
• If any of these conditions or risk factors worsen or first appear, women should be advised to contact their physician and consider whether discontinuation of Delsia is necessary.
• Combined hormonal contraceptives (CHCs) should be discontinued if suspected or confirmed venous or arterial thromboembolism (VTE or ATE) occurs. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided, due to the teratogenic effects of anticoagulants (e.g., coumarins).
• Circulatory disorders.

Risk of venous thromboembolism (VTE)

The use of any CHC increases the risk of VTE in women who use them compared to women who do not. Products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Use of other medicinal products, such as tablets containing 0.03 mg ethinylestradiol and 3 mg drospirenone, may result in a doubling of VTE risk. The decision to use products other than those with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure that she understands the VTE risk associated with Delsia, the impact of her individual risk factors, and the fact that VTE risk is highest during the first year of use. Some data suggest that VTE risk may increase when restarting CHC use after a break of 4 weeks or longer.

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

It has been established¹ that among 10,000 women using CHCs containing drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of 6–2 among women using CHCs containing levonorgestrel.

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

VTE may be fatal in 1–2% of cases.

Number of VTE events per 10,000 women per year:

• women not using CHCs – 2 cases;
• women using CHCs containing levonorgestrel – 5–7 cases;
• women using CHCs containing drospirenone – 5–7 cases.

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

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

Very rare cases of thrombosis in other vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, cerebral vessels, or retinal vessels, have been reported in women using CHCs.

Risk factors for VTE

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

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

Risk factors for VTE

Table 1

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

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

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

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

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or a segment along a vein in the leg; pain or tenderness in the leg, which may occur only when standing or walking; warmth in the affected leg; redness or discoloration of the skin on the leg.

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

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

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

Ocular vascular occlusion may initially present with blurred vision without pain, which may progress to vision loss. Sometimes, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological data indicate that the use of any COCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (TIA, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

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

Risk factors for ATE

Table 2

Arterial Thromboembolism (ATE) Symptoms

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

Symptoms of cerebrovascular disorders may include: sudden facial numbness, weakness or numbness of the limbs, particularly on one side of the body; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension difficulties; sudden vision loss in one or both eyes; sudden, severe or prolonged headache without apparent cause; loss of consciousness or fainting, with or without seizures.

Transient 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 fullness, indigestion, or choking; excessive sweating, nausea, vomiting, or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.

Tumors

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

A meta-analysis based on 54 epidemiological studies indicates a slight increase in the 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 current or recent users of COCs is minimal relative to the overall 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 indicating that breast cancer diagnosed in women who have ever used COCs tends to be less clinically advanced than in those who have never used COCs.

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

High-dose COCs (50 mcg ethinylestradiol) have been shown to reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether this benefit also applies to low-dose COCs.

Other Conditions

The progestin component of Delicia is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected during use. In clinical trials, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment who were also taking potassium-sparing medications during treatment with drospirenone. 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 ensure that serum potassium levels are not above the upper limit of normal before starting treatment, especially when concomitantly 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 is observed 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, COCs should be discontinued. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive treatment.

The following conditions have been reported to occur or worsen during pregnancy or COC use, although 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.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate angioedema symptoms.

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 link with COCs is ruled out.

COCs should be discontinued in case of recurrence of cholestatic jaundice and/or cholestatic pruritus previously observed during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to alter the therapeutic regimen in diabetic women using low-dose COCs (<0.05 mg ethinylestradiol). However, women with diabetes should be closely monitored during COC use, especially at the beginning of treatment.

Exacerbations of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis have also been reported during COC use.

Depressed mood and depression are well-known adverse reactions associated with hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should consult their physician if they experience mood changes or depressive symptoms, including soon after starting treatment.

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

One tablet of the medicinal product contains 60 mg of lactose monohydrate. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, or those on a lactose-free diet, this lactose content should be taken into account.

Consultations/Medical Examinations

Before initiating or resuming use of Delicia, 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 Warnings and Precautions for Use"). Women should be informed about venous and arterial thrombosis, including the associated risks with Delicia 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 its instructions.

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

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

Reduced Efficacy

The efficacy of COCs may be reduced if a tablet is missed (see section "Dosage and Administration"), in cases of gastrointestinal disturbances (see section "Dosage and Administration"), or when co-administered with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Irregular Bleeding

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

If irregular bleeding persists or occurs 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.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to the instructions in the "Dosage and Administration" section, pregnancy is unlikely. However, if COCs have been taken irregularly before the first missed 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 medicinal product is contraindicated during pregnancy. If pregnancy occurs during treatment with Delicia, use should be stopped immediately. However, epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs before pregnancy, nor do they indicate teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological Properties"). Based on these animal studies, adverse hormonal effects cannot be excluded. However, overall clinical experience with COC use during pregnancy does not indicate harmful effects in humans.

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

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

Breastfeeding. 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.

Effect on Ability to Drive and Use Machines

No studies have been conducted on the effect of this medicinal product on the ability to drive or operate machinery. There have been no reports of impaired ability to drive or operate machinery in women taking combined oral contraceptives.

Method of Administration and Dosage

Orally.

Dosing

The tablets should be taken regularly at approximately the same time each day, swallowed with a small amount of liquid if necessary, in the order indicated on the blister pack. The drug should be taken once daily for 21 consecutive days. The intake of tablets from the next pack should begin after a 7-day treatment-free interval, during which withdrawal bleeding usually occurs. Bleeding typically starts on the 2nd or 3rd day after taking the last tablet and may not end before the start of the next pack.

How to Start Delcya

• No previous use of hormonal contraceptives (last month)

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

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

It is recommended to take the first Delcya tablet the day after the last active tablet (containing the active ingredient) was taken, but no later than the day after the tablet-free interval. When switching from a vaginal ring or transdermal patch, Delcya should be started on the day of removal of the device, but no later than the day when the next application of these products would be due.

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

Delcya 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 during the first 7 days of taking Delcya.

• After a first-trimester abortion

Treatment may be started immediately. In this case, there is no need for additional contraceptive measures.

• After childbirth or second-trimester abortion

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

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

What to Do in Case of a Missed Dose

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

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

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

Accordingly, the following practical recommendations should be followed:

• Week 1

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

• Week 2

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

• Week 3

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

1. Take the last missed tablet as soon as remembered, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. Start the next pack immediately after finishing the current one, i.e., there should be no break between the two packs. Withdrawal bleeding is unlikely to occur 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 treatment-free interval should not exceed 7 days, including the days of missed tablets; tablet intake should resume with the next pack.

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

Recommendations in Case of Gastrointestinal Disorders

In case of severe gastrointestinal disorders such as vomiting or diarrhea, incomplete absorption of the drug may occur; additional contraceptive methods should therefore be used. If vomiting occurs within 3–4 hours after taking the tablet, a new (replacement) tablet should be taken 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, the recommendations provided above in the section "Method of Administration and Dosage", subsection "What to Do in Case of a Missed Dose", should be followed. If a woman does not wish to alter her tablet-taking schedule, she should take additional tablet(s) from the next pack.

How to Delay Withdrawal Bleeding

To delay withdrawal bleeding, continue taking Delcya tablets from a new pack without interruption. The duration of intake may be extended, if desired, until the tablets from the second pack are finished. Breakthrough bleeding or spotting may occur during this time. Usually, Delcya is resumed after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. It should be noted that the shorter the interval, the more frequently absence of withdrawal bleeding and breakthrough bleeding or spotting may occur during intake of tablets from the second pack (similar to delaying withdrawal bleeding).

Additional Information for Special Patient Groups

Elderly Patients. The drug should not be used after menopause.

Patients with Hepatic Impairment. Delcya is contraindicated in women with severe hepatic impairment (see sections "Pharmacological Properties" and "Contraindications").

Patients with Renal Impairment. Delcya is contraindicated in women with severe renal impairment or acute renal failure (see sections "Pharmacological Properties" and "Contraindications").

Children

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

Overdose

There are currently no clinical data on overdose with Delcya tablets. Based on general experience with COCs, overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in girls before menarche in case of accidental or unintentional intake of the drug. There is no specific antidote; treatment should be symptomatic.

Adverse reactions

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

Adverse reactions observed during use of the drug Delsia.

Table 3

Description of individual adverse reactions

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

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

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Arterial hypertension;
• Liver tumors;
• Development or exacerbation of diseases for which a definite link with COC use has not been established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• Chloasma;
• Acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function parameters return to normal;
• In women with hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

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 hemorrhagic stroke, ischemic stroke, TIA); erythema.

Other adverse reactions associated with the class of combined oral contraceptives are also mentioned in the sections "Contraindications" and "Special precautions for use" (e.g., hearing loss associated with otosclerosis, hypertriglyceridemia and increased risk of pancreatitis, gallstone formation, changes in glucose tolerance or effects on peripheral insulin resistance, jaundice and/or pruritus associated with cholestasis, hypersensitivity reactions including rash, urticaria).

The frequency of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases of breast cancer among women currently or recently using COCs is small relative to the overall risk of breast cancer. The relationship with COC use is unknown (see also sections "Contraindications" and "Special precautions for use").

Interactions

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in a place protected from light. Keep out of reach of children.

Packaging

21 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status

Prescription only.

Manufacturer

San Pharmaceuticals Industries Ltd.

Manufacturer’s address and location of operations

Baroda Highway, Halol, Gujarat, 389350, India.