Diphenda

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

Composition:

Active ingredients: drospirenone; ethinylestradiol;

One pink tablet contains ethinylestradiol 0.02 mg and drospirenone 3 mg;

Excipients: lactose monohydrate; pregelatinized starch; povidone; sodium croscarmellose; polysorbate 80; magnesium stearate;

Film coating: Opadry II Pink, containing: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172);

One white placebo tablet contains:

Excipients: anhydrous lactose, povidone, magnesium stearate;

Film coating: Opadry II White, containing: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated pink tablets and round, biconvex, film-coated white tablets (placebo).

Pharmacotherapeutic group.

Sex hormones and drugs used in pathologies of the reproductive system. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol. ATC code G03A A12.

Pharmacological Properties

Pharmacodynamics

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

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

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

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

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

According to clinical trial data, the moderate antimineralocorticoid properties of Daphne result in a moderate antimineralocorticoid effect.

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

Pharmacokinetics

Drospirenone

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

Distribution. After oral administration, the concentration of drospirenone in serum declines with a mean terminal half-life of about 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 its total amount in serum is present in free form. Ethinylestradiol-induced increases in SHBG do not affect the protein binding of drospirenone to serum proteins. The mean volume of distribution of drospirenone is 3.7±1.2 L/kg.

Metabolism. Drospirenone is extensively metabolized after oral administration. The main metabolites in plasma are acid forms of drospirenone formed by opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate formed by hydration followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Elimination. The metabolic clearance rate of drospirenone from serum is approximately 1.5±0.2 mL/min/kg. Drospirenone is excreted unchanged only in very small amounts. Metabolites are excreted in urine and feces in a ratio of 1.2 to 1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

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

Special patient populations

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

Women with 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. The observed alteration in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant therapy with spironolactone (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed. Therefore, drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnic groups. No clinically significant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between Japanese women and Caucasians.

Ethinylestradiol

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

Distribution. Serum levels of ethinylestradiol decline in a biphasic manner, with the terminal phase characterized by a half-life of approximately 24 hours. Ethinylestradiol binds strongly but non-specifically to serum albumins (approximately 98.5%) and induces an increase in serum concentrations of SHBG and CBG. The apparent volume of distribution is approximately 5 L/kg.

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first-pass through the liver. Ethinylestradiol is metabolized primarily by hydroxylation of the aromatic ring, forming a wide spectrum of hydroxylated and methylated metabolites, present in free form and as glucuronide and sulfate conjugates. The metabolic 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 almost 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 nearly 1 day.

Steady state. Steady state is reached in the second half of the treatment cycle, when serum concentrations of ethinylestradiol increase by 2.0–2.3 times.

Preclinical safety data.

In laboratory animals, effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological activity. In particular, reproductive toxicity studies in animals revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of Daphne, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies showed 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 in the presence of any of the conditions listed below. If any of these conditions appears for the first time during CHC use, the drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • Current VTE, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • known hereditary or acquired predisposition to VTE, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • high risk of VTE due to multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • current ATE or history of ATE (e.g., myocardial infarction), or presence of prodromal symptoms (e.g., angina pectoris);
  • current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to ATE, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of ATE due to multiple risk factors (see section "Special precautions") or due to a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function values return to normal range.
• Current or past hormone-sensitive breast cancer (see section "Special precautions", subsection "Malignant neoplasms").
• Severe or acute renal failure.
• Current or past hepatic tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., genital organs).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the drug.
• Dafynd is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Special safety measures.

This medicinal product may 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 on concomitantly used medicinal products should be reviewed to identify potential interactions.

• Effect of other medicinal products on Dafynd.

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

Therapy

Enzyme induction may be observed within a few days of treatment. Maximum enzyme induction generally occurs after several weeks. After discontinuation of treatment, 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 the combined oral contraceptive (COC). The barrier method should be used throughout the treatment period 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

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

The following interactions have been reported according to published data.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

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

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) antiviral agents, 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 HIV/HCV treatment 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.

Substances decreasing COC clearance (enzyme inhibitors)

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

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

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

Etoricoxib at doses of 60 to 120 mg/day demonstrated an increase in ethinylestradiol plasma concentrations by 1.4 to 1.6 times, respectively, when used concomitantly with a CHC containing 0.035 mg ethinylestradiol.

• Effect of Dafynd on other medicinal products

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

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as 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, causing weak (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

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

Therefore, patients should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) prior to starting such combination therapy. Dafynd may be resumed 2 weeks after completion of the combination treatment regimen.

In patients with normal renal function, concomitant use of drospirenone and angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Dafynd with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first treatment cycle (see also section "Special precautions").

Other forms of interaction

Laboratory tests

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

Special precautions for use.

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

Warning

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

In case of exacerbation or at the first signs of any of the listed conditions or risk factors, women are advised to consult a physician and determine the need to discontinue Dafne.

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

• Circulatory disorders

Risk of VTE

The use of any COC increases the risk of developing VTE in women using them compared to non-users. Preparations containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. The use of other medicinal products, such as Dafne, may double the risk. The decision to use preparations other than those with the lowest VTE risk should only be made after discussing this with the woman. It is essential to ensure that she understands the VTE risk associated with Dafne, the impact of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming COC use after a break of 4 weeks or longer.

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

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

In both cases, the annual number of VTE events is lower than typically expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

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

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

Factors increasing the risk of VTE

The risk of venous thromboembolic complications in women using COCs may be substantially increased by the presence of additional risk factors, especially multiple ones (see Table 2).

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

Table 2

Risk factors for VTE

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

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

Symptoms of VTE (deep vein thrombosis (DVT) and pulmonary embolism (PE))

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

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or along a vein in the leg; pain or tenderness in the leg, which may only be felt 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 hemoptysis; sudden chest pain; presyncope or dizziness; rapid or irregular heartbeat.

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

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

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

Risk of ATE

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

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 3). The use of Diphenda 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 ratio is unfavorable (see section "Contraindications").

Table 3

Risk factors for ATE

Arterial Thromboembolism (ATE) Symptoms

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

Symptoms of cerebrovascular disorders may include: sudden numbness of the face, weakness or numbness of the extremities, particularly on one side; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension difficulties; sudden visual impairment in one or both eyes; sudden, severe or prolonged headache without a known cause; loss of consciousness or fainting, with or without seizures.

Transient 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.

Malignant Tumors

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

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer among women currently using COCs. This increased risk gradually disappears within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among women currently or recently using COCs is minimal relative to the overall risk of breast cancer. These 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. 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.

In rare cases, benign and even more rarely 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 associated with COC use should be considered in differential diagnosis.

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

Breast Cancer (Warning issued by the Center for Drug Evaluation and Research (CDER) FDA)

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

Epidemiological studies have not consistently demonstrated an association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not show a link between current or past use of COCs and the risk of breast cancer. However, some studies report a slight increase in breast cancer risk among women who are currently using or have recently used COCs (<6 months since last use), compared to those who have never used COCs (see section "Adverse Reactions").

Other Conditions

The progestin component of the drug Difenda is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected. During clinical trials, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment who were concurrently using potassium-sparing medications while taking 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 maintain serum potassium levels not exceeding the upper limit of normal prior to initiating Difenda, particularly when potassium-sparing medications are used concomitantly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Women with hypertriglyceridemia or a family history of this condition represent a risk group for developing pancreatitis when using COCs.

Although minor increases in blood pressure have been reported in many women taking COCs, clinically significant hypertension occurs only rarely. Immediate discontinuation of COCs is required only in these rare cases. In cases of persistent hypertension or inability to control blood pressure with antihypertensive therapy, COCs should be discontinued in affected women. COC use may be resumed after normotension is achieved with antihypertensive treatment, if necessary.

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

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Acute or chronic liver function disorders may require discontinuation of COCs until liver function tests return to normal and a causal relationship with COCs is ruled out.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or cholestatic pruritus previously associated with pregnancy or prior use of sex hormones.

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

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

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

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

One pink tablet contains 44 mg of lactose; one white tablet contains 22 mg of lactose. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, or those on a lactose-free diet, the amount of lactose should be taken into account.

Consultations/Medical Examination

A complete medical and family history should be taken, and a full medical examination, including exclusion of pregnancy, is recommended before initiating or resuming use of Difenda. Blood pressure should be measured, and a medical examination should be performed, considering contraindications (see section "Contraindications") and special precautions (see section "Special Precautions for Use"). Women should be informed about venous and arterial thrombosis, including the risk associated with Difenda 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 follow-up examinations should be based on established medical practice guidelines, taking into account individual patient characteristics.

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

Reduced Efficacy

The efficacy of COCs may be reduced in case of missed doses (see section "Dosage and Administration"), gastrointestinal disturbances (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, particularly during the first few months. If such bleeding persists after three menstrual cycles, it should be considered clinically significant.

If irregular bleeding persists or reappears after a period of regular bleeding, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures undertaken, including evaluation to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to instructions in section "Dosage and Administration," pregnancy is unlikely. However, if COCs have been taken irregularly prior to the absence of the first withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be ruled out before continuing COC use.

Use during Pregnancy or Breastfeeding

Pregnancy. The drug is contraindicated during pregnancy.

If pregnancy occurs during use of Difenda, treatment must be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor a teratogenic effect from inadvertent COC use during pregnancy.

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

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

When resuming Difenda use, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration" and "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 not recommended during breastfeeding. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use and may affect the infant.

Fertility. Difenda is indicated for pregnancy prevention. Information on fertility recovery can be found in section "Pharmacological Properties."

Ability to Influence Reaction Speed When Operating Vehicles or Machinery

No studies on the effect on the ability to drive or operate machinery have been conducted. There are no reports of effects on the ability to drive or operate machinery in women taking COCs.

Dosage and Administration

Administer orally.

Dosage

How to take Difenda tablets

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

Initiating Difenda treatment

• No previous hormonal contraception used (past month)

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

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

It is recommended to start taking Difenda tablets the day after taking the last active tablet of the previous COC, but no later than the day after the tablet-free interval or after taking the placebo tablets of the previous COC.
When switching from a contraceptive vaginal ring or transdermal patch, start taking Difenda on the day of device removal, but no later than the day when the next application of these products would be due.

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

Difenda 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 Difenda.

• After first-trimester abortion

Difenda may be started immediately. In this case, additional contraceptive methods are not required.

• After childbirth or second-trimester abortion

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

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

Missed tablet instructions

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

If the delay in taking a tablet does not exceed 24 hours, contraceptive protection is not reduced. Take the missed tablet as soon as possible. Take the next tablet at the usual time.

If the delay in taking the missed tablet exceeds 24 hours, contraceptive protection may be reduced. In this case, follow one of the two main principles:

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

Accordingly, follow these practical recommendations:

• Days 1–7

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

• Days 8–14

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

• Days 15–24

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

1. Take the last missed tablet as soon as possible, even if two tablets must be taken simultaneously. Then continue taking tablets at the usual time until the end of the active tablets. Disregard the 4 placebo tablets in the last row. Start taking tablets from the next pack immediately after the last active tablet. Withdrawal bleeding is unlikely to occur before completing all active tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking active tablets from the current pack. Then take the placebo tablets from the last row for 4 days, including the days of missed tablets; start the next pack afterward.

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

Gastrointestinal disturbances

In case of severe gastrointestinal disturbances (e.g., vomiting or diarrhea), incomplete absorption of the drug may occur. In such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking an active tablet, take a new (replacement) tablet as soon as possible. The next tablet should be taken, if possible, within 24 hours according to the usual schedule. If more than 24 hours have passed, follow the recommendations above under "What to do if a tablet is missed". If a woman wishes to maintain her usual tablet schedule, she should take additional tablet(s) from the next pack.

Delaying withdrawal bleeding

To delay withdrawal bleeding, continue taking Difenda tablets from a new pack without taking the placebo tablets from the current pack. The duration of intake may be extended up to the end of active tablets in the second pack, if desired. Breakthrough bleeding or spotting may occur during this period. Usually, Difenda intake is resumed after taking the placebo tablets.

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

Additional information for special patient groups

Elderly patients. Difenda is not indicated after menopause.

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

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

Children

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

Overdose

There are no clinical data on overdose with Difenda tablets. Based on general experience with combined oral contraceptives, overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur even in premenarcheal girls in case of accidental or unintentional ingestion. There is no specific antidote; treatment should be symptomatic.

Adverse reactions

For serious adverse reactions in women using COCs, see also the section "Special precautions". The adverse reactions listed below were observed during the use of the drug Difenda (see Table 4).

Table 4 lists adverse reactions by MedDRA organ system classes. Frequencies are based on clinical data. The most appropriate MedDRA terms have been used to describe specific reactions and their synonyms and related conditions.

Table 4

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

*Irregular bleeding usually diminishes with continued use.

Description of selected adverse reactions

Women taking COCs have been observed to have an increased risk of developing venous or arterial thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attack (TIA), venous thrombosis, and pulmonary embolism, which are described in more detail in the section "Special precautions".

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

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• development or exacerbation of conditions for which a link with COC use has not been definitively established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function parameters return to normal;

The incidence of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer among women who are currently using or have recently used 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".

Interactions

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

Post-marketing data (Warnings issued by the Center for Drug Evaluation and Research (CDER) FDA)

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

In three studies comparing the risk of breast cancer in women currently using COCs or who had recently used COCs (< 6 months since last use) versus women who had never used COCs, one study reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies also found an increased risk of breast cancer with long-term use, with relative risk ranging from 1.03 for COC use of less than 1 year to approximately 1.4 for COC use of more than 8–10 years.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

28 film-coated tablets per blister (24 pink tablets and 4 white placebo tablets); 1 blister with a sticker indicating the days of the week, in a cardboard box.

Prescription status. Prescription only.

Marketing Authorization Holder.

Zentiva, k.s.

Address of the Marketing Authorization Holder and location of its business operations.

U Kablovny 130, Dolni Měcholupy, Prague-10, 10237, Czech Republic.

Manufacturer.

Laboratorios Leon Farma S.A.

Address of the Manufacturer and location of its business operations.

S/La Vallina s/n, Poligono Industrial Navatejera, Villacilambre, 24193 Leon, Spain.

If any adverse effects, side effects, or lack of therapeutic effect occur, please report to ZENTIVA UKRAINE LLC, 5I Brovarskyi Avenue, Kyiv, 02002, Ukraine, tel./fax +38 044 517-75-00, e-mail [email protected].