Jozegud

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZHOZEGUD® (ZHOZEGUD)

Composition:

Active substances: drospirenone, ethinylestradiol;

One tablet contains drospirenone 3 mg and ethinylestradiol 0.02 mg;

Excipients: lactose monohydrate; potassium polycriline; povidone K30; magnesium stearate; coating: film-coating mixture Opadry II Pink 85F34048: polyethylene glycol (macrogol); titanium dioxide (E 171); partially hydrolyzed polyvinyl alcohol; talc; iron oxide red (E 172), iron oxide yellow (E 172);

One placebo tablet contains: lactose monohydrate; potassium polycriline; povidone K30; colloidal silicon dioxide anhydrous; magnesium stearate; coating: film-coating mixture Opadry II White 85F18422: polyethylene glycol (macrogol); titanium dioxide (E 171); partially hydrolyzed polyvinyl alcohol; talc.

Medicinal form. Film-coated tablets.

Main physicochemical properties: cylindrical, biconvex film-coated tablets of pink color, and placebo tablets, cylindrical, biconvex, film-coated, white in color.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. ATC code G03A A12.

Pharmacological Properties.

Pharmacodynamics.

Pearl Index of contraceptive failures: 0.41 (upper two-sided 95% confidence interval: 0.85). Overall Pearl Index (contraceptive failures + patient errors): 0.80 (upper two-sided 95% confidence interval: 1.30).

The contraceptive effect of the drug JOZEGUD® 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 those in the 24-day regimen group. Ovarian activity returned to pre-treatment levels within the post-treatment cycle in 91.8% of women in the 24-day regimen group.

JOZEGUD® 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 study data, the moderate antimineralocorticoid properties of JOZEGUD® result in a moderate antimineralocorticoid effect.

Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the efficacy and safety of JOZEGUD® 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%), achieved "clear" or "almost clear" skin as assessed by the ISGA (Investigator’s Static Global Assessment) scale.

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Maximum serum concentration, amounting to 38 ng/mL, is reached approximately 1–2 hours after single oral administration. Bioavailability ranges from 76% to 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, without binding to SHBG or corticosteroid-binding globulin. Only 3–5% of its total serum concentration exists in free form. Ethinylestradiol-induced elevation of SHBG does not affect drospirenone binding to serum proteins. The mean volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.

Metabolism. Drospirenone undergoes extensive metabolism 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 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 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 serum concentration of drospirenone, amounting to approximately 70 ng/mL, is reached after 8 days of administration. Serum drospirenone levels accumulate 3-fold as a result of the relationship between the terminal half-life and the dosing interval.

Special patient groups

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

Women with impaired hepatic function.

In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in 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 apparent differences regarding serum potassium concentration. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper normal limit was observed. It can be concluded that 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 Europeans.

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 ethinylestradiol bioavailability by approximately 25% in the studied subjects, with no change in the remainder.

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

Metabolism. Ethinylestradiol undergoes extensive metabolism in the gastrointestinal tract and during first-pass through the liver. Ethinylestradiol is metabolized primarily via hydroxylation of the aromatic ring, forming a wide spectrum of hydroxylated and methylated metabolites, present in free form and as glucuronide and sulfate conjugates. Metabolic clearance of ethinylestradiol is approximately 5 mL/min/kg.

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

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

Steady state. Steady state is achieved in the second half of the treatment cycle, when serum ethinylestradiol concentration increases 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 actions. In particular, animal studies on reproductive toxicity revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of JOZEGUD®, 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 "Special precautions for safety").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

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

• Presence or risk of venous thromboembolism (VTE).
  • Current venous thromboembolism, including patients receiving 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 range.
• Severe renal impairment 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.
• Current or past history of breast cancer that may be hormone-sensitive [see section "Warnings and precautions", subsection "Malignant neoplasms"].

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

Special precautions.

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

Interaction with other medicinal products and other forms of interaction.

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

• Effect of other medicinal products on Jolessa®

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 treatment initiation. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

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

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

The following interactions have been reported based on published data.

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

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; HIV medications: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal preparations 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 either increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the medical use of the HIV/HCV medicinal product being taken concomitantly should be reviewed to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier contraceptive method 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, AUC(0-24h) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively, over 10 days.

Etoricoxib at doses of 60 to 120 mg/day demonstrated a 1.4- to 1.6-fold increase in ethinylestradiol plasma concentrations when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Jolessa® on other medicinal products

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

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

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

Pharmacodynamic interactions

Clinical data from studies involving patients treated with hepatitis C virus (HCV) drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, showed increased alanine aminotransferase (ALT) levels exceeding 5 times the upper limit of normal (ULN). This occurred more frequently in women using ethinylestradiol-containing medicinal products, including combined hormonal contraceptives (CHCs). Additionally, increased ALT levels were observed in women taking ethinylestradiol-containing drugs, such as CHCs, during treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Contraindications").

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

In patients with normal renal function, concomitant use of drospirenone with ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Jolessa® 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 levels 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 due to its moderate antimineralocorticoid activity.

Special precautions.

The decision to prescribe the medicinal product JOZEGUD® should be made taking into account individual risk factors currently present in the woman, including risk factors for the development of venous thromboembolism (VTE), as well as the VTE risk associated with JOZEGUD® compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Warning

If any of the conditions or risk factors listed below are present, the need for use of JOZEGUD® should be discussed with the woman.

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

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

• Circulatory disorders

Risk of venous thromboembolism (VTE)

Use of any CHCs increases the risk of venous thromboembolism (VTE) in women using them compared to those who do not use CHCs. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Use of other medicinal products, such as JOZEGUD®, may double the risk. The decision to use medicinal products other than those with the lowest risk of VTE should be made only after discussion with the woman. It is necessary to ensure that she understands the risk of VTE associated with JOZEGUD®, 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 CHC use after a break of 4 weeks or longer.

VTE occurs in 2 out of 10,000 women who are not using CHCs and are not pregnant during 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 in women using CHCs containing levonorgestrel.

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

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

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

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

Risk factors for VTE

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

Use of JOZEGUD® 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, CHCs should not be prescribed (see section "Contraindications").

Table 1.

Risk factors for VTE

There is no consensus regarding the potential 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 regarding pregnancy or breastfeeding, see section "Use in pregnancy or breastfeeding").

Symptoms of VTE (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 following symptoms occur.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or area 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; syncope or dizziness; rapid or irregular heartbeat.

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

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

Ocular vascular occlusion may initially present with painless blurred vision, which may progress to vision loss. In some cases, 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 (transient ischemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The use of the medicinal product Jolessa® is contraindicated in women who have one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the risk increase may be greater than the sum of risks associated with each individual factor; therefore, the overall risk should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2.

Risk factors for ATE

ATE Symptoms

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

Symptoms of cerebrovascular disorders may include: sudden numbness of the face, weakness or numbness of extremities, especially on one side of the body; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or vision disturbances; 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 nature of symptoms may indicate transient ischemic attack (TIA).

Symptoms of myocardial infarction may include: chest pain, discomfort, tightness or heaviness in the chest, arm, or below the sternum; discomfort radiating to the back, jaw, throat, arm, or stomach; sensation of fullness, indigestion, or suffocation; excessive sweating, nausea, vomiting, or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.

Tumors

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs (>5 years), although this finding remains controversial due to uncertainty about whether the study results adequately account for confounding risk factors such as sexual behavior and human papillomavirus infection.

Malignant neoplasms

Breast cancer

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

Epidemiological studies have not shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not indicate an association between ever use (current or past) of COCs and breast cancer risk. However, some studies have reported a slight increase in breast cancer risk among women who have previously used COCs (see section "Adverse Reactions", subsection "Post-marketing data").

In rare cases, benign and even more rarely malignant liver tumors have been observed in women taking COCs, which in some instances 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 should be considered in differential diagnosis during COC use.

Use of COCs at high doses (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these data apply to low-dose COCs as well.

Other conditions

The progestin component of the medicinal product Jolessa® 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 concurrently 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 maintain serum potassium levels within the normal range prior to starting treatment, 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 are at increased risk of pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension occurs only rarely. Immediate discontinuation of COCs is required only in these rare cases. In cases of persistent hypertension or inability to control blood pressure with antihypertensive therapy, 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 and with COC use, although their association with estrogen/progestin use has not been definitively 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 symptoms of angioedema.

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

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

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data suggesting the need to alter therapeutic regimens 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 epilepsy, Crohn's disease, and ulcerative colitis have also been reported during COC use.

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

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

Consultations/Medical examination

Prior to initiating or resuming use of the medicinal product Jolessa®, a complete medical and family history should be taken, a full medical examination performed, and pregnancy excluded. Blood pressure should be measured and a clinical examination conducted, considering contraindications (see section "Contraindications") and special precautions (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Jolessa® compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

Patients should be 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 tablet intake (see section "Method of administration and dosage"), gastrointestinal disorders (see section "Method of administration and dosage"), 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 measures 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 "Method of administration and dosage", 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 excluded before continuing COC use.

If you have an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Each light pink film-coated tablet contains 46 mg of lactose; each white film-coated 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, this lactose content should be taken into account.

Use during pregnancy or breastfeeding.

Pregnancy. The product is contraindicated during pregnancy.

If pregnancy occurs while taking Jolessa®, treatment must be stopped immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers took COCs prior to pregnancy, nor is there evidence of 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 effects due to the hormonal activity of the active substances cannot be excluded. However, overall experience with COC use during pregnancy does not indicate a harmful effect in humans.

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

When resuming use of Jolessa®, the increased risk of VTE in the postpartum period should be considered (see sections "Method of administration and dosage", "Special precautions for use").

Breastfeeding. COCs may affect breastfeeding, as they can 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, which may affect the infant.

Fertility. The product Jolessa® is indicated for prevention of pregnancy. Information on fertility recovery is provided in section "Pharmacological properties".

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the medicinal product Jolessa® on reaction speed during driving or operating machinery have been conducted. No effect on the ability to drive a car or operate machinery has been reported in women using COCs.

Method of Administration and Dosage

Method of administration: Oral.

Dosing

How to take the medicinal product JOSEGUD®

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

Initiating treatment with JOSEGUD®

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

Tablet intake should begin 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 JOSEGUD® the day after taking the last hormone-containing tablet of the previous COC, but no later than the day after the tablet-free interval or after taking the non-hormonal tablets of the previous COC. When switching from a contraceptive vaginal ring or transdermal patch, start JOSEGUD® 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’, injections, implants) or an intrauterine system containing progestogen

JOSGUD® can be started on any day after stopping the ‘mini-pill’ (in the case of an implant or intrauterine system – on the day of removal, in the case of injections – instead of the next injection). However, in all cases, it is recommended to use an additional barrier method of contraception during the first 7 days of taking JOSEGUD®.

• After a first-trimester abortion

Treatment with JOSEGUD® can be started immediately. In this case, there is no need to use additional contraceptive methods.

• After childbirth or second-trimester abortion

It is recommended to start taking JOSEGUD® on days 21–28 after childbirth or second-trimester abortion. If tablet intake is started 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 the medication, or wait until the first menstrual period occurs.

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

What to do if a tablet is missed

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

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

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

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

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

• Days 1–7

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

• Days 8–14

Take the last missed tablet as soon as possible, even if two tablets have to 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 tablet, there is no need for additional contraceptive methods. If this is not the case, or if more than one tablet has been missed, additional contraceptive methods are recommended for 7 days.

• Days 15–24

The risk of reduced efficacy increases as the placebo tablet phase approaches. However, following one of the regimens below can prevent a reduction in contraceptive protection. 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 tablet. If this is not the case, the first option below should be followed, and additional barrier methods used for the next 7 days.

1. Take the last missed tablet as soon as possible, even if two tablets have to be taken simultaneously. Then continue taking tablets at the usual time until the end of the active tablets. The 4 placebo tablets in the last row should be disregarded. Start 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 when tablets were missed; start taking tablets from the next pack.

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

Recommendations in case of gastrointestinal 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 another (replacement) tablet as soon as possible. The next tablet should be taken, if possible, within 24 hours according to the usual dosing schedule. If more than 24 hours have passed, follow the recommendations given above under "What to do if a tablet is missed". If a woman does not wish to change her tablet-taking schedule, she should take additional tablet(s) from the next pack.

Delaying withdrawal bleeding

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

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the 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 delayed menstruation or withdrawal bleeding).

Additional information for special patient groups

Elderly patients. JOSEGUD® is not indicated after menopause.

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

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

Children

The medicinal product is indicated for use only after menarche and under medical supervision.

Overdose

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

Adverse reactions.

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

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

Table 3.

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

*irregular bleeding usually stops with continued therapy

Description of individual adverse reactions

In women taking COCs, an increased risk of venous or arterial thrombotic and thromboembolic events has been observed, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis, and pulmonary embolism, which are described in more detail in the section "Special precautions".

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

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumours;
• development or worsening of conditions for which the relationship to COC use has not been definitively established: Crohn's disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC until liver function tests return to normal;
• in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

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 or recently used COCs is small relative to the overall risk of breast cancer. The relationship to COC use is unknown. See also sections "Contraindications" and "Special precautions".

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

Five studies comparing the risk of breast cancer between current users (current or past use) of COCs and never users of COCs reported no association between any use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

Relative studies of breast cancer risk associated with the use of

combined oral contraceptives

RR = relative risk, OR = odds ratio, HR = hazard ratio, "ever COC" – women who used or are using COCs, "never COC use" – women who have never used COCs.

Three studies compared the risk of breast cancer between current or recent users of COCs (<6 months since last use) and never users of COCs. One of these studies reported no association between breast cancer risk and COC use. Two other studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with longer duration of current COC use, with relative risks ranging from 1.03 for less than one year of COC use to approximately 1.4 for more than 8–10 years of COC use.

Reporting suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows ongoing monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach of children.

Packaging.

28 tablets (24 pink tablets + 4 placebo tablets, white) in a blister; 1 blister together with a cardboard blister holder, weekly calendar sticker in a carton.

Prescription category. Prescription only.

Manufacturer.

1. JSC "KYIV VITAMIN PLANT".
2. Synerdea Pharma, S.L.

Manufacturer's address and location of business activity.

1. 38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua

2. Poligono Industrial Emiliano Revilla Sans. Avenida de Agreda, 31, Olvega, 42110 Soria, Spain.