Jastinda

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT JASTINDA (ZHASTINDA)

Composition:

Active substances: dienogest; ethinylestradiol;

One film-coated tablet contains 0.03 mg of ethinylestradiol and 2 mg of dienogest;

Excipients: lactose monohydrate; corn starch; povidone; magnesium stearate; talc;

Tablet coating: Opaglos 2 purified, containing: sodium carboxymethylcellulose, maltodextrin, dextrose monohydrate, soy lecithin, sodium citrate dihydrate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets, free from extraneous impurities, coated with a film coating.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the genital system. Systemic hormonal contraceptives. Fixed combinations of progestogens and estrogens. Dienogest and ethinylestradiol. ATC code G03A A16.

Pharmacological Properties.

Pharmacodynamics.

All hormonal contraceptive methods are characterized by a very low rate of contraceptive failure when used according to instructions. The rate of contraceptive failure may be higher if contraceptives are not used as directed (e.g., missed tablet intake).

During clinical studies, the following Pearl Index was calculated:

• Unadjusted Pearl Index: 0.454 (upper 95% confidence interval (CI): 0.701);
• Adjusted Pearl Index: 0.182 (upper 95% confidence interval: 0.358).

Jasmina is a combined oral contraceptive (COC) containing ethinylestradiol and the progestogen dienogest.

The contraceptive effect of the medicinal product Jasmina is based on the interaction of several factors, the most important of which are suppression of ovulation and changes in cervical secretion.

Dienogest is a derivative of nortestosterone with an in vitro affinity for progesterone receptors that is 10–30 times lower compared to other synthetic progestogens. In vivo data in animals indicate strong progestogenic and antiandrogenic activity. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

The dose of dienogest required to suppress ovulation is 1 mg/day.

When high-dose COCs (50 mcg ethinylestradiol) are used, the risk of endometrial and ovarian cancer is reduced. Whether this also applies to low-dose COCs remains unclear.

Pharmacokinetics.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Peak serum concentration is approximately 67 pg/mL and is reached within 1.5–4 hours. During absorption and first-pass metabolism in the liver, ethinylestradiol undergoes extensive metabolism, resulting in an average oral bioavailability of approximately 44%.

Distribution. Ethinylestradiol binds strongly, but non-specifically, to serum albumin (approximately 98%) and induces an increase in serum concentrations of sex hormone-binding globulin (SHBG). The apparent volume of distribution of ethinylestradiol is approximately 2.8–8.6 L/kg.

Metabolism. Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. Ethinylestradiol is metabolized primarily via aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are also formed, including both free metabolites and conjugates with glucuronides and sulfates. Clearance is 2.3–7 mL/min/kg.

Elimination. Serum levels of ethinylestradiol decline in a biphasic manner, with half-lives of approximately 1 hour and 10–20 hours, respectively. Ethinylestradiol is not excreted unchanged; its metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is approximately one day.

Steady-state. Steady-state is achieved during the second half of the treatment cycle, when serum concentrations of ethinylestradiol are approximately twice as high as those after a single dose.

Dienogest

Absorption. After oral administration, dienogest is rapidly and completely absorbed. Maximum serum concentration is reached within 2.5 hours after a single oral dose of the medicinal product Jasmina and amounts to 51 ng/mL. The absolute bioavailability of dienogest in combination with ethinylestradiol is approximately 96%.

Distribution. Dienogest binds to serum albumin and does not bind to SHBG or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum exists as free steroid, while 90% is non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG levels does not affect the protein binding of dienogest in serum. The apparent volume of distribution of dienogest ranges from 37 to 45 L.

Metabolism. Dienogest is primarily metabolized via hydroxylation and conjugation, forming mainly endocrinologically inactive metabolites. These metabolites are rapidly eliminated from plasma such that no active metabolites are detectable in plasma, only unchanged dienogest. Total clearance is approximately 3.6 L/h after single administration.

Elimination. Serum levels of dienogest decline with a half-life of approximately 9 hours. Only a small amount of dienogest is excreted unchanged by the kidneys. After administration of an oral dose of 0.1 mg/kg body weight, the ratio of renal to fecal excretion is 3.2. Approximately 86% of the administered dose is eliminated within 6 days, with the majority (42%) excreted in urine within the first 24 hours.

Steady-state. The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, serum concentrations increase 1.5-fold, reaching steady-state after 4 days of treatment.

Preclinical safety data

Preclinical studies with ethinylestradiol and dienogest revealed the expected estrogenic and progestogenic effects.

Results from standard preclinical studies of repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk to humans. However, it should be noted that sex steroids may promote the growth of pre-existing hormone-dependent tissues and tumors.

Environmental risk assessment studies have shown that ethinylestradiol and dienogest may potentially pose a risk to the aquatic environment (see section "Special precautions for disposal").

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, treatment must be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE)
  • Current (during anticoagulant therapy) or history of venous thromboembolism (e.g., deep vein thrombosis (DVT), 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 for use");
  • high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions for use").
• Presence or risk of arterial thromboembolism (ATE)
  • arterial thromboembolism – current or history of arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • current or history of cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions for use") or due to the presence of a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or history of pancreatitis associated with severe hypertriglyceridemia.
• Severe liver disease currently or in history, until liver function tests return to normal.
• Current or history of liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breasts).
• Established or suspected pregnancy.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

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

Special safety precautions.

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

Interaction with other medicinal products and other forms of interaction.

Note: Information on the concurrently administered medicinal product should be reviewed to identify potential interactions.

Effect of other medicinal products on Jestimonda

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

Therapy

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction generally occurs after several weeks. After discontinuation of 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 COCs. The barrier method should be used throughout the duration of treatment with the respective medicinal product and for an additional 28 days after discontinuation of its use. If treatment is initiated during the period of taking the last tablets of the COC pack, the next pack of COCs should be started immediately after finishing the previous pack, without the usual tablet-free interval.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing active substances are advised to choose another reliable non-hormonal method of contraception.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example: barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; HIV drugs ritonavir, nevirapine, and efavirenz; also possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and medicinal products containing St. John's wort (Hypericum perforatum).

Active substances with variable effects on COC clearance

When used concomitantly with COCs, many combinations of HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogens or progestins. The overall effect of such changes may be clinically significant in some cases.

Therefore, the package leaflet of the medicinal product used for HIV/HCV treatment should be consulted to identify potential interactions. In case of any doubts, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that reduce 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.

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

Effect of Jestimonda on other medicinal products

COCs may affect the metabolism of other medicinal products. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). However, in vitro data indicate that inhibition of CYP enzymes by dienogest at therapeutic doses is unlikely.

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

Pharmacodynamic interactions

During clinical trials in patients receiving antiviral hepatitis C (HCV) treatment regimens containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevated transaminases (ALT) more than 5 times the upper limit of normal (ULN) were observed. This occurred with significantly higher frequency in women who were using 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 must switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) before initiating treatment with these combined antiviral regimens. Jestimonda may be resumed 2 weeks after completion of treatment with these combined regimens.

Other forms of interaction

Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma concentrations of carrier proteins such as SHBG, lipid/lipoprotein fractions, carbohydrate metabolism parameters, as well as coagulation and fibrinolysis parameters. Usually, such changes remain within normal limits.

Special precautions.

The decision to prescribe the medicinal product Jaztinda should be made taking into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with the use of Jaztinda compared to other combined oral contraceptives (COCs) (see sections "Contraindications" and "Special precautions").

Warning. In the presence of any of the following conditions or risk factors, the appropriateness of using Jaztinda should be discussed with the woman.

If any of these conditions or risk factors worsen or appear for the first time, women are advised to consult a physician to determine whether continued use of Jaztinda should be discontinued.

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

• Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any COCs increases the risk of developing venous thromboembolism (VTE) in women who use them compared to women who do not. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. The use of other medicinal products, such as Jaztinda, may increase the risk of VTE by a factor of 1.6. The decision to prescribe a COC other than those with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure that she understands the risk of VTE associated with COC use, the extent to which her individual risk factors contribute, 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 restarting 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 one year. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

Epidemiological studies in women using low-dose COCs (< 50 µg ethinylestradiol) show that 6–12 out of 10,000 women will develop VTE within one year.

It is estimated that among 10,000 women using low-dose COCs containing levonorgestrel, approximately 61 will develop VTE within one year.

It is estimated² that among 10,000 women using low-dose COCs containing dienogest and ethinylestradiol, 8–11 will develop VTE within one year.

The annual incidence of VTE is lower than that expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

¹ On average, 5–7 cases per 10,000 woman-years, based on the calculated relative risk of using COCs containing levonorgestrel compared to non-users (approximately 2.3–3.6 cases).

² According to meta-analysis data, the risk of VTE in women using Jaztinda is slightly higher compared to women using COCs containing levonorgestrel (RR = 1.57, 95% CI: 1.07–2.30).

Number of VTE cases per 10,000 women per year

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

Risk factors for VTE

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

The use of Jaztinda 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 1

Risk factors for VTE

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

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

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

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

Symptoms of DVT may include:

• unilateral swelling of the thigh, lower leg, and/or foot or along a vein in the leg;
• pain or increased tenderness in the leg, which may occur only when standing or walking;
• sensation of warmth in the affected leg;
• redness or discoloration of the skin on the leg.

Symptoms of PE may include:

• sudden unexplained shortness of breath or rapid breathing;
• sudden cough, possibly with hemoptysis;
• sudden chest pain;
• severe dizziness or lightheadedness;
• 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, and mild cyanosis of a limb.

In ocular vessel occlusion, initial symptoms may include blurred vision without pain, 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 (e.g., transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for ATE

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

Table 2

Risk factors for ATE

ATE Symptoms

Women should be advised to seek immediate medical attention and inform their doctor if they are using COCs if any of the following symptoms occur.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision changes in one or both eyes;
• sudden, severe, or prolonged headache with no known cause;
• loss of consciousness or fainting, with or without seizures.

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

Symptoms of myocardial infarction may include:

• chest pain, discomfort, pressure, heaviness, tightness, or fullness in the chest, arm, or below the sternum;

• discomfort radiating to the back, jaw, throat, arm, or stomach;

• sensation of fullness, indigestion, or heartburn;

• excessive sweating, nausea, vomiting, or dizziness;

• unusual 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, but this finding remains controversial, as it is not fully established whether study results adequately account for confounding risk factors such as sexual behavior and other factors, including human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer among women using COCs. This increased risk gradually returns to the baseline age-related risk level 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 current or recent users of COCs is small relative to the overall risk of breast cancer.

Benign, and very rarely malignant, liver tumors have been observed in women using COCs, in some cases leading 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.

Such neoplasms may be life-threatening or result in fatal outcomes.

• Other conditions

Women with hypertriglyceridemia or a family history of this disorder are at increased risk of pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension is rare. However, if persistent clinically significant hypertension develops during COC use, COCs should be discontinued and hypertension treated. COC use may be resumed after normotension is achieved with antihypertensive therapy, if appropriate. COCs should be discontinued if consistently high blood pressure values persist during COC use in women with pre-existing hypertension diagnosed before starting COCs, despite adequate antihypertensive therapy. The following conditions have been reported to occur or worsen during pregnancy and with COC use, but their causal relationship to COC 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.

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

COC use may need to be discontinued in cases of acute or chronic liver dysfunction until liver function tests return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis that first occurred during pregnancy or previous use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest a need to alter the therapeutic regimen in diabetic women taking low-dose COCs (< 0.05 mg 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 reported during COC use.

Mental disorders

Depressed mood and depression are well-known adverse reactions 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 soon after starting treatment.

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

Medical examination/consultation

Before initiating or resuming use of the medicinal product YAZIDNA, a complete medical and family history should be taken and pregnancy should be ruled out. Blood pressure should be measured and a medical examination 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 use of YAZIDNA 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 depend on established treatment protocols and be adapted to each individual woman.

Patients should be warned 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 tablets (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 use of all COCs, especially during the first few months. Therefore, evaluation of any irregular bleeding should only be performed after an adaptation period (usually after three cycles of use).

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

Some women may not experience withdrawal bleeding during the tablet-free interval. If COCs have been taken according to the recommendations in the section "Dosage and administration", pregnancy is unlikely. However, if COC use was irregular before the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before continuing COC use.

Excipients

Each tablet of the medicinal product contains up to 54.6 mg of lactose per tablet. In patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, this amount of lactose should be taken into consideration, especially for those on a lactose-free diet.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is not indicated during pregnancy.

If pregnancy occurs during use of YAZIDNA, treatment should be stopped immediately. Results of extensive 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 or breastfeeding (see section "Pharmacological properties"). Based on animal data, adverse effects due to the hormonal influence of the active substances cannot be excluded. However, overall clinical experience with COC use during pregnancy does not indicate any adverse effects in humans.

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

Breastfeeding. COCs may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the infant. Therefore, YAZIDNA is not recommended until complete cessation of breastfeeding.

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

No studies on the effect on the ability to drive or operate machinery have been conducted.

No effect on the ability to drive or operate machinery has been observed in women using COCs.

Method of Administration and Dosage

For oral use.

Dosing

How to take the medicinal product Justina

Take 1 tablet daily at approximately the same time, swallowing with a small amount of liquid if necessary, following the order indicated on the blister pack. The medicinal product should be taken as one tablet per day for 21 consecutive days. The next pack should be started after a 7-day break, during which withdrawal bleeding usually occurs. Withdrawal bleeding typically begins on the 2nd or 3rd day after the last tablet and may not end before starting the next pack.

How to start treatment with Justina

• No previous hormonal contraceptives used (previous month)

Begin 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)

It is recommended to start taking tablets of Justina the day after taking the last active (hormone-containing) tablet of the previous COC, but no later than the day after the usual tablet-free interval or after the last placebo tablet of the previous COC.

• Switching from a vaginal ring or transdermal patch

It is recommended to start using Justina on the day of removal of the vaginal ring or transdermal patch, but no later than the day when the next application of these products would normally occur.

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

You may start taking Justina at 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 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 Justina.

• After first-trimester abortion

You may start taking Justina immediately. In this case, additional contraceptive methods are not required.

• After childbirth or second-trimester abortion

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

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

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

What to do if a tablet is missed

If the delay in taking a tablet does not exceed 12 hours, the contraceptive effect 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 12 hours, contraceptive protection may be reduced. In such cases, two main principles should be followed:

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

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

• Week 1

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

• Week 2

Take the 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 tablets were taken correctly during the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use additional contraceptive methods for 7 days.

• Week 3

The risk of reduced effectiveness increases as the 7-day tablet-free interval approaches. However, by following one of the two options below, a reduction in contraceptive protection can be avoided, provided tablets were taken correctly during the 7 days before the missed dose. Otherwise, it is recommended to follow the first option below and use additional contraceptive methods for the next 7 days.

• 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. Start tablets from the next pack immediately after finishing the current one, i.e., there should be no break between packs. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
• Alternatively, stop taking tablets from the current pack. In this case, the tablet-free interval (including the days of missed tablets) should not exceed 7 days; tablet intake should resume with the next pack.

If 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, incomplete absorption of the medicinal product may occur; in such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, another tablet should be taken as soon as possible. If more than 12 hours have passed, apply 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.

How to delay withdrawal bleeding

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

To shift the timing of withdrawal bleeding to another day of the week than that indicated by the current schedule, it is recommended to shorten the tablet-free interval by the number of days desired. It should be noted that the shorter the break, the more likely it is that withdrawal bleeding will not occur and the higher the risk of breakthrough bleeding or spotting during intake of tablets from the second pack (as also occurs when delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients

Not to be used. The medicinal product Justina is not indicated after menopause.

Patients with hepatic impairment

Justina is contraindicated in women with severe liver disease. See also section "Contraindications".

Patients with renal impairment

Justina has not been specifically studied in patients with impaired kidney function. Available data do not indicate the need for dosage adjustment in this patient group.

Children

The product is indicated for use only after the onset of menstruation.

Overdose

Acute toxicity of ethinylestradiol and dienogest following oral administration is very low. If, for example, a child accidentally takes several tablets of Justina at once, symptoms of intoxication are unlikely. Possible symptoms in such cases include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche following accidental or unintentional intake of the medicinal product. Specific treatment is usually not required. Symptomatic therapy may be administered if necessary. There are no antidotes for this medicinal product.

Adverse reactions.

The frequency of adverse reactions reported in women who used the medicinal product as an oral contraceptive is summarized in Table 3. Within each frequency subgroup, adverse reactions are listed in order of decreasing severity. Frequency is defined as: common (≥ 1/100 to ≤ 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Other adverse reactions observed only during the post-marketing period, for which frequency cannot be estimated, are listed under the subgroup "Frequency not known".

Table 3

Frequency of adverse reactions reported during clinical studies with the medicinal product Jestimond

2 including increased heart rate;

3 including upper and lower abdominal pain, abdominal discomfort/distension;

4 including macular rash;

5 including generalized pruritus;

6 including breast discomfort and breast tension;

7 including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea;

8 including vaginal bleeding and metrorrhagia;

9 including breast tenderness and breast swelling;

10 including weakness and malaise.

The most appropriate MedDRA term has been used to describe each adverse reaction.

Synonyms or related conditions are not listed but should be taken into consideration.

Description of selected adverse reactions

The following serious adverse reactions have been observed in women using COCs (also see section "Special warnings").

Tumours

• The frequency of breast cancer diagnosis is slightly increased among women using oral contraceptives. Since breast cancer is rare in women under 40 years of age, the frequency is small in relation to the overall risk of breast cancer. A causal relationship with COC use is not known.
• Liver tumours (benign and malignant).
• Cervical cancer.

Other conditions

• Hypertriglyceridaemia (increased risk of pancreatitis with COC use).
• Arterial hypertension.
• Development or worsening of conditions for which the relationship to COC use has not been definitively established: cholestatic jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
• Disorders of liver function.
• Changes in glucose tolerance or effects on peripheral insulin resistance.
• Crohn's disease, ulcerative colitis.
• Chloasma.

Interactions

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

Reporting of suspected adverse reactions

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

21 film-coated tablets per blister made of polyvinyl chloride film and aluminium foil. 1 or 3 blisters per cardboard carton.

Prescription category. Prescription only.

Manufacturer.

Laboratorios Leon Farma S.A.

Manufacturer's address and location of operations.

C/La Vallina s/n, Polígono Industrial Navatejera, Villacarramba, 24193 León, Spain.

Marketing Authorisation Holder.

Zentiva, k.s.

Address of the Marketing Authorisation Holder.

Prague-10 Dolní Měcholupy, U kabelovny 130, postal code 10237, Czech Republic.

In case of adverse events, adverse reactions or lack of therapeutic effect, please report to Zentiva Ukraine LLC, 5I Brovarskiy Avenue, Kyiv, 02660, Ukraine; tel./fax +38 044 517-75-00; e-mail [email protected].