Justinda film-coated tablets blister No. 63

Instructions for Justinda film-coated tablets blister pack No. 63

Composition

active ingredients: dienogest; ethinylestradiol;

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

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

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

Dosage form

Film-coated tablets.

Main physicochemical properties: white or almost white, round biconvex tablets, free from foreign impurities, film-coated.

Pharmacotherapeutic group

Hormonal contraceptives for systemic use. ATX code G03A A16.

Pharmacological properties

Pharmacodynamics

All hormonal contraceptive methods have very low contraceptive failure rates when used as directed. Contraceptive failure rates may be higher if they are not used as directed (e.g., missing a pill).

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).

Justinda is a combined oral contraceptive (COC) with ethinylestradiol and the progestogen dienogest.

The contraceptive effect of the drug Justinda is based on the interaction of various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

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

The dose of dienogest that leads to ovulation suppression is 1 mg/day.

The risk of endometrial and ovarian cancer is reduced with high-dose COCs (50 mcg ethinylestradiol). Whether this also applies to low-dose COCs remains unclear.

Pharmacokinetics

Ethinylestradiol

Adsorption: Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentrations of approximately 67 pg/mL are reached within 1.5–4 hours. Ethinylestradiol is extensively metabolized during absorption and first-pass metabolism, resulting in a mean oral bioavailability of approximately 44%.

Distribution: Ethinylestradiol binds strongly but nonspecifically to serum albumin (approximately 98%) and induces an increase in serum concentrations of sex steroid binding globulin (SSGB). The apparent volume of distribution of ethinylestradiol is approximately 2.8–8.6 l/kg.

Metabolism. Ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and in the liver. Ethinylestradiol is metabolized mainly by aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are additionally formed, among which there are both free metabolites and conjugates with glucuronides and sulfates. Clearance is 2.3–7 ml/min/kg.

Elimination. Serum ethinylestradiol levels 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 the urine and bile in a ratio of 4:6. The half-life of the metabolites is approximately one day.

Steady state. Steady state is reached during the second half of the administration cycle, when the concentration of ethinylestradiol in the blood serum is approximately twice as high as after a single dose.

Dienogest.

Absorption. After oral administration, dienogest is rapidly and completely absorbed. The maximum serum concentration is reached within 2.5 hours after a single oral dose of Justin and is 51 ng/ml. The absolute bioavailability of dienogest in combination with ethinylestradiol is approximately 96%.

Distribution: Dienogest is bound to serum albumin and does not bind to GCS or corticoid-binding globulin (CBG). Only 10% of the total serum concentration of dienogest is found as free steroid, and 90% is nonspecifically bound to albumin. The ethinylestradiol-induced increase in GCS does not affect the binding of dienogest to serum proteins. The apparent volume of distribution of dienogest is in the range of 37 to 45 liters.

Excretion. The serum level of dienogest decreases with a half-life of about 9 hours. Only a small amount of dienogest is excreted unchanged by the kidneys. After an oral dose of 0.1 mg/kg body weight, the ratio of renal to faecal excretion is 3.2. About 86% of the administered dose is excreted within 6 days, the majority, 42%, is excreted in the urine within the first 24 hours.

Steady state. The pharmacokinetics of dienogest are independent of the level of GSH. With daily use, the concentration of the substance in the blood serum increases by 1.5 times, reaching a steady state after 4 days of use.

Preclinical safety data

Preclinical studies of ethinylestradiol and dienogest have shown the expected estrogenic and progestogenic effects.

The results of conventional non-clinical studies of repeated 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 certain pre-existing hormone-dependent tissues and tumors.

Indication

Oral contraception.

Contraindication

Justin should not be used if any of the following conditions are present. If any of these conditions appear for the first time during CHC use, it should be discontinued immediately.

Presence or risk of venous thromboembolism (VTE) Current (while on 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 resistance to activated protein C (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;

major surgical interventions with prolonged immobilization (see section "Special instructions for use");

high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and 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); current or history of cerebrovascular accident, presence of prodromal symptoms (e.g. transient ischemic attack (TIA)); known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin 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 warnings and precautions for use") or due to the presence of one serious risk factor, such as:

diabetes mellitus with vascular complications; severe arterial hypertension; severe dyslipoproteinemia; smoking; pancreatitis present or in history, associated with severe hypertriglyceridemia. severe liver disease present or in history, until liver function tests have returned to normal (also Dubin-Johnson and Rotor syndrome). presence or in history of liver tumors (benign or malignant). known or suspected malignant tumors (e.g. genitals or mammary glands) that are dependent on sex hormones. established or suspected pregnancy. vaginal bleeding of unknown etiology. undiagnosed amenorrhea. hypersensitivity to the active substances or to any of the components of the drug.

Justinda is contraindicated for concomitant use with medicinal products containing ombitavir/paritarevir/ritonavir and dasabuvir.

Interaction with other medicinal products and other types of interactions

Note: The information for the concomitant medicinal product should be consulted for potential interactions.

The effect of other medicines on Justinda.

Interactions are possible with drugs 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 detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method should be used throughout the entire period of treatment with the drug and for 28 days after stopping its use. If therapy is started during the last COC tablet-taking period, the next COC pack should be started immediately after the previous pack is finished without the usual tablet-taking break.

Women on long-term therapy with active substances that induce liver enzymes are recommended to choose another reliable non-hormonal method of contraception.

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

Active substances with inconsistent effects on COC clearance

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

Therefore, the Summary of Product Characteristics of the concomitant HIV/HCV medicinal product should be consulted to identify potential interactions. In case of any doubt, 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 the potential interaction 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 been shown to increase plasma concentrations of ethinyl estradiol by 1.4- to 1.6-fold, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.

The effect of Justinda on other medicines

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

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a slight (e.g. with theophylline) or moderate (e.g. with tizanidine) increase in their plasma concentrations.

Pharmacodynamic interactions.

Concomitant use of Justinda with medicinal products containing ombitavir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, may increase the risk of elevated ALT levels. Therefore, the patient should switch to an alternative method of contraception (e.g., progestogen-only contraceptive or non-hormonal methods) before starting treatment with this combination regimen. Justinda may be restarted 2 weeks after completing treatment with this combination regimen.

Other types of interactions

Laboratory tests

The use of contraceptive steroids may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of (carrier) proteins such as GSK, lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and indicators of coagulation and fibrinolysis. These changes are usually within normal limits.

Application features

The decision to prescribe Justinda should take into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with Justinda compared with other CHCs (see sections “Contraindications” and “Special warnings and precautions for use”).

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

In case of exacerbation or at the first manifestations of any of these conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue the use of Justinda.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).

Circulatory disorders

Risk of developing venous thromboembolism (VTE)

The use of any CHC increases the risk of venous thromboembolism (VTE) in women who use it compared with those who do not use it. Products containing levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. The risk of using Justin compared with products with a lower risk is currently unknown. The decision to use a product other than those with the lowest risk of VTE should only be made after discussion with the woman. She should be made sure that she is aware of the risk of VTE associated with CHC use, the extent of her existing risk factors and the fact that the risk of VTE is highest during the first year of use. Some data suggest that the risk of VTE may increase when CHC use is resumed after a break of 4 weeks or longer.

Epidemiological studies in women using low-dose (< 50 μg ethinylestradiol) CHCs have shown that out of 10,000 women, 6–12 will develop VTE within 1 year.

It is estimated that out of 10,000 women who use a CHC containing levonorgestrel, about 61 will develop a VTE in one year.

Limited epidemiological data suggest that the risk of VTE with CHCs containing dienogest may be similar to that with CHCs containing levonorgestrel.

The reported number of VTE cases per year was lower than would be expected during pregnancy or in the postpartum period.

VTE can be fatal in 1-2% of cases.

Thrombosis in other blood vessels, such as the arteries and veins of the liver, kidneys, mesenteric vessels or retinal vessels, has been reported extremely rarely in women using CHCs.

1 On average 5-7 cases per 10,000 women-years based on the calculation of the relative risk of using levonorgestrel-containing CHCs compared to that in women not using CHCs (approximately 2.3-3.6 cases).

Risk factors for developing VTE

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

The use of Justin 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 increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of VTE should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1. Risk factors for VTE development

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

Attention should be paid to the increased risk of thromboembolism during pregnancy, especially during the 6 weeks after 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 contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of DVT may include:

unilateral swelling of the thigh, lower leg and/or foot or an area along a vein in the leg; pain or increased sensitivity in the leg that may only be felt when standing or walking; a feeling of heat in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include:

sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; severe dizziness or loss of balance; fast or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific or 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, and slight blueness of the limb.

In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and which can progress to loss of vision. Sometimes the loss of vision develops almost instantly.

Epidemiological studies have shown that the use of any CHC 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 developing ATE

The risk of arterial thromboembolic complications or cerebrovascular events is increased in women with risk factors when using CHCs (see table). The use of Justin is contraindicated if women 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 increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 2. Risk factors for the development of ATE

Symptoms of ATE

Women should be advised to contact their doctor immediately if they experience such symptoms and to inform them that they are using CHCs.

Symptoms of a cerebrovascular accident may include:

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

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

Symptoms of a myocardial infarction may include:

pain, discomfort, heaviness, heaviness, a feeling of squeezing or fullness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; feeling of fullness in the stomach, indigestion or heartburn; increased sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or shortness of breath; fast or irregular heartbeat. Tumors

The results of some epidemiological studies indicate an additional increase in the risk of developing cervical cancer with long-term use of COCs, but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior and other factors, such as human papillomavirus infection.

A meta-analysis of epidemiological studies has shown a small increased relative risk (RR = 1.24) of breast cancer in women who use COCs. This increased risk gradually returns to the baseline risk associated with the woman's age within 10 years after stopping COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women who are current or recent users of COCs is small in relation to the overall risk of breast cancer.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women using COCs, which in some cases led to life-threatening intra-abdominal bleeding. In the event of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis when using COCs.

Some studies have shown an increased risk of developing liver carcinoma with long-term use of combined oral contraceptives; however, such tumors develop extremely rarely.

Neoplasms can be life-threatening or fatal.

Other states

Although a slight increase in blood pressure has been reported in many women taking COCs, a clinically significant increase in blood pressure is rare. However, if persistent clinically significant hypertension develops during COC use, it is advisable to discontinue the COC and treat the hypertension. If appropriate, COC use can be resumed after normotensive status has been achieved with antihypertensive therapy. COCs should be discontinued if, during their use for hypertension diagnosed before COC use, persistently high blood pressure persists despite adequate antihypertensive therapy. The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship to COC use is not definitively established: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

In women with a hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

In acute or chronic liver dysfunction, it may be necessary to discontinue COC use until liver function tests return to normal. In the event of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis, which first occurred during pregnancy or previous use of sex hormones, COC use should be discontinued.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest that diabetic women taking low-dose COCs (<0.05 mg ethinylestradiol) should be monitored closely during COC use, especially at the beginning of treatment.

Cases of exacerbation of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis have also been observed during COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while using COCs.

Each tablet of the drug contains no more than 54.6 mg of lactose per tablet. In case of rare hereditary diseases of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, patients who are on a lactose-free diet are advised to take this amount of lactose into account.

Medical examination/consultation

Before initiating or reinstituting Justinda, a complete medical history (including family history) and pregnancy should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and the specific features of use (see section 4.4). The woman should be advised of the information on venous and arterial thrombosis, including the risk associated with Justinda compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and the actions to be taken if thrombosis is suspected.

Patients are advised to carefully read the instructions for medical use of the medicinal product and follow the recommendations contained therein. The frequency and nature of the examinations should depend on the established treatment protocols and be adapted to each individual woman.

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

Decreased efficiency

The effectiveness of COCs may be reduced in the event of missed tablets (see section "Method of administration and dosage"), gastrointestinal disorders (see section "Method of administration and dosage") or concomitant use of other medicines (see section "Interaction with other medicines and other types of interactions").

Cycle disruption

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first few months. Therefore, any irregular bleeding should only be assessed after a period of adaptation to the drug (usually after three cycles of use).

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

Some women may not have a withdrawal bleed during the tablet-free interval. If COCs are used according to the instructions in section 4.2, pregnancy is unlikely. However, if COC use was irregular before the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy should be ruled out before COC use is resumed.

In clinical trials in patients treated for hepatitis C virus infection with the medicinal products containing ombitavir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, significant elevations of transaminases (ALT) exceeding the upper limit of normal (ULN) occurred more frequently in women using ethinylestradiol-containing products, such as combined hormonal contraceptives (CHCs).

Ability to influence reaction speed when driving vehicles or other mechanisms

No studies on the effects of the drug on the ability to drive or use machines have been conducted. No effects of COCs on the ability to drive or use machines have been observed.

Use during pregnancy or breastfeeding

Pregnancy. The drug is not indicated for use during pregnancy.

If pregnancy occurs during use of Justinda, its use should be discontinued immediately. The results of extensive epidemiological studies do not indicate an increased risk of congenital malformations in children born to women who used COCs before pregnancy, as well as the existence of a teratogenic effect in the event of inadvertent use of COCs during pregnancy.

Animal studies have shown adverse effects during pregnancy or (see section 5.1). Based on these animal studies, adverse effects due to the hormonal effects of the active substances cannot be excluded. However, general experience with COCs during pregnancy does not indicate any adverse effects in humans.

When resuming the use of Justinda, the increased risk of VTE in the postpartum period should be taken into account (see sections “Method of administration and dosage” and “Special precautions for use”).

Breastfeeding. COCs may affect breastfeeding, as they may reduce the amount of breast milk and change its composition. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the child. Therefore, Justinda is not recommended for use until the breastfeeding period is complete.

Method of administration and doses

For oral use.

Dosage

How to take Justinda.

Take 1 tablet per day regularly at about the same time, if necessary with a small amount of liquid, in the order specified on the blister. Take the drug 1 tablet / day for 21 consecutive days. Taking the tablets from each subsequent package should be started after a seven-day break in taking the drug, during which withdrawal bleeding should occur. As a rule, withdrawal bleeding begins on the 2-3rd day after taking the last tablet and may not end before starting the next package.

How to start treatment with Justinda

Hormonal contraceptives were not used in the previous period (last month)

Tablet-taking should be started on the first day of the natural cycle (i.e. on the first day of menstrual bleeding).

Switching from another COC

It is advisable to start taking Justinda tablets the day after taking the last hormone-containing tablet of your previous COC, but no later than the day after the usual tablet-free period or after taking a placebo tablet.