Jeanine film-coated tablets No. 21

Instructions for use of Jeanine film-coated tablets No. 21

Composition

active ingredients: ethinylestradiol, dienogest;

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

excipients: lactose monohydrate, corn starch, maltodextrin, magnesium stearate, sucrose, glucose syrup, calcium carbonate, povidone K25, macrogol 35000, carnauba wax, titanium dioxide (E171).

Dosage form

Film-coated tablets.

Main physicochemical properties: shiny, film-coated tablets, white in color.

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 conducted with the drug Janine®, 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).

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

The contraceptive effect of Janine® 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 an in vitro affinity for progesterone receptors 10-30 times lower than that of other synthetic progestogens. In vivo animal data 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

Adsorption: Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentrations of approximately 67 pg/mL are reached within 1.5 to 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 non-specifically 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 Jeanine® 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.

Metabolism: Dienogest is metabolized mainly by hydroxylation and conjugation to form mainly endocrinologically inactive metabolites. These metabolites are very rapidly eliminated from plasma such that no active metabolite is observed in the blood plasma, only dienogest in unchanged form. The total clearance is approximately

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

Combined hormonal contraceptives (CHCs) should not be used if any of the conditions listed below are present. If any of these conditions appear for the first time during CHC use, it should be stopped 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 antibodies to phospholipids (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. Pancreatitis present or in history, if associated with severe hypertriglyceridemia. Severe liver disease present or in history, until liver function tests have returned to normal. Presence or in history of liver tumors (benign or malignant). Known or suspected malignant tumors (e.g., genital or breast) that are dependent on sex hormones. Established or suspected pregnancy. Vaginal bleeding of unknown etiology. Hypersensitivity to the active substances or to any of the components of the drug.

The drug Janine® is contraindicated when used simultaneously with drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”).

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 drugs on the drug Janine®

Interactions are possible with drugs that induce microsomal enzymes. This may lead to an increase in the 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), e.g. barbiturates, carbamazepine, phenytoin, primidone, rifampicin; 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.

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 the drug Janine® on other drugs

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 estradiol-containing medicinal products with direct-acting antiviral medicinal products containing ombitasvir, paritaprevir or dasabuvir and their combinations increases the risk of alanine aminotransferase (ALT) elevations greater than 20 times the upper limit of normal in healthy patients and in patients with hepatitis C virus (see section "Contraindications").

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin increases the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, women using the drug Jeanine® should use an alternative method of contraception (e.g. progestogen-only contraceptives or non-hormonal methods) before starting therapy with this combination of drugs. The use of the drug Jeanine® can be resumed 2 weeks after completing therapy with this combination.

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 Janine® should be made taking into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with Janine® compared with other CHCs (see sections “Contraindications” and “Special Precautions”).

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

In the event of exacerbation or the first appearance of any of these conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue the use of the drug Janine®.

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

The use of any CHC increases the risk of VTE in women who use it compared with those who do not use it. Medicines containing levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. The use of other medicines, such as Jeanine®, may increase the risk of VTE by 1.6 times. The decision to use a medicine 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 the use of Jeanine®, the extent of her existing 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 CHC use is resumed after a break of 4 weeks or more.

About 2 in 10,000 women who are not using CHCs and are not pregnant will develop a VTE in a 1-year period. However, the risk for an individual woman may be much higher, depending on the risk factors she has (see below).

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

It is estimated that out of 10,000 women who use low-dose CHCs containing levonorgestrel, about 61 will develop VTE within 1 year.

It is estimated2 that out of 10,000 women who use low-dose CHCs containing dienogest and ethinylestradiol, 8–11 will develop VTE within 1 year.

The number of VTE cases per year was lower than 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.

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 the drug Janine® is contraindicated in women with multiple risk factors that may increase the risk of developing 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 developing 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 within 6 weeks after delivery (for information on pregnancy and lactation, 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.

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.

Risk of developing arterial thromboembolism (ATE)

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

When using CHCs, the risk of arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see table). The use of the drug Jeanine® is contraindicated if women have one serious or multiple risk factors for ATE that may increase the risk of developing 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 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.

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.

Neoplasms can be life-threatening or fatal.

Other states

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

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant increases in blood pressure are 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 may 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.

Mental disorders

Depressed mood and depression are well-known side effects that can occur with hormonal contraceptives (see section 4.8). Depression can be a serious condition and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including shortly after starting treatment.

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 medicinal product contains 27 mg of lactose and 1.65 mg of glucose. In case of rare hereditary diseases of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, patients on a lactose-free diet are advised to take this amount of lactose into account.

Elevated ALT levels

In clinical trials in patients treated for hepatitis C with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using ethinylestradiol-containing medicinal products such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

Medical examination/consultation

Before initiating or reinstituting Janine, a complete medical history (including family history) and pregnancy should be taken. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and the specifics of use (see section 4.4). The woman should be made aware of the information on venous and arterial thrombosis, including the risk associated with Janine 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 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

Irregular bleeding (spotting or breakthrough bleeding) may occur with all COCs, 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).

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.

Ability to influence reaction speed when driving vehicles or other mechanisms

No studies have been conducted on the effects on the ability to drive or use machines.

No effect on the ability to drive or use machines has been found in women using COCs.

Use during pregnancy or breastfeeding

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

If pregnancy occurs while taking Janine®, the drug 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 lactation (see section "Pharmacological properties"). Based on these animal studies, adverse effects due to the hormonal effects of the active substances cannot be excluded. However, the general experience of COC use during pregnancy does not indicate any adverse effects in humans. When resuming the use of the drug Janine®, the increased risk of VTE in the postpartum period should be taken into account (see sections "Method of administration and dosage" and "Special instructions 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, the use of Janine® is not recommended until the breastfeeding period is complete.

Method of administration and doses

For oral use.

Dosage

How to take the drug Janine®

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 medicine 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 medicine, for