Lindinet 20 film-coated tablets blister No. 63

Instructions Lindinet 20 film-coated tablets blister No. 63

Composition

active ingredients: ethinylestradiol, gestodene;

1 tablet contains ethinylestradiol 0.02 mg and gestodene 0.075 mg;

excipients: sodium calcium edetate, magnesium stearate, colloidal anhydrous silicon dioxide, povidone, corn starch, lactose monohydrate, quinoline yellow (E 104), titanium dioxide (E 171), macrogol 6000, talc, calcium carbonate, sucrose.

Dosage form

Film-coated tablets.

Main physicochemical properties: light yellow, round, biconvex, film-coated tablets, plain on both sides. Diameter: about 5.6 mm, nominal weight: 90.0 mg.

Pharmacotherapeutic group

Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. ATX code G03A A10.

Pharmacological properties

Pharmacodynamics.

Combined oral contraceptives work by inhibiting gonadotropins. Although the primary mechanism of action is inhibition of ovulation, other mechanisms, including changes in cervical mucus (which makes it more difficult for sperm to enter the uterus) and endometrium (which makes it less likely for an egg to implant), contribute to the contraceptive effect of the drug.

When taken correctly and continuously, the risk of failure of the combined oral contraceptive method is 0.1% per year. However, with typical use, the overall risk of failure of the combined oral contraceptive method is 5% per year. The effectiveness of most contraceptive methods depends on how reliably they are used. The most likely cause of failure of the combined oral contraceptive method is missed pills.

Pharmacokinetics.

Gestodene.

Absorption. Orally administered gestodene is rapidly and almost completely absorbed. The maximum serum concentration is reached 1 hour after a single dose. The bioavailability of gestodene is approximately 99%.

Distribution: In serum, gestodene is mainly bound to sex hormone binding globulin (SHBG) (50-70%) and to a lesser extent to serum albumin. Only 1-2% of the total serum concentration is in the form of free steroid.

The increase in GSH levels caused by ethinylestradiol causes an increase in the amount of gestodene bound to plasma proteins, which leads to an increase in the GSH-bound fraction and a decrease in the albumin-bound fraction. When taking multiple doses, gestodene accumulates in the blood serum. The equilibrium concentration of the substance is reached in the second half of the cycle, when the concentration of the drug in the blood serum increases by 3-5 times.

Biotransformation: Gestodene is completely metabolized by reduction of the C3-keto group and the delta-4 double bond and by multiple hydroxylation steps. It has not been established whether gestodene, when used simultaneously with ethinylestradiol, has a significant effect on the kinetics of the latter.

Excretion. Serum levels of gestodene decrease in two stages. With repeated administration, the terminal half-life is about 20-28 hours. Metabolites are excreted in greater quantities in the urine than in the feces.

Ethinylestradiol.

Absorption. Orally administered ethinylestradiol is rapidly and almost completely absorbed. The maximum concentration in the blood serum is reached 1-2 hours after taking the drug. The bioavailability of ethinylestradiol due to presystemic conjugation and primary metabolism in the liver is approximately 40-60%.

Distribution: Ethinylestradiol is completely but nonspecifically bound to albumin (almost 98%) and leads to an increase in serum sex hormone binding globulin (SHBG). Steady-state plasma concentrations are reached in the second half of the cycle, when plasma drug concentrations increase by 25-50% compared to a single dose.

Biotransformation. Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver and enters the enterohepatic circulation. The primary oxidation reaction is 2-hydroxylation by cytochrome P450 enzymes. The substance forms a large number of different hydroxylated and ethylated metabolites, present as free metabolites, as well as conjugates with glucuronides and sulfates.

Elimination: The concentration of ethinylestradiol in the blood serum decreases in two stages.

The terminal half-life of ethinylestradiol is 16-18 hours. Metabolites of ethinylestradiol in the form of glucuronide and sulfate conjugates are excreted in greater quantities in the feces than in the urine.

Indication

Oral contraception.

When deciding whether to prescribe Lindinet 20, it is necessary to take into account the current risk factors for the individual woman, especially risk factors for venous thromboembolism (VTE), and how high the risk of VTE is when using Lindinet 20 compared with other combined hormonal contraceptives (see sections “Contraindications” and “Special instructions for use”).

Contraindication

Combined hormonal contraceptives (CHCs) should not be used in the following cases. If any of these conditions occur during use of the drug, its use should be discontinued immediately.

• Hypersensitivity to the active substances or to any of the excipients.
• Presence or risk of venous thromboembolism (VTE):
• Venous thromboembolism – current VTE (use of anticoagulants) or history of VTE (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]);
• known hereditary or acquired predisposition to venous thromboembolism, e.g. resistance to activated protein C (APC, including factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
• major surgical intervention with prolonged immobilization (see section "Special instructions for use");
• increased 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 arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal state (e.g. angina);
• cerebrovascular disease – current stroke, history of stroke, prodromal state (e.g., transient ischemic attack, TIA);
• known hereditary or acquired predisposition to arterial thromboembolism, e.g. hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• history of migraine with focal neurological symptoms;
• increased risk of arterial thromboembolism due to the presence of several risk factors (see section "Special warnings and precautions for use") or due to the presence of one of the serious risk factors, such as:
• diabetes mellitus with vascular symptoms;
• severe arterial hypertension;
• severe dyslipoproteinemia.
• Presence of pancreatitis or history of pancreatitis if associated with severe hypertriglyceridemia.
• Presence of severe liver dysfunction or history of such disorders (until liver function is restored).
• Presence of liver tumors (benign or malignant) or a history of such tumors.
• Known or suspected steroid-dependent malignant tumors (e.g., genitals, mammary glands).
• Undiagnosed abnormal vaginal bleeding.

The simultaneous use of Lindinet 20 with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir is contraindicated (see sections “Special warnings and precautions 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 appropriate prescribing information for other concomitantly administered medicinal products should be consulted for potential interactions.

Pharmacodynamic interactions

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, may increase the risk of ALT elevations (see sections "Contraindications" and "Special warnings and precautions for use"). Therefore, patients taking Lindinet 20 should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the above combination medicinal products. The use of Lindinet 20 can be resumed 2 weeks after completing treatment with these combination medicinal products.

Pharmacokinetic interactions

Effect of other medicines on Lindinet 20

Interactions with drugs that induce microsomal enzymes are possible, which may lead to increased clearance of sex hormones and cause breakthrough bleeding and/or loss of contraceptive efficacy.

Treatment

Enzyme induction may occur after a few days of treatment. Maximum enzyme induction is usually observed within a few weeks. After discontinuation of treatment, enzyme induction may occur for approximately 4 weeks.

Short-term treatment

Women receiving treatment with enzyme inducers should temporarily use a barrier method or another method of contraception in addition to COC use. The barrier method should be used throughout the entire period of treatment with concomitant medications and for 28 days after stopping such treatment.

If therapy with an enzyme-inducing drug continues after the end of the tablets in the COC pack, the next COC pack should be started immediately after the end of the previous one, without the usual break in taking the tablets.

Long-term treatment

For women receiving long-term treatment with enzyme-inducing active substances, another reliable non-hormonal method of contraception is recommended.

Such interactions have been reported in the literature.

Substances that increase the clearance of PDA (reduced PDA effectiveness due to enzyme induction)

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin and HIV drugs - ritonavir, nevirapine and efavirenz; interactions are also possible with felbamate, griseofulvin, oxcarbazepine, topiramate and drugs containing St. John's wort (Hypericum perforatum).

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus inhibitors, may increase or decrease plasma concentrations of estrogen or progestins. The combined effect of these effects may in some cases be clinically significant.

Therefore, when concomitantly using HIV/HCV drugs, the prescribing information for these drugs should be consulted for potential interactions and appropriate recommendations. In case of doubt, women receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors are advised to use an additional barrier method of contraception.

The effect of Lindinet 20 on other medicines

Oral contraceptives may affect the metabolism of some other active substances. Accordingly, the concentrations of such substances in the blood plasma and tissues may increase (e.g. cyclosporine, theophylline) or decrease (e.g. lamotrigine, tizanidine, levothyroxine).

Application features

Warning

If a woman has any of the conditions or risk factors listed below, the appropriateness of using Lindinet 20 should be discussed with the patient.

In case of deterioration of the condition or the appearance of any of the symptoms or risk factors listed below, the woman is advised to consult her doctor, who will decide whether to discontinue taking Lindinet 20.

Circulatory disorders.

Risk of venous thromboembolism (VTE)

The use of any combined oral contraceptive (COC) increases the risk of venous thromboembolism (VTE) compared with no use.

Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. Other products such as Lindinet 20 may be associated with a double risk. The decision to use any product instead of a product with a lower risk of VTE should only be made after discussion with the patient to ensure that she understands the risk of VTE with Lindinet 20, the impact of existing risk factors on the likelihood of VTE, and that the risk of VTE is highest during the first year of use. There is also some evidence that this risk is increased when COCs are restarted after a break of 4 weeks or longer.

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

It is estimated that[1] 9-12 out of 10,000 women who use COCs containing gestodene will develop VTE in one year; this compares with around 6 cases[2] in women who use COCs containing levonorgestrel.

In both cases, the annual rate of VTE is lower than the rate of VTE 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 COCs.

Number of VTE cases per 10,000 women per year

Risk factors for VTE

The risk of venous thromboembolic complications in women using COCs may be significantly increased in patients with additional risk factors, including multiple factors (see Table 1).

Lindinet 20 is contraindicated if the patient has several risk factors that put her at high risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, it is possible that the increased risk will be greater than the sum of the individual factors - in this case, the overall risk of VTE for the patient should be weighed. If the benefit-risk ratio is considered negative, COCs should not be prescribed (see section "Contraindications").

Table 1

Risk factors for VTE

In such situations, it is advisable to stop using the patch/pill/ring (in the case of elective surgery, four weeks before the operation) and not resume use until 2 weeks after full recovery of mobility. Another method of contraception should be used to avoid unwanted pregnancy.

If Lindinet 20 has not been discontinued in advance, anticoagulant treatment should be considered.

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

The risk of thromboembolism should be considered during pregnancy, particularly during the 6-week period after delivery (for information on use during pregnancy or breastfeeding, see section “Use during pregnancy or breastfeeding”).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If symptoms occur, the woman is advised to seek medical attention immediately and to inform the doctor that she is taking a COC.

Symptoms of deep vein thrombosis (DVT) may include:

• unilateral swelling of the leg and/or foot or an area along a vein on 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 pulmonary embolism (PE) may include:

• sudden shortness of breath for an unexplained reason or rapid breathing;
• sudden cough, possibly with hemoptysis;
• acute chest pain;
• severe dizziness;
• fast or irregular heartbeat.

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

Other signs of vascular occlusion may include: sudden pain, swelling, and a bluish discoloration of the limb.

Symptoms of an ocular vascular occlusion can range from painless blurred vision that can progress to vision loss. Sometimes, vision loss can occur almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of COCs with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular accidents (e.g. transient ischemic attack, stroke). Arterial thromboembolic complications can be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or cerebrovascular accidents in patients taking COCs is increased in women with risk factors (see Table 2). Lindinet 20 is contraindicated if the patient has one serious risk factor or several risk factors for ATE that put her at high risk of arterial thromboembolism (see section "Contraindications"). If a woman has more than one risk factor, it is possible that the increased risk will be greater than the sum of the individual factors - in this case, the overall risk of ATE for the patient should be weighed. If the benefit-risk ratio is considered negative, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for ATE

Symptoms of ATE

If symptoms occur, the woman is advised to seek medical attention immediately and to inform the doctor that she is taking a COC.

Symptoms of a stroke may include:

Transient symptoms indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

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

Oncological diseases.

The most important risk factor for cervical cancer is persistent infection with human papillomavirus (HPV). Some epidemiological studies suggest that long-term use of COCs may be associated with an increased risk of developing cervical cancer in women infected with human papillomavirus. However, this statement remains controversial, as it is not clear to what extent these studies take into account concomitant risk factors (e.g. cervical screening or sexual behaviour, including the use of barrier methods of contraception).

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of breast cancer in women using combined oral contraceptives. This increased risk gradually disappears within 10 years after stopping combined oral contraceptives. Since breast cancer rarely occurs in women under 40 years of age, the increase in breast cancer diagnoses in women who are using or have recently used oral contraceptives is small in relation to the overall lifetime risk of breast cancer. The results of these studies do not provide evidence of a causal relationship.

The increased risk may be explained by earlier diagnosis of breast cancer in women using combined oral contraceptives, or by the biological action of combined oral contraceptives, or by both factors. It has been noted that breast cancer detected in women who have ever used COCs is clinically less severe than in those who have never used COCs.

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 case of complaints of severe pain in the epigastric region, liver enlargement or in case of signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis when using oral contraceptives.

Other states.

Depressed mood and depression are common adverse reactions with hormonal contraceptives (see section 4.8). Depression can be severe and is a known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood swings and symptoms of depression, even if they occur soon after starting treatment.

Women with a history of depression who use COCs should be closely monitored and the drug discontinued in the event of a recurrence of depression. Patients who develop severe depression while using COCs should discontinue the drug and be given an alternative method of contraception in order to determine the relationship to the drug.

Women with hypertriglyceridemia or a family history of this disorder are at increased risk of developing acute pancreatitis when using combined oral contraceptives.

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 COC use and treat the hypertension. If appropriate, COC use can be resumed after the blood pressure has been normalized with antihypertensive therapy.

The following diseases/conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship between the two is not conclusive: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, haemolytic uraemic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis.

In acute or chronic liver dysfunction, it may be necessary to discontinue COC use until liver function tests return to normal. In cases of liver dysfunction, the metabolism of steroid hormones may be significantly reduced. In the event of recurrence of cholestatic jaundice and/or pruritus, 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 that there is a need to change the therapeutic regimen in diabetic women taking low-dose COCs (containing <0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored while taking COCs.

Crohn's disease and ulcerative colitis have been reported in women using COCs.

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.

Conditions requiring special attention.

Medical examination/consultation.

Before starting the use of Lindinet 20, a detailed family history and a general medical and gynecological examination of the patient should be taken. This examination should be repeated periodically. This medical examination should include blood pressure measurement, breast examination, abdominal palpation and gynecological examination with cytological examination, as well as laboratory tests.

It is important to draw the woman's attention to information on venous and arterial thrombosis, including the risk of using Lindinet 20 compared with other COCs, the symptoms of VTE and ATE, as well as known risk factors and actions to take if thrombosis is suspected.

The woman should be advised to carefully read the instructions for medical use of the medicinal product and to follow the advice given. The frequency and nature of examinations should be based on established practical recommendations and be adapted to the individual woman.

Women should be warned that the drug does not protect against sexually transmitted diseases, including HIV infection (AIDS).

Other information.

Decreased efficiency

The effectiveness of combined oral contraceptives 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").

Short cycle control

Intermenstrual bleeding (spotting or breakthrough bleeding) may occur with any oral contraceptive, especially during the first few months. Therefore, assessment of irregular intermenstrual bleeding should only be carried out after a period of adaptation to the drug after three cycles of tablet use.

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

Some women may not have menstrual bleeding during a break in taking the drug.

If the COC is used according to the instructions in the section "Method of administration and dosage", pregnancy is unlikely. However, if the drug has been taken irregularly or if there are no menstrual bleeding for two cycles, pregnancy must be excluded before continuing COC use.

Pediatric population

Lindinet 20 is recommended for use only after the first menstruation.

Elderly patients

The use of combined oral contraceptives after menopause is not indicated.

Liver dysfunction

Lindinet 20 is contraindicated for use in women with impaired liver function (see section "Contraindications").

Kidney dysfunction

There are no data on the use of the drug in patients with impaired renal function.

Impact on the results of laboratory and other diagnostic tests

The use of combined oral contraceptives may cause certain physiological changes that may affect the results of some laboratory tests, including:

• biochemical parameters of liver function (including decreased bilirubin and alkaline phosphatase), thyroid function (increased total T3 and T4 due to increased thyroxine-binding globulin (TBG), decreased free T3 uptake), adrenal function (increased plasma cortisol, increased cortisol-binding globulin, decreased dehydroepiandrosterone sulfate (DHEA-S)), and renal function (increased plasma creatinine and decreased creatinine clearance);
• plasma levels of proteins (carriers) such as corticosteroid-binding globulin and lipid/lipoprotein fractions;
• carbohydrate metabolism parameters;
• coagulation and fibrinolysis parameters;
• decreased folate levels in blood plasma.

Changes usually remain within the normal laboratory range.

In studies of patients treated for hepatitis C virus infection with 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 taking ethinylestradiol-containing products, such as CHCs (see sections 4.3 and 4.5).

This medicinal product contains lactose and sucrose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase insufficiency, glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol (23 mg) sodium/tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Pregnancy.

Before starting the use of Lindinet 20, pregnancy should be excluded.

If pregnancy occurs during the use of an oral contraceptive, its use should be discontinued immediately.

There is no convincing evidence that the estrogen and progestin contained in combined oral contraceptives can cause birth defects in children if pregnancy accidentally occurs while taking combined oral contraceptives.

When re-prescribing Lindinet 20, 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. Small amounts of steroids contained in oral hormonal contraceptives and/or their metabolites have been reported to be excreted in breast milk, and some adverse reactions in infants, including jaundice and breast enlargement, have been reported. Oral contraceptives may affect lactation because their use may reduce the amount and change the composition of breast milk.

The use of combined oral contraceptives is usually not recommended until breastfeeding is completely completed.

Ability to influence reaction speed when driving vehicles or other mechanisms

Lindinet 20 has no or negligible influence on the reaction speed when driving vehicles or using other mechanisms.

Method of administration and doses

The tablets should be taken at approximately the same time each day, in the order indicated on the blister pack. You should take 1 tablet per day (preferably at the same time of day) for 21 consecutive days. Then you should take a seven-day break from taking the tablets. During the seven-day break, menstrual-like bleeding should occur due to withdrawal of the drug. Usually, bleeding begins on the 2nd or 3rd day after taking the last tablet and may continue until the start of the next pack of tablets.

The next day after the seven-day break, you should start taking pills from the next pack, which contains 21 pills.

First dose of the drug.

Taking Lindinet 20 should begin on the first day of the menstrual cycle.

You can also start taking the pills from the 2nd to the 7th day of menstruation, but in this case you must use an additional contraceptive.