Vendiol film-coated tablets 0.06 mg + 0.015 mg blister No. 28

Instructions Vendiol film-coated tablets 0.06 mg + 0.015 mg blister No. 28

Composition

active ingredients: gestodene, ethinylestradiol;

1 active tablet contains 0.060 mg of micronized gestodene and 0.015 mg of micronized ethinylestradiol;

excipients: lactose monohydrate, microcrystalline cellulose (type 102), polacrilin potassium, magnesium stearate;

film coating: opadry II yellow 31KZ2378, lactose monohydrate, hypromellose (type 2910), titanium dioxide (E 171), triacetin, quinoline yellow dye (E 104);

1 placebo tablet contains:

active ingredients: none;

excipients: microcrystalline cellulose, anhydrous lactose, pregelatinized corn starch, magnesium stearate, colloidal anhydrous silicon dioxide;

film coating: opadry II green 85F21389, polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, indigo carmine dye (E 132), quinoline yellow dye (E 104), iron oxide black dye (E 172), sunset yellow FCF dye (E 110).

Dosage form

Film-coated tablets.

Main physicochemical properties:

active tablets: round biconvex tablets, film-coated, yellow;

engraving on one side: "G43", the other side without engraving;

Placebo tablets: round biconvex tablets, film-coated, green, diameter about 6 mm.

Pharmacotherapeutic group

Sex hormone and drugs used in genital pathology. Progestogens and estrogens, fixed combinations. ATX code G0ZA A10.

Pharmacological properties

Pharmacodynamics.

Monophasic combined oral contraceptive.

Pearl index taking into account incorrect use: 0.24 (21521 cycles), 95% confidence interval 0.04-0.57.

The contraceptive effect of the drug Vendiol is provided by three complementary mechanisms:

effect on the hypothalamic-pituitary system by inhibiting ovulation;

the effect on cervical mucus makes it impermeable to sperm;

The effect on the endometrium worsens the conditions for implantation of the fertilized egg.

Pharmacokinetics.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. After administration of 15 μg, the maximum serum concentration of 30 pg/ml is reached within 1-1.5 hours. Ethinylestradiol undergoes a first-pass effect through the liver with high individual variability. Absolute bioavailability is approximately 45%.

Distribution

The apparent volume of distribution of ethinylestradiol is 15 l/kg, and plasma protein binding is approximately 98%. Ethinylestradiol induces the synthesis of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in the liver. During treatment with 15 μg of ethinylestradiol, the plasma concentration of SHBG increases from 86 to approximately 200 nmol/l.

Metabolism

Ethinylestradiol is completely metabolized (plasma clearance of metabolites is approximately 10 ml/min/kg). Metabolites are excreted in urine (40%) and feces (60%).

Breeding

The half-life of ethinylestradiol is approximately 15 hours. Only a small part of ethinylestradiol is excreted unchanged. Ethinylestradiol metabolites are excreted from the body with urine and bile in a ratio of 4/6.

Equilibrium state

Steady state is reached in the second half of the cycle, when serum concentrations of ethinylestradiol increase by 1.4–2.1 times.

Gestodene

Absorption

Gestodene is rapidly and completely absorbed after oral administration. Absolute bioavailability is approximately 100%. After a single dose of 60 μg, the maximum serum concentration of 2 ng/ml is reached approximately 1 hour later. The plasma concentration is highly dependent on the level of GH.

Distribution

The apparent volume of distribution is 1.4 l/kg after a single dose of 60 mcg. 30% of gestodene binds to plasma albumin, 50 to 70% binds to GH.

Metabolism

Gestodene is completely metabolized. Metabolic clearance is approximately 0.8 ml/min/kg after a single dose of 60 mcg. Inactive metabolites are excreted in the urine (60%) and feces (40%).

Breeding

The expected half-life is approximately 13 hours. The half-life increases to 20 hours when gestodene is administered with ethinylestradiol.

Equilibrium state

After repeated administration of the gestodene/ethinylestradiol combination, serum concentrations increase 2–4-fold.

Indication

Hormonal oral contraception.

When deciding whether to prescribe Vendiol, 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 with Vendiol compared with other combined hormonal contraceptives (see sections “Contraindications” and “Special instructions”).

Contraindication

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

hypersensitivity to the active substances or to any of the excipients of the drug (see section "Composition");

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");

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 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, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);

migraine with focal neurological symptoms in history;

high risk of arterial thromboembolism due to multiple risk factors (see section "Special warnings and precautions for use") or the presence of any of the following serious risk factors:

diabetes mellitus with vascular complications;

severe arterial hypertension;

severe dyslipidemia;

established pregnancy or possible pregnancy;

the presence of a malignant neoplasm of the mammary glands or suspicion of it;

endometrial carcinoma or the presence or suspicion of any other estrogen-dependent tumor;

presence of liver tumors (benign or malignant) or a history of such tumors, severe liver disease (until liver function is restored);

severe renal failure or acute renal failure;

vaginal bleeding of unclear etiology;

presence of pancreatitis or a history of pancreatitis if it is associated with severe hypertriglyceridemia.

The concomitant use of Vendiol and medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, and medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section “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.

Pharmacodynamic interactions

In clinical trials in patients treated with hepatitis C virus (HCV) 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) have been observed. This occurred at a significantly higher frequency in women taking ethinylestradiol-containing medicinal products, including combined oral contraceptives (COCs). In addition, ALT elevations have also been observed in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir when taking ethinylestradiol-containing medicinal products, such as combined oral contraceptives (COCs) (see section 4.3). Therefore, patients taking Vendiol should switch to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) before starting treatment with these combination drugs. Vendiol can be resumed 2 weeks after completing treatment with these combination drugs.

Pharmacokinetic interactions

Effect of other drugs on Vendiol

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

Therapy

Enzyme induction can 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 approximately 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 duration of treatment with the drug and for 28 days after stopping its use.

If therapy with an inducer drug is started during the period of taking the last active COC tablets from the current package, the placebo tablets should be discarded, and the tablets from the next COC package should be started immediately after the tablets in the previous package are finished.

Long-term treatment

For women on long-term therapy with active substances that induce liver enzymes, another reliable non-hormonal method of contraception is recommended.

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

There is a risk of reduced contraceptive efficacy during treatment and for one cycle after stopping modafinil treatment.

Active substances with inconsistent effects on PDA clearance

When used concomitantly with COCs, a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV 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 prescribing information for the concomitant HIV/HCV medicinal product and any associated recommendations 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 the clearance of PDA (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 Vendiol on other medicines

COCs may affect the metabolism of some other drugs, resulting in increased (e.g. cyclosporine) or decreased (e.g. lamotrigine) plasma and tissue concentrations.

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

Laboratory studies

Contraceptive steroids may affect the results of some laboratory tests, including biochemical parameters of liver, kidney, thyroid, adrenal function, plasma (transport) protein levels such as corticosteroid-binding globulin, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and parameters of the blood coagulation and fibrinolysis systems. Changes are usually within normal limits.

Application features

With caution

If a woman has any of the conditions or risk factors listed below, the appropriateness of using Vendiol should be discussed with the patient. If the condition worsens or any of the symptoms or risk factors listed below appear, the woman is advised to consult her doctor, who will decide whether to discontinue Vendiol.

Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any CHC increases the risk of VTE compared with no use. Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. Other products such as Vendiol may be associated with a double risk. The decision to use any product over 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 CHC use, 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 CHCs are restarted after a break of 4 weeks or longer.

About 2 in 10,000 women who are not using CHCs 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 gestodene-containing CHCs will develop VTE in one year; this compares with approximately 6 cases[2] in women who use levonorgestrel-containing CHCs.

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.

1These cases were identified as a result of a general epidemiological study conducted with different levonorgestrel-containing CHCs (relative risks used).

2Average rate in the range of 5-7 per 10,000 woman-years for levonorgestrel-containing CHCs compared to a control group of 2.3-3.6.

Number of VTE cases per 10,000 women per year

Thrombosis of other blood vessels, such as hepatic, mesenteric, renal, retinal veins and arteries, has been observed very rarely in women using CHCs.

Risk factors for VTE

The risk of venous thromboembolic complications among CHC users may be significantly higher in the presence of additional risk factors, especially if multiple risk factors are present (see Table 1).

Vendiol is contraindicated in women with multiple risk factors, the presence of which indicates a high probability of venous thromboembolism (see section "Contraindications"). The presence of more than one risk factor may increase the probability of VTE more significantly than the sum of some individual factors, in which case the probability of VTE should be carefully calculated. If the risk of complications exceeds the benefit of use, CHCs should not be prescribed (see section "Contraindications").

Risk factors for VTE

Table 1

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 venous thromboembolism (deep vein thrombosis and PE)

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

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 no apparent reason or rapid breathing;

sudden cough, possibly with hemoptysis;

acute chest pain;

severe confusion or 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 CHCs with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular accidents (e.g. transient ischemic attack, stroke). Arterial thromboembolic complications may be fatal.

The risk of arterial thromboembolic complications or cerebrovascular accidents in patients taking CHCs is increased in women with risk factors (see Table 2). The drug Vendiol is contraindicated if the patient has one serious risk factor or several risk factors for ATE that put her at high risk of arterial 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, so in this case the overall risk of ATE for the patient should be weighed. If the benefit-risk ratio is considered negative, CHCs should not be prescribed (see section "Contraindications").

Risk factors for ATE

Table 2

Symptoms of ATE

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

Symptoms of a stroke 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, speech or perception disorders;

sudden vision loss in one or both eyes;

sudden, severe, or prolonged headache with no known cause;

fainting or fainting with or without seizures.

Transient symptoms indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

pain, discomfort, feeling of tightness, heaviness, feeling of tightness 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.

Cancer in gynecology

Some epidemiological studies indicate an increased risk of cervical cancer in women who take COCs for a long time (more than 5 years), however, as before, there is conflicting evidence about the dependence of cervical cancer on sexual behavior and other factors, such as human papillomavirus (HPV).

A meta-analysis of 54 epidemiological studies suggests a slightly increased relative risk (RR = 1.24) of developing breast cancer in women who use combined oral contraceptives. This increased risk gradually disappears within 10 years after stopping COC use. Since breast cancer rarely occurs in women under 40 years of age, the increase in the number of cases diagnosed with breast cancer in women who use 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 who use COCs, the biological action of COCs, or both. Breast cancer detected in women who have ever used COCs is clinically less severe than in women who have never used COCs.

The use of high-dose COCs (0.05 mg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. Whether this statement also applies to low-dose COCs remains to be seen.

Liver neoplasm

There have been isolated reports of benign liver tumours and even more rare cases of malignant liver tumours in women using COCs. In some cases, these tumours have led to life-threatening intra-abdominal haemorrhage.

Headache

The occurrence or exacerbation of migraine, the occurrence of unusual, recurring, prolonged or severe headache requires immediate discontinuation of treatment and clarification of the cause.

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 hypertriglyceridemia or a strong family history of hypertriglyceridemia who use COCs may be at increased risk of pancreatitis.

Although a small increase in blood pressure has been reported in women taking COCs, clinically significant changes are rare. Only in such rare cases is immediate discontinuation of COC use justified. If COCs are used in the setting of hypertension and a persistent or significant increase in blood pressure occurs that is not adequately controlled by antihypertensive therapy, COC use should be discontinued. If appropriate, COC use may be resumed when blood pressure has been normalized with antihypertensive therapy.

Conditions such as jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, and hearing loss associated with otosclerosis may develop or worsen both during pregnancy and during COC use, but a causal relationship with COC use has not been proven.

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

Acute liver disease or exacerbation of chronic liver disease may require discontinuation of COC use until liver function tests have returned to normal. Recurrent cholestatic jaundice, which first developed during a previous pregnancy or previous use of sex hormones, requires discontinuation of COC use.

Although COCs may affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose COCs (<0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored while taking COCs.

There are reports of increased endogenous depression, epilepsy, Crohn's disease and ulcerative colitis with the use of 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.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Placebo tablets contain sunset yellow dye (E 110), which may cause allergic reactions.

Physical examination

Before initiating or reinstituting Vendiol, a careful medical history (including family history) should be taken and pregnancy should be excluded. Blood pressure should be measured and a full medical examination should be performed, taking into account the contraindications (see section "Contraindications") and precautions (see section "Special warnings and precautions for use"). The woman should be informed about the information on venous and arterial thrombosis, including the risk of Vendiol compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and actions to take if thrombosis is suspected.

The woman should also carefully read the instructions and follow these recommendations. The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient.

A woman should be warned that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted infections.

Decreased efficiency

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

Menstrual cycle disorders

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 3 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.

Use during pregnancy or breastfeeding

Pregnancy

The drug Vendiol is contraindicated for use during pregnancy.

Clinically, unlike diethylstilbestrol, numerous epidemiological studies have not established a relationship between the risk of malformations and the use of estrogens alone or in combination in early pregnancy.

Furthermore, the risks for sexual differentiation of the fetus (especially the female sex) described for older, highly androgenic progestogens should not be extrapolated to modern progestogens (such as in this medicinal product), which have significantly less androgenic properties or none at all.

Thus, the detection of pregnancy while taking a drug containing estrogen and progestogen does not require termination of pregnancy.

The increased risk of VTE in the postpartum period should be taken into account when resuming the use of Vendiol (see sections “Special instructions for use” and “Method of administration and dosage”).

Breastfeeding period

COCs may affect lactation by reducing the amount and changing the composition of breast milk. The use of this drug is not recommended during breastfeeding, as estrogen and progestogen pass into breast milk, which may adversely affect the baby.

If the patient wishes to continue breastfeeding, another method of contraception should be recommended.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug Vendiol has no or negligible influence on the ability to drive vehicles and use machines.

Method of administration and doses

How to take Vendiol

The tablets should be swallowed whole, without chewing, if necessary with a little liquid every day at about the same time in the order indicated on the blister pack. One tablet should be taken per day (preferably at the same time of day) for 28 consecutive days (1 yellow tablet per day for 24 days, then 1 green placebo tablet per day for the next 4 days) without a break between taking the tablets from the next pack. Withdrawal bleeding usually begins 2-3 days after taking the last tablet containing the active substance and may continue until the start of taking the tablets from the new pack.

How to start taking Vendiol

If hormonal contraception was not used in the previous month

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

Switching from another combined hormonal contraceptive, vaginal ring or transdermal patch

It is best to start taking Vendiol on the day after the last active tablet (the last tablet containing the active substance) of your previous contraceptive, but in no case later than the day after the usual tablet-free interval or after taking the placebo tablets of your previous contraceptive. If you are using a transdermal patch or vaginal ring, you should start taking the drug on the day of removal, but in no case later than the day when a new ring or patch would be due.

Switching from progestogen-only contraceptives (mini-pills, injections, implant) or a progestogen-releasing intrauterine system (IUD)

Switching from the mini-pill is possible at any time, from the implant or IUD on the day of their removal, from injections on the day the next injection is due, but in all these cases, an additional barrier method of contraception must be used during the first 7 days of taking Vendiol.

Use after abortion in the first trimester of pregnancy

The woman can start taking the drug immediately. In this case