Levomin 30 film-coated tablets blister No. 21

Instructions Levomin 30 film-coated tablets blister No. 21

Composition

active ingredients: ethinylestradiol, levonorgestrel;

1 film-coated tablet contains: ethinylestradiol 0.03 mg, levonorgestrel 0.15 mg;

excipients: lactose monohydrate, corn starch, maltodextrin, sodium starch glycolate (type A), magnesium stearate, yellow film-coating mixture (hypromellose 6 cP, titanium dioxide, macrogol 400, iron oxide yellow E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: round tablets, film-coated, yellow in color, without coating defects.

Pharmacotherapeutic group

Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combination. Levonorgestrel and ethinylestradiol.

ATX code G03A A07.

Pharmacological properties

Pharmacodynamics

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

Pharmacokinetics

Levonorgestrel.

Absorption.

After oral administration, levonorgestrel is rapidly and completely absorbed. The peak concentration of the substance in serum is approximately 2.3 ng/ml and is reached approximately 1.3 hours after a single dose of Levomin 30. Bioavailability is almost 100%.

Distribution.

Levonorgestrel is bound to serum albumin and sex steroid binding globulin. Only 1.1% of the total serum concentration is present as free steroid, approximately 65% is specifically bound to sex steroid binding globulin and 35% is nonspecifically bound to albumin. The ethinylestradiol-induced increase in sex steroid binding globulin affects the distribution of levonorgestrel between serum proteins, resulting in an increase in the fraction bound to sex steroid binding globulin and a decrease in the fraction bound to albumin. The apparent volume of distribution of levonorgestrel is 129 L after a single dose.

Metabolism.

Levonorgestrel is completely metabolized. The main metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. According to the results of in vitro and in vivo studies, the main enzyme in the metabolism of levonorgestrel is CYP3A4. The serum clearance rate is approximately 1.0 ml/min/kg.

Excretion from the body.

The serum level of levonorgestrel decreases in two phases. The terminal phase distribution is characterized by a half-life of about 25 hours.

Levonorgestrel is not excreted unchanged. Metabolites are excreted in urine and bile (feces) in a ratio of 1:1. The half-life of metabolites is approximately one day.

State of equilibrium.

During long-term use of Levomin 30 tablets, the level of levonorgestrel in serum increases approximately threefold, reaching a steady state in the second half of the course of use. The pharmacokinetics of levonorgestrel are influenced by the level of sex steroid binding globulin, which increases approximately 1.5-1.6 times after oral administration of estradiol. This also leads to a decrease in clearance and volume of distribution at steady state (0.7 ml/min/kg and about 100 l).

Ethinylestradiol.

Absorption.

After oral administration, ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations are approximately 50 pg/ml and are reached within 1–2 hours after administration of a Levomin 30 tablet. During absorption and first-pass metabolism, ethinylestradiol is extensively metabolized, resulting in an average oral bioavailability of approximately 45% (individual variation ranges from 20 to 65%).

Distribution.

Ethinylestradiol is highly (approximately 98%), but nonspecifically bound to serum albumin and causes an increase in serum concentrations of sex steroid binding globulin. The apparent volume of distribution has been determined to be 2.8–8.6 l/kg.

Metabolism.

Ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and in the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation, with the formation of many other hydroxylated and methylated metabolites, which are found as free metabolites, as well as conjugated sulfates and glucuronides in serum. Metabolic clearance is approximately 2.3–7 ml/min/kg.

Excretion from the body.

Serum ethinylestradiol levels decline in a biphasic manner with half-lives of approximately 1 hour and 10–20 hours, respectively.

Ethinylestradiol is not excreted from the body unchanged, ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is approximately one day.

State of equilibrium.

The concentration of ethinyl estradiol in serum with prolonged use of Levomin 30 tablets increases in a biphasic manner. Due to the variable serum half-life in the terminal phase, with daily administration, the equilibrium concentration of ethinyl estradiol in serum is reached after approximately one week.

Indication

When deciding to prescribe Levomin 30, the existing risk factors of each individual patient should be taken into account, in particular the risk of venous thromboembolism (VTE), and how the risk of VTE with Levomin 30 compares with the risk with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Instructions for Use").

Contraindication

Combined oral contraceptives (COCs) should not be used if any of the conditions or diseases listed below are present. If any of these conditions or diseases appear for the first time during use of a COC, the drug should be stopped immediately.

Venous thromboembolism (VTE).

Venous thromboembolism, current (including anticoagulant therapy) or history (e.g. deep vein thrombosis, pulmonary embolism). Hereditary or acquired predisposition to venous thrombosis, manifested by resistance to activated protein C, including factor V Leiden, antithrombin III deficiency, protein C deficiency, protein S deficiency.

Extensive surgery with prolonged immobilization (see section "Special instructions").

High risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

Arterial thromboembolism (ATE).

Current or history of arterial thromboembolism (e.g. myocardial infarction), prodromal symptoms of thrombosis (e.g. angina pectoris). Current or history of cerebrovascular disorders, prodromal symptoms (e.g. transient ischemic attack). Hereditary or acquired predisposition to arterial thrombosis, manifested by hyperhomocysteinemia and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). History of migraine with focal neurological symptoms.

Presence of severe or multiple risk factors for arterial thrombosis (see section "Special warnings and precautions for use"):
diabetes mellitus with vascular symptoms; severe hypertension; severe dyslipoproteinemia.

Severe liver disease, including a history of it, until liver function tests return to normal. Current or history of liver tumors (benign or malignant). Known or suspected malignant tumors (e.g., genital or breast) that are dependent on sex hormones. Vaginal bleeding of unknown etiology. Amenorrhea of unknown etiology. Hypersensitivity to the active substances (levonorgestrel, ethinylestradiol) or to any of the components of the drug. Concomitant use with drugs containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir.

Interaction with other medicinal products and other types of interactions

Caution: Please consult the prescribing information for concomitant medications to identify potential interactions.

The effect of other drugs on "Levomin 30".

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

Tactics

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

Short-term use

When treated with any of these drugs, a woman should temporarily use a barrier method in addition to taking COCs or choose another method of contraception. When treated with drugs that induce microsomal enzymes, a barrier method should be used throughout the entire period of treatment with the corresponding drug and for 28 days after stopping its use. If the use of such a drug is continued and the tablets in the COC blister pack are finished, the use of tablets from the next COC blister pack should be started immediately, without the usual tablet-free interval.

Long-term use

Women who use active substances that induce liver enzymes for a long time are recommended to choose another reliable non-hormonal method of contraception.

The following types of interactions have been reported in the literature:

Drugs that increase the clearance of COCs (reduced efficacy of COCs due to enzyme induction), for example: phenytoin, bosentan, barbiturates, primidone, carbamazepine, rifampicin and drugs for the treatment of HIV - ritonavir, nevirapine and efavirenz, and possibly oxicarbazepine, topiramate, felbamate, griseofulvin and drugs containing the herbal preparation St. John's wort (hypericum perforatum).

Drugs with different effects on COC clearance:

Therefore, the package leaflet of concomitant HIV/HCV medicinal products should be consulted for potential interactions and any necessary recommendations. In case of any doubt, a woman taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use an additional barrier contraceptive method.

Drugs that increase COC clearance (enzyme inhibitors).

The clinical relevance of the potential interaction with enzyme inhibitors remains unknown. Concomitant use of potent CYP3A4 inhibitors may increase plasma concentrations of estrogen or progestin, or both.

When etoricoxib is used at a dose of 60–120 mg per day, the concentration of ethinyl estradiol in plasma increases by 1.4 or 1.6 times when taken simultaneously with a COC containing 35 μg of ethinyl estradiol.

Effect of COCs on other drugs.

COCs may affect the metabolism of other drugs. Increased plasma concentrations of ciclosporin have been observed with concomitant use of oral contraceptives. COCs may induce the metabolism of lamotrigine and thus lead to a decrease in lamotrigine plasma levels below the therapeutic range.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, leading to a slight (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Pharmacodynamic interaction

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

Therefore, patients using Levomin 30 should switch to an alternative method of contraception (e.g. progestogen-only or non-hormonal methods) before starting this combination regimen. Levomin 30 can be restarted 2 weeks after completing this combination regimen.

Other forms of interaction.

Laboratory studies.

The use of contraceptive steroids may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, as well as levels of plasma (transport) proteins (e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions), indicators of carbohydrate metabolism and parameters of blood coagulation and fibrinolysis. Changes usually occur within the limits of laboratory norms.

Pharmacodynamic interactions.

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, with or without ribavirin, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir increases the risk of alanine aminotransferase elevations (see sections “Contraindications” and “Special warnings and precautions for use”). Therefore, patients using Levomin 30 should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) before starting therapy with these drug regimens. Levomin 30 can be resumed 2 weeks after completing treatment with these drug regimens.

Application features

Reservation.

If you have any of the conditions/risk factors listed below, you should individually weigh the benefits and possible risks of using COCs before starting them. If your condition worsens or any of these risk factors appear, you should consult your doctor to decide whether to stop using the drug.

Risk of VTE.

The use of combined hormonal contraceptives carries an increased risk of venous thromboembolism (VTE). The decision to use Levomin 30 should only be made after discussion with the woman, during which it is necessary to ensure that she understands the following:

the risk of VTE when using the drug "Levomin 30"; how the existing individual risk factors of a woman affect; the increased risk of VTE is highest during the first year of using a combined contraceptive.

There is evidence that the risk is increased if CHC use is resumed after a break of 4 weeks or more.

In women who are not using CHCs and are not pregnant, the incidence of venous thromboembolism (VTE) is 2 in 100,000 women per year. However, the risk for any individual woman may be much higher, depending on her underlying risk factors.

The incidence of venous thromboembolism (VTE) in women using hormonal contraceptives containing levonorgestrel is about 61 cases per 100,000 women per year.

The incidence of venous thromboembolism (VTE) with low-estrogen COCs is lower than the risk of VTE associated with pregnancy or the postpartum period.

VTE is fatal in 1–2% of cases.

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

The risk of VTE in women using CHCs is significantly increased if additional risk factors are present (see Table below). Levomin 30 is contraindicated if a woman has multiple 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 is greater than the sum of the individual factors - in this case, her overall risk of VTE should be considered. If the benefit-risk balance is considered negative, COCs should not be prescribed (see section "Contraindications").

Table: Risk factors for VTE

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism.

The increased risk of thromboembolism during pregnancy and the 6-week postpartum period should be taken into account (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 immediate medical attention and to inform the healthcare professional that she is taking CHCs.

The occurrence of one or more of these symptoms may be a reason to immediately discontinue the use of the drug "Levomin 30".

Symptoms of deep vein thrombosis may include:

unusual unilateral swelling of the lower limb and/or veins of the lower limb; pain in the leg that may only be felt when standing or walking; increased temperature in the affected leg; redness or paleness of the skin of the leg.

Symptoms of pulmonary embolism may include:

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

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

Other signs of vascular occlusion may include sudden pain or swelling, as well as slight blueness in the extremities.

If the vascular occlusion occurs in the eye, symptoms can range from painless blurred vision to complete vision loss. In some cases, vision loss can occur very suddenly.

Risk of arterial thromboembolism (ATE).

Epidemiological data also link CHC use to an increased risk of myocardial infarction, transient ischemic attack and stroke. Arterial thromboembolism can be fatal.

Factors that increase the risk of arterial thromboembolism (ATE) in women who use COCs.

The risk of ATE in women using CHCs is significantly increased if additional risk factors are present (see Table below). The presence of one serious risk factor or several risk factors for arterial or venous disease may be a contraindication (see section “Contraindications”). If the risk-benefit ratio is unfavorable, CHCs should not be used (see section “Contraindications”).

Table. Risk factors for ATE

Symptoms of ATE.

If symptoms occur, the woman is advised to seek immediate medical attention and inform healthcare professionals that she is taking CHCs.

In case of impaired cerebral circulation, the following symptoms may occur:

sudden numbness or extreme weakness of the face, arm or leg, especially on one side or part of the body; sudden motor impairment, dizziness, loss of balance or coordination; sudden speech impairment or aphasia; sudden partial or complete loss of vision; sudden, severe or prolonged headache for no reason; loss of consciousness with or without seizures.

Symptoms that indicate a transient ischemic attack.

In the event of a myocardial infarction, the following symptoms may occur:

pain, discomfort, pressure, heaviness, a feeling of heaviness or fullness in the chest, arms or below the breastbone; discomfort spreading to the back, jaw, throat, arm, stomach; a feeling of heaviness, indigestion or shortness of breath; 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 increased risk of cervical cancer with long-term use of COCs, but this statement is still 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 infection with the human papillomavirus (HPV).

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of developing breast cancer in women who use COCs. This increased risk gradually disappears within 10 years after stopping COCs. Since breast cancer is rare in women under 40 years of age, the increase in the incidence of breast cancer in women who use or have recently used 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. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. In women taking COCs, complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding should be considered in the differential diagnosis.

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 any COC, reports of clinically significant increases in blood pressure have been isolated. Only in rare cases is withdrawal of COC use justified. A systemic relationship between COC use and hypertension with clinical manifestations has not been established. If, while taking COCs, a woman with a history of hypertension develops prolonged clinically significant hypertension or if significant increases in blood pressure do not respond adequately to antihypertensive therapy, COCs should be discontinued. If appropriate, COC use may be resumed after normotensive status has been achieved with 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 conclusive: jaundice and/or pruritus associated with cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis; depressed mood.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired 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 that a change in therapeutic regimen is necessary in diabetic women taking low-dose COCs. However, women with diabetes should be closely monitored, especially in the early stages of COC use.

Cases of worsening of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis have been reported during COC use.

Mood swings and depression are well-known side effects of hormonal contraceptives (see section 4.8). Depression can be serious and is a known risk factor for suicidal behaviour and suicide. Women should seek medical advice if they experience mood swings and depressive symptoms, including shortly after starting treatment.

Increased alanine aminotransferase.

In clinical trials, patients treated for hepatitis C virus (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, significantly increased transaminase (alanine aminotransferase) levels exceeding 5 times the upper limit of normal (ULN) occurred more frequently in women using ethinylestradiol-containing products such as combined hormonal contraceptives (CHCs). Elevations in alanine aminotransferase have also been observed with the medicinal products containing glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see sections 4.3 and 4.5).

Medical examination/consultation.

Before starting or resuming the use of Levomin 30, the patient's medical history, including family history, should be carefully examined and pregnancy should be ruled out. Blood pressure should also be measured and a physical examination should be performed, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special instructions for use"). The instructions for medical use should be read carefully and the recommendations given in it should be followed. It is important to draw the woman's attention to information on venous and arterial thrombosis, in particular the risk of Levomin 30 compared with other CHCs, the symptoms of VTE and ATE, known risk factors and what to do in case of suspected thrombosis. The frequency and nature of the examinations should be based on current medical practice standards, taking into account the individual characteristics of each woman. It should be noted that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Decreased efficiency.

The effectiveness of COCs may be reduced, for example, if pills are missed, vomiting, diarrhea, or if other medications are taken at the same time.

Decreased cycle control.

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

If irregular bleeding persists or occurs after several normal cycles, non-hormonal causes should be considered and appropriate diagnostic measures should be taken to exclude malignancy or pregnancy. These may include curettage.

Some women may not have a menstrual period during the COC break. If the COC has been taken according to the instructions in the section "Method of administration and dosage", pregnancy is unlikely. However, if the contraceptive has been used irregularly or if menstrual bleeding is absent for two cycles before COC use is resumed, pregnancy should be excluded.

Ability to influence reaction speed when driving vehicles or other mechanisms

No negative effects of combined oral contraceptives on the ability to drive or use other mechanisms have been identified.

Use during pregnancy or breastfeeding

Pregnancy

The drug "Levomin 30" is contraindicated for use during pregnancy.

If pregnancy occurs while using the drug "Levomin 30", its use must be stopped immediately.

However, the results of epidemiological studies do not indicate an increased risk of birth defects in children born to women who took oral contraceptives before pregnancy, as well as the existence of a teratogenic effect in the event of unintentional use of oral contraceptives in early pregnancy.

The increased risk of VTE during the postpartum period should be taken into account when resuming Levomin 30 (see sections “Method of administration and dosage” and “Special precautions for use”).

Breast-feeding

Contraceptive pills may affect lactation, as they may reduce the amount of breast milk and change its composition. Therefore, combined oral contraceptives are not recommended for nursing mothers until the child has been weaned. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk. These amounts may have an effect on the child.

Method of administration and doses

Method of application.

For oral use.

The tablets should be taken orally daily in the order indicated on the blister, at about the same time, washed down with a small amount of liquid if necessary. The drug is taken 1 tablet per day for 21 consecutive days. Taking the tablets from each subsequent package should be started after a 7-day break in taking the tablets, during which withdrawal bleeding usually occurs. As a rule, it begins on the 2-3rd day after taking the last tablet and may not end before starting to take the tablets from the next package.

How to start using the drug "Levomin 30".

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

Tablet-taking should be started on day 1 of the natural cycle, i.e. on the first day of menstrual bleeding. It is also possible to start taking the tablets on days 2-5, but in this case it is necessary to use an additional method of contraception (for example, a barrier method) for the first 7 days of taking the drug.

Switching from another combined oral contraceptive (COC, vaginal ring, transdermal patch).

It is advisable to start taking Levomin 30 the day after taking the last active tablet of the previous COC (or after removing the vaginal ring or transdermal patch), but no later than the day after the usual break in taking the tablets (period without a vaginal ring or transdermal patch) or after taking a placebo tablet of the previous hormonal contraceptive.

Switching from a progestogen-only method (mini-pill, injection, implant) or intrauterine system (IUD).

You can start taking Levomin 30 any day after stopping the mini-pill (in the case of an implant or IUD - on the day of their removal, in the case of an injection - instead of the next injection), but in all cases it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the drug.

After an abortion in the first trimester of pregnancy.

You can start taking the drug immediately. In this case, there is no need to use additional contraceptive methods.

After childbirth or abortion in the second trimester.

If you are breastfeeding, see the section “Use during pregnancy or breastfeeding”.

It is recommended to start taking the drug from 21-28 days after childbirth or abortion in the second trimester of pregnancy. If taking the tablets is started later, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if sexual intercourse has already taken place, then before starting COC use, you should exclude a possible pregnancy or wait for the onset of the first menstruation.

Missed pill.

"Levomin 30" contains a very low dose of hormones, and, as a result, if you miss a pill, the contraceptive effectiveness is limited.

If the delay in taking the tablets does not exceed 12 hours, the contraceptive effect of the drug is not reduced. The missed tablet should be taken as soon as possible, and the next tablet should be taken at the usual time.

If you are more than 12 hours late in taking your pill, contraceptive protection may be reduced. In this case, there are two main rules to consider:

The break in taking the tablets should never exceed 7 days. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous tablet taking for 7 days.

In accordance with the above, the following recommendations should be followed in everyday life:

1st week.

You should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking the tablets at the usual time. In addition, you should use a barrier method of contraception, such as a condom, for the next 7 days. If you have had sexual intercourse in the previous 7 days, you should consider the possibility of pregnancy.