Levomin® 30: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMIN® 30

Composition:

Active substances: ethinylestradiol, levonorgestrel;

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

Excipients: lactose monohydrate, maize starch, maltodextrin, sodium starch glycolate (type A), magnesium stearate, yellow coating mixture (hypromellose 6 cP, titanium dioxide, polyethylene glycol 400, iron oxide yellow E 172).

Pharmaceutical form. Film-coated tablets.

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

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

ATC code G03A A07.

Pharmacological Properties

Pharmacodynamics

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several 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. Peak serum concentration is approximately 2.3 ng/mL and is reached about 1.3 hours after a single dose of "Levomin® 30". Bioavailability is nearly 100%.

Distribution. Levonorgestrel binds to serum albumin and sex hormone-binding globulin (SHBG). Only 1.1% of the total drug concentration in serum exists as free steroid, approximately 65% is specifically bound to SHBG, and 35% is non-specifically bound to albumin. Ethinylestradiol-induced increase in SHBG levels affects the distribution of levonorgestrel among serum proteins, resulting in an increased fraction bound to SHBG and a decreased 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 unconjugated and conjugated forms of 3α,5β-tetrahydrolevonorgestrel. According to in vitro and in vivo studies, the primary enzyme involved in levonorgestrel metabolism is CYP3A4. The serum clearance rate is approximately 1.0 mL/min/kg.

Elimination. Serum levels of levonorgestrel decline in two phases. The terminal distribution phase is characterized by a half-life of approximately 25 hours.

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

Steady state. During prolonged use of "Levomin® 30" tablets, serum levels of levonorgestrel increase by about three times, reaching steady state in the second half of the treatment cycle. The pharmacokinetics of levonorgestrel are influenced by SHBG levels, which increase approximately 1.5–1.6 times after oral administration of ethinylestradiol. This also leads to a reduction in clearance and volume of distribution at steady state (0.7 mL/min/kg and approximately 100 L).

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Peak serum concentration is nearly 50 pg/mL and is reached within 1–2 hours after taking a "Levomin® 30" tablet. During absorption and first-pass metabolism in the liver, ethinylestradiol is extensively metabolized, resulting in a mean oral bioavailability of approximately 45% (individual variations range from 20% to 65%).

Distribution. Ethinylestradiol is highly bound (approximately 98%), but non-specifically, to serum albumin and induces an increase in serum concentration of sex hormone-binding globulin (SHBG). The apparent volume of distribution is reported to be 2.8–8.6 L/kg.

Metabolism. Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. It is primarily metabolized via aromatic hydroxylation, forming numerous other hydroxylated and methylated metabolites, which are detected as free metabolites as well as conjugated sulfates and glucuronides in serum. Metabolic clearance is approximately 2.3–7 mL/min/kg.

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

Steady state. Serum concentration of ethinylestradiol increases biphasically during prolonged use of "Levomin® 30" tablets. Due to the variable terminal half-life in serum, steady-state concentration of ethinylestradiol is reached after approximately one week of daily administration.

Clinical characteristics.

Indications.

Oral contraception.

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

Contraindications.

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

Venous thromboembolism (VTE).

Current (including anticoagulant therapy) or previous history of venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism).
Hereditary or acquired predisposition to venous thrombosis, such as activated protein C resistance, including factor V Leiden, deficiency of antithrombin III, deficiency of protein C, deficiency of protein S.
Major surgery with prolonged immobilization (see section "Special precautions for use").
High risk of venous thromboembolism due to presence of multiple risk factors (see section "Special precautions for use").

Arterial thromboembolism (ATE).

Current or previous history of arterial thromboembolism (e.g., myocardial infarction), or prodromal symptoms of thrombosis (e.g., angina pectoris).
Current or previous cerebrovascular disorders, or prodromal symptoms (e.g., transient ischemic attack).
Hereditary or acquired predisposition to arterial thrombosis, such as hyperhomocysteinemia and 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 precautions for use"):
- diabetes mellitus with vascular symptoms;
- severe hypertension;
- severe dyslipoproteinemia.
Severe liver disease, including in the past, until liver function tests return to normal.
Current or previous history of liver tumors (benign or malignant).
Breast cancer, including history, which may be hormone-sensitive (see section "Special precautions for use", subsection "Tumors").
Vaginal bleeding of unknown etiology.
Amenorrhea of unknown etiology.
Hypersensitivity to the active substances (levonorgestrel, ethinylestradiol) or to any other component of the medicinal product.
Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Warning: instructions for use of concomitant medicinal products should be reviewed to identify potential interactions.

Effect of other medicinal products on "Levomin® 30".

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

Strategy

Enzyme induction may be observed within a few days of starting treatment. 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. During treatment with any of these drugs, women should temporarily use a barrier method in addition to taking COCs or choose another contraceptive method. When taking drugs that induce microsomal enzymes, a barrier method should be used throughout the entire treatment period and for an additional 28 days after stopping the drug. If the use of such a medicinal product continues and the tablets in the COC blister pack are finished, the next COC blister pack should be started immediately without the usual tablet-free interval.

Long-term use. Women who are taking enzyme-inducing substances long-term are advised to choose another reliable non-hormonal contraceptive method.

Scientific publications have reported the following types of interactions:

Drugs that increase COC clearance (reduced COC efficacy due to enzyme induction), e.g.: phenytoin, bosentan, barbiturates, primidone, carbamazepine, rifampicin, and HIV treatments – ritonavir, nevirapine, and efavirenz, as well as possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing the herbal preparation St. John’s wort (hypericum perforatum).

Drugs with variable effects on COC clearance.

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, instructions for use of concomitant medicinal products for treatment of HIV/HCV should be reviewed to identify potential interactions and to establish necessary recommendations. In case of any doubt, women 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 potential interactions with enzyme inhibitors remains unknown. Concomitant use of potent CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both.

When etoricoxib is administered at doses of 60–120 mg daily, plasma concentrations of ethinylestradiol increase by 1.4 or 1.6 times when co-administered with a COC containing 35 mcg ethinylestradiol.

Effect of COCs on other medicinal products.

Troleandomycin may increase the risk of intrahepatic cholestasis when used concomitantly with COCs.

COCs may affect the metabolism of other medicinal products. Increased plasma concentrations of cyclosporine have been observed when oral contraceptives are used concomitantly. COCs may induce lamotrigine metabolism and thus lead to plasma levels of lamotrigine below the therapeutic range.

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

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and a non-reversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. Clinical data indicate that ethinylestradiol does not increase or only slightly increases plasma concentrations of CYP3A4 substrates (e.g., midazolam), whereas ethinylestradiol inhibits the clearance of CYP1A2 substrates, causing mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interaction

During clinical trials in patients treated for hepatitis C virus (HCV) infection with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, alanine aminotransferase (ALT) levels increased significantly, exceeding the upper limit of normal (ULN) 5 times more frequently in women using ethinylestradiol-containing products, such as combined hormonal contraceptives (CHCs). Additionally, increased ALT levels were also observed with antiviral medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir in women using ethinylestradiol-containing products such as CHCs (see sections "Contraindications").

Therefore, patients using "Levomin® 30" should switch to an alternative contraceptive method (e.g., progestogen-only contraceptives or non-hormonal methods) prior to starting such combination therapy. "Levomin® 30" may be restarted 2 weeks after completion of treatment with these combination regimens.

Other forms of interaction.

Laboratory tests.

Use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, as well as levels of (transport) plasma proteins (e.g., corticosteroid-binding globulin) and lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within normal laboratory ranges.

Pharmacodynamic interactions.

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir increases the risk of elevated alanine aminotransferase (ALT) levels (see sections "Contraindications" and "Special precautions for use"). Therefore, patients using "Levomin® 30" should switch to an alternative contraceptive method (e.g., progestogen-only contraception or non-hormonal methods) before initiating therapy with these regimens. Use of "Levomin® 30" may be resumed 2 weeks after completion of treatment with these regimens.

Special precautions.

Warning.

If any of the diseases or risk factors listed below are present, the benefits and possible risks of using combined oral contraceptives (COCs) should be individually assessed before starting treatment. If the condition worsens or any of these risk factors appear, the patient should consult a physician to determine whether discontinuation of the drug is necessary.

Risk of venous thromboembolism (VTE).

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

the risk of VTE associated with use of "Levomin® 30";
how her individual risk factors may affect this risk;
the risk of VTE is highest during the first year of using a combined oral contraceptive.

Evidence indicates that the risk increases if CHC use is resumed after a break of 4 weeks or more.

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

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

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

VTE can result in fatal outcomes in 1–2% of cases.

Number of VTE cases per 10,000 women per year

Rare and very rare cases of thrombosis in other blood vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, and retinal vessels, have been reported in women using hormonal contraceptives.

Factors that increase the risk of VTE in women using COCs.

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 together confer a high risk of venous 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 individual factors— in such cases, the overall risk of VTE should be considered. If the benefit-risk ratio is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Table. Risk factors for VTE

Risk factors	Comments
Obesity (body mass index over 30 kg/m2).	Risk increases significantly with increasing body mass index. Particularly significant when other risk factors are present.
Long-term immobilization, major surgical interventions, any surgical procedures on the lower limbs, major trauma. Note: temporary immobilization, including air travel over 4 hours, may also be a risk factor for VTE, especially in women with other risk factors.	In these cases, it is recommended to discontinue the use of tablets (in planned surgeries — at least four weeks prior) and not restart them earlier than two weeks after full mobility has been restored. Another method of contraception should be used to prevent unintended pregnancy. The need for antithrombotic therapy should be considered if the medication was not stopped in advance.
Family history of thrombosis (e.g., cases of venous thromboembolism in siblings or parents at a relatively young age, e.g., under 50 years).	If hereditary predisposition is present or suspected, it is recommended to consult a physician before starting any COC.
Other conditions associated with VTE.	Cancer, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia.
Age over 35 years.

There is no consensus regarding 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 must be taken into account (see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism). If any of these symptoms occur, women are advised to seek immediate medical attention and inform healthcare providers that they are taking a COC.

The occurrence of one or more of these symptoms may necessitate immediate discontinuation of the medicinal product "Levomin® 30".

Symptoms of deep vein thrombosis may include:

unusual unilateral swelling of the leg and/or superficial veins of the leg;
pain in the leg, which may only be felt while standing or walking;
increased temperature in the affected leg; redness or pallor 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 hemoptysis;
sharp chest pain;
dizziness;
rapid or irregular heartbeat.

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

Other signs of vascular occlusion may include sudden pain or swelling, as well as pale or cyanotic discoloration of the extremities.

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

Risk of arterial thromboembolism (ATE).

Epidemiological data also associate COC use with an increased risk of myocardial infarction, transient ischemic attack, and stroke. Arterial thromboembolism can have fatal consequences.

Factors increasing the risk of arterial thromboembolism (ATE) in women using COCs.

The risk of ATE in women using COCs increases significantly 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 constitute a contraindication (see section "Contraindications"). If the risk-benefit ratio is unfavorable, COCs should not be used (see section "Contraindications").

Table. Risk factors for ATE

Risk factors	Comments
Age over 35 years.
Smoking.	Women are strongly advised not to smoke if they wish to use COCs. Women over the age of 35 who continue to smoke are strongly advised to use another method of contraception.
Hypertension.
Obesity (body mass index over 30 kg/m²).	Risk increases significantly with increasing body mass index. Particularly significant in the presence of other risk factors.
Family history of complications (any cases of arterial thromboembolism in siblings or parents at a relatively young age, e.g., under 50 years).	If hereditary predisposition is present or suspected, medical consultation is recommended before starting any COC.
Migraine.	An increase in frequency or severity of migraine during COC use (which may precede cerebrovascular events) may be a reason for immediate discontinuation of COC use.
Other conditions associated with ATE.	Diabetes mellitus, hyperhomocysteinemia, heart valve disorders and atrial fibrillation, dyslipoproteinemia, and systemic lupus erythematosus.

Symptoms of ATE.

If any symptoms occur, women are advised to seek immediate medical attention and inform healthcare professionals that they are taking COCs.

Symptoms of cerebral circulation disorders may include:

sudden numbness or severe weakness of the face, arm, or leg, especially on one side of the body;
sudden motor impairment, dizziness, loss of balance, or coordination disturbances;
sudden speech disturbances or aphasia;
sudden partial or complete vision loss;
sudden, severe, or prolonged headache without apparent cause;
loss of consciousness with or without seizures.

Symptoms indicating transient ischemic attack.

Symptoms of myocardial infarction may include:

pain, discomfort, pressure, heaviness, or aching sensation in the chest, arms, or below the sternum;
discomfort radiating to the back, jaw, throat, arm, or stomach;
sensation of heaviness, indigestion, or shortness of breath;
sweating, nausea, vomiting, or dizziness;
extreme weakness, anxiety, or dyspnea;
rapid or irregular heartbeat.

Tumors.

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs; however, this remains controversial, as it has not been definitively established whether study results adequately account for confounding risk factors such as sexual behavior and human papillomavirus (HPV) infection.

Breast cancer

Levonorgestrel/ethinylestradiol is contraindicated in women with current or past history of breast cancer, as breast cancer may be hormone-sensitive (see section "Contraindications").

Epidemiological studies have not shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not demonstrate a link between current or previous use of COCs and breast cancer risk. However, some studies have reported a slight increase in breast cancer risk among women currently taking COCs or who have recently discontinued them (within less than 6 months since last use) (see section "Adverse reactions").

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer in women using COCs. This increased risk gradually diminishes over 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnosis rates among women currently or recently using COCs is small in relation to the overall risk of breast cancer.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhage. In women taking COCs who present with severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, liver tumor should be considered in differential diagnosis.

Other conditions.

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

Although minor increases in blood pressure have been reported in many women using any COC, reports of clinically significant hypertension are rare. Discontinuation of COC use is justified only in rare cases. A systemic relationship between COC use and clinically manifest hypertension has not been established. If a woman with a history of hypertension develops persistent, clinically evident hypertension or significant blood pressure elevations unresponsive to antihypertensive therapy during COC use, COCs should be discontinued. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive treatment.

The following conditions have been reported to occur or worsen during pregnancy and with COC use, but their association with COC use has not been definitively established: jaundice and/or pruritus associated with cholestasis; gallbladder stone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis; and depressive mood.

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

Acute or chronic liver dysfunction may necessitate discontinuation of COC use until liver function tests return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis that first occurred during pregnancy or previous use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to alter therapeutic regimens in women with diabetes who use low-dose COCs. However, women with diabetes should be closely monitored, especially during the initial stages of COC use.

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

Chloasma may occasionally occur, particularly in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during COC use.

Mood deterioration and depression are well-known adverse reactions associated with hormonal contraceptives (see section "Adverse reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should consult a physician if they experience mood changes or depressive symptoms, including shortly after initiating treatment.

Medical examination/consultations.

Before initiating or resuming use of "Levomin® 30", a thorough patient history, including family history, should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination performed, considering contraindications (see section "Contraindications") and special warnings (see section "Special precautions for use"). The instructions for medical use must be carefully read and followed. It is important to inform women about venous and arterial thrombosis, including the risk associated with "Levomin® 30" compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis. The frequency and nature of examinations should be based on current medical practice guidelines and individual patient characteristics. Women should be informed that oral contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Reduced efficacy.

The effectiveness of COCs may be reduced, for example, due to missed doses, vomiting, diarrhea, or concomitant use of other medicinal products.

Reduced cycle control.

During use of all COCs, intermenstrual bleeding (spotting or breakthrough bleeding) may occur, particularly during the first months of use. Therefore, evaluation of any irregular bleeding should only be performed after an adaptation period of approximately three cycles.

Intermenstrual bleeding (spotting or breakthrough bleeding) occurs in more than 50% of women using oral contraceptives containing ethinylestradiol/levonorgestrel during the first six cycles.

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

In some women, withdrawal bleeding may not occur during the COC-free interval. If COCs have been taken according to the instructions in the section "Dosage and administration", pregnancy is unlikely. However, if COCs have been taken irregularly or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be ruled out.

"Levomin® 30" contains 54.72 mg of lactose. Patients with rare hereditary conditions related to galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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

Use during pregnancy or breastfeeding.

Pregnancy

"Levomin® 30" is contraindicated during pregnancy.

If pregnancy occurs during use of "Levomin® 30", treatment must be stopped immediately.

However, epidemiological studies do not indicate an increased risk of congenital malformations in children born to women who used oral contraceptives before pregnancy, nor is there evidence of teratogenic effects from inadvertent use of oral contraceptives in early pregnancy.

The increased risk of VTE during the postpartum period should be considered when resuming use of "Levomin® 30" (see sections "Dosage and administration" and "Special precautions for use").

Breastfeeding

Contraceptive tablets may affect lactation, as they may reduce the quantity and alter the composition of breast milk. Therefore, combined oral contraceptives are not recommended for breastfeeding mothers until weaning. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk and may affect the infant.

Ability to affect reaction speed when driving or operating machinery.

No negative effects of combined oral contraceptives on the ability to drive or operate machinery have been observed.

Dosage and Administration.

Route of administration.

For oral use.

How to take Levomin® 30 tablets.

Tablets should be taken orally every day at approximately the same time, following the order indicated on the blister pack, with a small amount of liquid if necessary. The medication is taken as 1 tablet daily for 21 consecutive days. The next pack should be started after a 7-day tablet-free interval, during which withdrawal bleeding usually occurs. This bleeding typically begins on the
2nd–3rd day after the last tablet and may continue until the start of the next pack.

How to start taking Levomin® 30.

No hormonal contraceptives were used in the previous cycle (last month).

Tablet intake should begin on day 1 of the natural cycle, i.e., the first day of menstrual bleeding. It is also possible to start on days 2–5; however, in this case, an additional contraceptive method (e.g., barrier method) must be used for the first 7 days of taking the medication.

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

It is recommended 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 tablet-free interval (or ring/patch-free period) or after taking the placebo tablet of the previous hormonal contraceptive.

Switching from a progestogen-only method (‘mini-pill’, injections, implants) or intrauterine system (IUS).

Levomin® 30 can be started at any time after discontinuing the ‘mini-pill’ (in the case of an implant or IUS—on the day of removal; in the case of an injection—instead of the next scheduled injection). However, in all cases, it is recommended to use an additional barrier method of contraception for the first 7 days of taking the medication.

After first-trimester abortion.

The medication can be started immediately. In this case, there is no need for additional contraceptive measures.

After childbirth or second-trimester abortion.

In case of breastfeeding, see section "Use during pregnancy or breastfeeding."

It is recommended to start taking the medication on days 21–28 after childbirth or second-trimester abortion. If tablet intake begins later, an additional barrier method of contraception should be used for the first 7 days. However, if sexual intercourse has already occurred, possible pregnancy should be ruled out before starting the COC, or the woman should wait for the onset of the first menstruation.

Missed tablet.

Levomin® 30 contains a very low hormone dose, and therefore, the margin for contraceptive effectiveness in case of a missed tablet is narrow.

If the delay in taking the tablet does not exceed 12 hours, contraceptive protection 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 the delay in taking the tablet exceeds 12 hours, contraceptive protection may be reduced. In this case, two main rules should be observed:

The tablet-free interval must never exceed 7 days.
Adequate suppression of the hypothalamus–pituitary–ovary system is achieved by continuous tablet intake for 7 days.

Accordingly, in daily practice, the following recommendations should be followed:

Week 1.

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. Additionally, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer to the tablet-free interval, the higher the risk of pregnancy.

Week 2.

The woman should take the last missed tablet as soon as possible, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. If tablets were taken correctly during the 7 days before the missed tablet, no additional contraceptive methods are needed. Otherwise, or if more than one tablet was missed, a barrier method of contraception should be used for 7 days.

Week 3.

The risk of reduced effectiveness increases as the 7-day tablet-free interval approaches. However, by following the dosing schedule, a reduction in contraceptive protection can be avoided. If one of the following recommendations is followed, no additional contraceptive methods are required, provided tablets were taken correctly during the 7 days before the missed dose. Otherwise, the first recommendation below should be followed, and additional contraceptive methods used for the next 7 days.

The woman should take the last missed tablet as soon as possible, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. The next pack should be started immediately after finishing the previous one, i.e., without any break. Menstrual-like bleeding is unlikely to occur before finishing tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
Alternatively, the woman may stop taking tablets from the current pack. In this case, the medication-free interval should not exceed 7 days, including the days of missed tablets; tablet intake should then resume with the next pack.

If the expected menstruation does not occur during the first normal tablet-free interval after a missed tablet, pregnancy should be considered.

Gastrointestinal disturbances.

In case of severe gastrointestinal disturbances, incomplete absorption of the active ingredient may occur; additional contraceptive methods should therefore be used.

If vomiting or severe diarrhea occurs within 3–4 hours after taking a tablet, the woman should follow the instructions for a missed tablet. If the woman does not wish to change her usual tablet-taking schedule, she should take an additional tablet(s) from another pack.

Changing or delaying menstruation.

To delay menstruation, continue taking tablets from a new pack without a break. The duration of intake may be extended up to the end of the second pack if desired. Breakthrough bleeding or spotting may occur. Normal use of Levomin® 30 should be resumed after a 7-day tablet-free interval.

If a woman wishes to shift the timing of menstruation to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. The shorter the interval, the more likely the absence of menstrual-like bleeding and the occurrence of breakthrough bleeding or spotting during intake of tablets from the second pack (as with menstruation delay).

Children.

The medication is not intended for use in children. It may be prescribed by a physician only after a regular menstrual cycle has been established.

Overdose.

There are no reports of serious adverse effects from overdose. Symptoms of overdose may include nausea, vomiting, and slight vaginal bleeding in young girls.

Treatment. No specific antidote exists; treatment is symptomatic.

Side effects

Among the most common side effects associated with the use of ethinylestradiol/levonorgestrel are headache (including migraine), vaginal bleeding, and intermenstrual bleeding.

Other side effects reported during the use of combined oral contraceptives, including «Levomin® 30», are:

Organ system	Common (> 1/100 — < 1/10)	Uncommon (> 1/1000 — < 1/100)	Rare (< 1/1000)	Frequency not known (cannot be estimated from available data)
Eye disorders			Intolerance to contact lenses
Gastrointestinal disorders	Nausea, abdominal pain	Vomiting, diarrhoea
Hepatobiliary disorders				Elevated transaminase levels
Immune system disorders		Hypersensitivity		Exacerbation of symptoms of hereditary and acquired angioedema
Metabolism and nutrition disorders		Fluid retention
Nervous system disorders	Headache	Migraine
Psychiatric disorders	Depressed mood, mood swings	Decreased libido	Increased libido
Reproductive system and breast disorders	Swollen and tender breasts	Swelling of the breasts	Galactorrhea, vaginal discharge
Skin and subcutaneous tissue disorders	Acne	Rash, urticaria	Nodular erythema, polymorphic erythema
Vascular disorders			Thromboembolism (VTE), arterial thromboembolism (ATE)
Investigations	Weight increase		Weight decrease

Regarding the increased risk of arterial and venous thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism, see section "Special precautions".

Women using COCs may experience serious adverse effects described in the section "Special precautions":

venous thromboembolic disorders;
arterial thromboembolic disorders;
cervical cancer;
hypertension;
hypertriglyceridemia;
peripheral insulin resistance and glucose tolerance;
liver tumors;
impaired liver function;
chloasma, Crohn’s disease, ulcerative colitis;
epilepsy;
migraine;
endometriosis, uterine fibroids;
porphyria;
systemic lupus erythematosus;
herpes gestationis;
Sydenham's chorea;
hemolytic-uremic syndrome;
cholestatic jaundice;
otosclerosis.

Among women taking COCs, the incidence of breast cancer is slightly increased. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases of breast cancer is minimal compared to the baseline risk of breast cancer in the general population. A causal relationship with COC use has not been established. More detailed information is provided in the sections "Contraindications" and "Special precautions".

Post-marketing data

Based on results from five studies comparing the risk of breast cancer in women who have ever used or are currently using COCs versus those who have never used COCs, no association between COC use and the risk of breast cancer was found, with effect estimates ranging from 0.90 to 1.12 (see figure).

Figure. Relevant studies on the risk of breast cancer associated with the use of combined oral contraceptives

In three studies, the risk of breast cancer was compared between women currently using or who recently used COCs (<6 months since last use) and those who have never used COCs (see figure). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies also observed an increased risk of breast cancer with prolonged current use, with relative risk ranging from 1.03 for less than one year of COC use to approximately 1.4 for more than 8–10 years of use.

Suspected adverse reactions reporting

Reporting of suspected adverse reactions following drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report all suspected adverse reactions.

Shelf life. 3 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Keep out of reach of children.

Store in the original packaging at a temperature not exceeding 30°C.

Packaging. 21 tablets per blister. 1, 3, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

mibe GmbH & Co. KG Arzneimittel.

Manufacturer's name and address.

Muenchener Strasse 15, Brehna, Saxony-Anhalt, 06796, Germany.