Leveret mini

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVERET MINI (LEVERETT MINI)

Composition:

Active substances: levonorgestrel, ethinylestradiol;

1 tablet contains 0.1 mg levonorgestrel and 0.02 mg ethinylestradiol;

Excipients: anhydrous lactose, povidone K-30, magnesium stearate;

Film coating contains: polyvinyl alcohol, talc (E 553b), titanium dioxide (E 171), macrogol/PEG 3350, carmine red aluminum (E 129), lecithin (E 322), iron oxide red (E 172), aluminum blue dye (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round tablets with pink film coating.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use.

ATC code: G03A A07.

Pharmacological properties.

Pharmacodynamics.

The contraceptive effect of a combined oral contraceptive (COC) is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical mucus.

Pharmacokinetics.

Ethinylestradiol

Absorption. Ethinylestradiol is rapidly and almost completely absorbed; maximum serum concentration (C_max) is reached within 1.5 hours. After presystemic conjugation and first-pass metabolism, absolute bioavailability is approximately 60%. The area under the curve (AUC) and C_max may slightly increase over time.

Distribution. Ethinylestradiol is 98% bound to plasma proteins, primarily to albumins.

Metabolism. Ethinylestradiol undergoes presystemic conjugation. It passes through the intestinal wall (first phase of metabolism) and enters the liver, where conjugation occurs (second phase of metabolism). The most important metabolites of the first phase are 2-OH-ethinylestradiol and 2-methoxyethinylestradiol. Both ethinylestradiol and first-phase metabolites are excreted as conjugates (sulfates and glucuronides) into bile and enter the enterohepatic circulation.

Elimination. Ethinylestradiol is eliminated from plasma with an average half-life of 29 hours (range 26–33 hours); plasma clearance ranges from 10 to 30 L/hour. Elimination of ethinylestradiol conjugates and its metabolites occurs via urine and feces in a ratio of 1:1.

Levonorgestrel

Absorption. When administered orally, levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is nearly 100% due to the absence of significant first-pass metabolism.

Distribution. The majority of levonorgestrel is bound to plasma proteins, primarily to albumin and sex hormone-binding globulin.

Metabolism. Metabolism mainly involves reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most circulating metabolites in blood are sulfates of 3α,5β-tetrahydrolevonorgestrel. Drug excretion occurs primarily in the form of glucuronides. A certain amount of unchanged levonorgestrel also circulates as the 17β-sulfate. Metabolic clearance shows individual variability, which may partially explain the significant differences in levonorgestrel concentrations observed among patients.

Elimination. The elimination half-life of levonorgestrel shows individual variability and is approximately 36 hours under steady-state conditions. Levonorgestrel is excreted in urine (40–68%) and feces (16–48%) in the form of metabolites (sulfate and glucuronide conjugates).

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

• Current or past history of venous thrombosis (e.g., deep vein thrombosis, pulmonary embolism);
• Current or past history of arterial thrombosis (e.g., myocardial infarction) or prodromal conditions (e.g., angina pectoris or transient ischemic attack);
• Current or past history of stroke;
• Hereditary or acquired predisposition to venous or arterial thrombosis, e.g., activated protein C resistance, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of serious and multiple risk factors for arterial thrombosis (see section "Special precautions");
• Heart valve disorders, thrombogenic cardiac arrhythmias;
• Diabetes mellitus with micro- or macroangiopathy;
• Severe arterial hypertension;
• Severe dyslipoproteinemia;
• History of migraine with focal neurological symptoms;
• Current or past history of pancreatitis associated with severe hypertriglyceridemia;
• Severe liver disease, current or past, until liver function tests return to normal;
• Presence or history of liver tumors (benign or malignant);
• Diagnosed or suspected hormone-dependent malignant neoplasms (e.g., of genital organs);
• Current or past history of breast cancer that may be hormone-sensitive (see section "Special precautions", subsection "Malignant neoplasms");
• Vaginal bleeding of unknown etiology;
• Hypersensitivity to the active substances (levonorgestrel, ethinylestradiol) or to any excipient of the medicinal product;
• Contraindicated concomitant use of Leveret mini with St John’s wort (Hypericum perforatum) preparations (see section "Interaction with other medicinal products and other forms of interaction").

The medicinal product Leveret mini is contraindicated during 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.

Information regarding any concomitantly used medicinal product should be reviewed to identify potential interactions.

Pharmacodynamic interactions

During clinical studies in patients receiving medicinal products for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased transaminase (ALT) levels more than 5 times the upper limit of normal (ULN) were observed. This occurred more frequently in women receiving medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, in patients receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were observed in women taking ethinylestradiol-containing medicinal products such as CHCs (see section "Contraindications").

Therefore, women using the medicinal product Leveret mini must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the aforementioned combination of medicinal products. Treatment with Leveret mini may be resumed 2 weeks after completion of therapy with the specified combination.

Pharmacokinetic interactions

Effect of other medicinal products on Leveret mini

An interaction with enzyme-inducing medicinal products is possible, which may increase the clearance of sex hormones, leading to changes in the pattern of menstrual bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of treatment. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing agent, enzyme induction may persist for up to 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another method of contraception in addition to the COC. If treatment with an enzyme-inducing agent is initiated during the period of taking the last tablets from the current COC pack, the active tablets from the next COC pack should be started immediately after finishing the active tablets from the previous pack, omitting the placebo tablets.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use another non-hormonal method of contraception.

The following interactions have been reported according to published data.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction), e.g., barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and medicinal products used for the treatment of HIV infection: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and medicinal products containing St John’s wort (Hypericum perforatum).

Substances with variable effects on COC clearance

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

Therefore, information regarding the medical use of the medicinal product for HIV/HCV treatment taken concomitantly should be reviewed to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Effect of Leveret mini on other medicinal products

COCs may affect the metabolism of other drugs, thereby altering plasma and tissue concentrations of active substances—either increasing (e.g., cyclosporine) or decreasing (e.g., lamotrigine).

Troleandomycin

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

Modafinil

There is a risk of reduced contraceptive effect during and in the subsequent cycle after discontinuation of modafinil, as it is a hepatic microsomal enzyme inducer.

Standard oral contraceptives (not low-dose) should be used, or alternative methods of contraception should be employed.

Vemurafenib

There is a risk of decreased estrogen and progestogen concentrations, leading to potential loss of efficacy.

Perampanel

When perampanel is used at a dose equal to or exceeding 12 mg per day, there is a risk of reduced contraceptive effect. Alternative methods of contraception, preferably barrier methods, are recommended.

Rufinamide

Causes moderate reduction in ethinylestradiol concentration. Alternative methods of contraception, preferably barrier methods, are recommended.

Etoricoxib

Concomitant use with etoricoxib results in increased ethinylestradiol concentration.

Laboratory tests

Use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and renal function, as well as plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Changes usually remain within normal laboratory reference ranges.

Special precautions for use.

Special warnings

In the presence of any of the diseases or risk factors listed below, the benefits of combined oral contraceptives (COCs) and the possible risks associated with their use should be carefully evaluated for each individual woman, and the relevant benefits and risks should be discussed with her before she decides to use these medications. If any of these conditions or risk factors first appear, worsen, or recur, the woman should consult her physician. The physician must decide whether to discontinue COC use.

Circulatory disorders

Use of all combined oral contraceptives increases the risk of venous thromboembolic complications (deep vein thrombosis, pulmonary embolism) in women compared to non-users. The risk of these conditions is highest during the first year of COC use. In women using low-dose estrogen oral contraceptives (<0.05 mg ethinylestradiol) and without established risk factors for venous thromboembolism, the incidence of venous thromboembolic complications is approximately 20 cases per 100,000 woman-years (in women using COCs containing levonorgestrel) and 40 cases per 100,000 woman-years (in women using COCs containing desogestrel or gestodene). In women not using COCs, this risk is 5–10 cases per 100,000 woman-years and 60 cases per 100,000 pregnancies. Venous thromboembolism leads to fatal outcomes in 1–2% of cases.

In 1–2% of cases, venous thromboembolism may result in a fatal outcome.

Some epidemiological studies have established an association between COC use and an increased risk of arterial thromboembolic disorders (myocardial infarction, transient ischemic attack).

Rarely, thrombosis in other blood vessels, such as hepatic, mesenteric, renal, cerebral veins, retinal veins, or arteries, has been reported in women using oral contraceptives. There is no consensus on whether these events are related to the use of hormonal contraceptives.

Symptoms of venous or arterial thrombotic/thromboembolic events or stroke may include:

• unusual leg pain and/or swelling of one leg;
• sudden severe chest pain, radiating or non-radiating to the left arm;
• sudden shortness of breath;
• any unusual, severe, prolonged headache;
• sudden partial or complete loss of vision;
• double vision;
• slurred speech or aphasia;
• vertigo;
• loss of consciousness with or without focal epileptic seizure;
• weakness or severe numbness suddenly affecting one side or part of the body;
• motor disturbances;
• "acute abdomen."

The risk of venous thromboembolic complications in women using COCs is increased:

• with age;
• with a family history (venous thromboembolism in a sibling or parent at a relatively young age); if hereditary predisposition is suspected, consultation with a specialist is necessary before using any COC;
• during prolonged immobilization, major surgery, any leg surgery, or serious trauma; in such cases, COC use should be discontinued (in the case of elective surgery — at least 4 weeks prior) and not resumed until at least 2 weeks after full recovery;
• in obesity (body mass index above 30 kg/m²);
• there is no consensus regarding the possible role of varicose veins and superficial thrombophlebitis in the development or progression of venous thrombosis.

The risk of arterial thromboembolic complications or stroke in women using COCs is increased:

• with age;
• with smoking (women aged 35 years and older are strongly advised not to smoke if they wish to use COCs);
• in dyslipoproteinemia;
• in arterial hypertension;
• in migraine;
• in obesity (body mass index above 30 kg/m²);
• with a family history of arterial thromboembolism (arterial thromboembolism in a sibling or parent at a relatively young age); if hereditary predisposition is suspected, the woman should consult a specialist before using an oral contraceptive;
• in heart valve disorders;
• in atrial fibrillation.

The presence of one serious risk factor or multiple risk factors for venous or arterial thromboembolism may also be a contraindication. The potential need for anticoagulant therapy should also be considered. Women using COCs should consult a physician if symptoms of thrombosis occur. In suspected or confirmed thrombosis, COC use should be discontinued. Alternative contraception should also be initiated due to the teratogenicity of anticoagulant therapy (coumarins).

In the postpartum period, the increased risk of venous thromboembolism should be considered (see section "Use during pregnancy or breastfeeding").

Other conditions associated with adverse cardiovascular side effects include: diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), and sickle cell anemia.

An increase in frequency or severity of migraine during COC use (which may be a prodromal or cerebrovascular event) may necessitate immediate discontinuation of COC use.

Tumors

Some epidemiological studies have reported an increased risk of cervical cancer in women who have used COCs for a long time (>5 years), although this finding remains controversial, as it is not fully established to what extent study results account for confounding risk factors such as sexual behavior and human papillomavirus (HPV) infection.

A meta-analysis of data from 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using COCs. This increased risk gradually decreases over 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among women currently or recently using COCs is small compared to the overall risk of breast cancer. Causal relationships have not been demonstrated in these studies.

The increased risk may be related to earlier diagnosis of breast cancer in women using COCs, the biological effects of COCs, or a combination of both factors.

Breast cancer is diagnosed at a slightly earlier stage in women using oral contraceptives compared to women who have not used COCs.

Rarely, benign (adenoma, focal nodular hyperplasia) and even more rarely malignant liver tumors have been observed in women using COCs. In individual cases, these tumors may lead to life-threatening intra-abdominal hemorrhage. The possibility of a liver tumor should be considered in the differential diagnosis when women using COCs develop severe upper abdominal pain, hepatomegaly, or signs of intra-abdominal hemorrhage.

Malignant neoplasms (warnings issued by the Center for Drug Evaluation and Research (CDER) FDA).

Breast cancer

The medicinal product Leveret mini 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 consistently demonstrated an association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not show a link between current or past use of COCs and breast cancer risk. However, some studies report a slight increase in breast cancer risk among current or recent users (within 6 months of last use) and among those currently taking COCs (see section "Adverse reactions," subsection "Post-marketing data").

Other conditions

Hypertriglyceridemia

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

Arterial hypertension

A slight increase in blood pressure has been reported in many women using COCs, although clinically significant elevations are rare. Immediate discontinuation of COC use is justified only in rare cases. If blood pressure levels continue to rise during COC use in women with existing hypertension, or if significant hypertension does not respond adequately to antihypertensive treatment, COC use should be discontinued. In some cases, COC use may be resumed if normal blood pressure values can be achieved with antihypertensive therapy.

Angioedema

Exogenous estrogens may trigger or exacerbate symptoms of angioedema in women with hereditary angioedema.

Liver disease

In acute or chronic liver dysfunction, consideration should be given to discontinuing COC use until liver function tests return to normal.

Glucose tolerance/diabetes mellitus

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to alter the therapeutic regimen in women with diabetes who are taking low-dose COCs (containing <0.05 mg ethinylestradiol). However, women with diabetes should be under close medical supervision throughout the period of COC use.

Other conditions

Depressed mood and depression are common 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 be informed of the need to consult a physician if mood changes or symptoms of depression occur, even shortly after starting treatment.

COC use should be discontinued in case of recurrence of cholestatic jaundice that first occurred during pregnancy or previous use of sex steroid hormones.

Cases of development or worsening of the following conditions have been reported during pregnancy and COC use (a causal link with COC use has not been established): jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

Exacerbation of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis has been observed during COC use.

Chloasma may occasionally occur, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation while using COCs.

Special attention should be paid to patients with hyperprolactinemia.

Medical examination/consultation

Before initiating or resuming use of Leveret mini, a thorough patient history, including family history, should be taken and pregnancy should be ruled out. Blood pressure should be measured and a general physical examination performed, taking into account contraindications (see section "Contraindications") and special warnings (see section "Special precautions for use"). The instructions for medical use should be carefully read and the recommendations followed. The frequency and nature of examinations should be based on current medical practice guidelines, considering the individual characteristics of each woman.

The patient should also be informed that oral contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Reduced effectiveness

The effectiveness of COCs may be reduced, for example, in case of missed tablet intake (see section "Dosage and administration"), vomiting, diarrhea (see section "Dosage and administration"), or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Reduced cycle control

As with all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, particularly during the first few months of use; therefore, evaluation of any irregular bleeding should only be performed after completion of the adaptation period, which is approximately three cycles.

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

In some women, menstruation may not occur during the usual COC-free interval. If COCs have been used according to the "Dosage and administration" section, pregnancy is unlikely. However, if the instructions in the "Dosage and administration" section prior to the first missed withdrawal bleed were not followed, or if menstruation is absent for two consecutive cycles, pregnancy should be excluded before continuing COC use.

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

Excipients

The medicinal product Leveret mini contains anhydrous lactose. Women with rare hereditary disorders of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product Leveret mini is contraindicated during pregnancy.

If a woman becomes pregnant while taking the tablets, further use should be discontinued immediately.

Results from numerous epidemiological studies have not shown an increased risk of congenital malformations in children born to women who used COCs prior to pregnancy, nor teratogenic effects from inadvertent use of contraceptive tablets in early pregnancy.

Period of breastfeeding. Oral hormonal contraceptives may affect lactation, as they may reduce the quantity and alter the composition of breast milk. Therefore, COC use is not recommended until breastfeeding is discontinued. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk. These amounts may affect the infant. If a woman wishes to breastfeed, alternative contraceptive methods should be offered.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the influence on the ability to drive vehicles or operate machinery have not been conducted. No effect on the ability to drive vehicles or operate machinery has been observed in women using COCs.

Dosage and Administration.

Administration method. Take orally as directed on the package, approximately at the same time each day, one tablet daily, swallowed with a small amount of liquid.

For women who have not previously used a contraceptive method, the first tablet should be taken on the first day of menstruation and one tablet taken daily for 21 days (preferably at the same time each day). Starting on days 2–7 of the cycle is also possible; however, during the first cycle, it is recommended to additionally use a non-hormonal contraceptive method (such as condoms or spermicides) for the first 7 days of tablet intake.

After completing the 21-day course, a 7-day break is taken, during which withdrawal bleeding usually occurs (typically on day 2 or 3). The next pack should be started after the 7-day break, even if bleeding has not yet stopped.

This regimen may be continued as long as pregnancy prevention is desired. With regular use of the drug Leveret mini, the contraceptive effect persists throughout the 7-day break.

Switching from another combined hormonal contraceptive (oral tablets, vaginal ring, or transdermal patch): Begin taking Leveret mini the day after taking the last active tablet (or removing the vaginal ring or transdermal patch), but no later than the day after the tablet-free interval (placebo tablets, removal of vaginal ring or transdermal patch) of the previous contraceptive method.

Switching to Leveret mini from a progestogen-only contraceptive (low-dose oral contraceptive, injection, implant, or intrauterine device): Switching from a low-dose oral contraceptive can occur on any day of the menstrual cycle (from an implant or intrauterine device—on the day of removal; from an injection—on the day the next injection would have been due). In this case, it is recommended to additionally use a barrier contraceptive method for the first 7 days of tablet intake.

After first-trimester abortion: Begin taking the drug immediately on the same day as the procedure. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester abortion: Begin taking the drug from day 21 to 28 after childbirth or second-trimester abortion, due to the risk of thromboembolic disorders during the postpartum period. If a woman starts taking the tablets later, she should additionally use barrier contraceptive methods for the first 7 days of drug use. However, if sexual intercourse has already occurred, possible pregnancy should be ruled out before starting the combined contraceptive, or wait for the first menstrual period.

Lactation: Information on use during lactation is provided in the section "Use during pregnancy or breastfeeding."

Missed tablet

If less than 12 hours have passed since the scheduled time of the missed tablet, contraceptive protection is not reduced. The woman should take the missed tablet as soon as she remembers, and take the next tablet at the usual time.

If more than 12 hours have passed since the scheduled time of the missed tablet, contraceptive protection may be reduced. In this case, two main rules should be followed:

1. The interval between tablet intakes must never exceed 7 days.
2. To achieve adequate suppression of the hypothalamic-pituitary-ovarian system, tablets must be taken continuously for 7 days.

Accordingly, the following practical recommendations should be followed:

Week 1

The most recently missed tablet should be taken as soon as the woman remembers, even if this means taking two tablets at the same time. Subsequent tablets should be taken at the usual time. Additionally, barrier contraceptive methods (e.g., condoms) 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 the missed dose is to the 7-day drug-free interval, the higher the risk of pregnancy.

Week 2

The most recently missed tablet should be taken as soon as the woman remembers, even if two tablets must be taken simultaneously. Subsequent tablets should be taken at the usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, additional contraceptive methods are not required. Otherwise, if more than one tablet has been missed, a barrier contraceptive method should be additionally used for 7 days.

Week 3

The risk of significantly reduced contraceptive protection is inevitable due to the upcoming 7-day drug-free interval. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided, provided tablets were taken correctly for the 7 days before the missed dose. Otherwise, the first of the following options should be followed, and additional contraceptive methods used for the next 7 days.

1. The most recently missed tablet should be taken immediately upon remembering, even if two tablets must be taken at the same time. Subsequent tablets should be taken at the usual time. The patient should start the next pack the day after taking the last tablet from the current pack, i.e., there should be no break between packs. Withdrawal bleeding is unlikely to occur before finishing the tablets from the second pack, although spotting or breakthrough bleeding may occur.
2. The patient may also be advised to stop taking tablets from the current pack. In this case, the patient should take a break in drug use of up to 7 days, including the days when tablets were missed, and then start taking tablets from the next pack.

If a woman missed tablets and does not experience withdrawal bleeding during the first usual drug-free interval, pregnancy should be considered.

Gastrointestinal disorders

In cases of vomiting or diarrhea, drug efficacy may be reduced due to incomplete absorption of active ingredients.

If vomiting occurs within 3–4 hours after tablet intake, the woman should follow the recommendations described in the section "Missed tablets."

If diarrhea occurs and the woman does not wish to change her usual tablet-taking schedule, she should take an additional tablet daily from another pack for as many days as necessary.

Delaying or accelerating the menstrual cycle

To delay menstrual bleeding, start the next pack of Leveret mini the day after finishing the current pack, without a break. The duration of menstrual delay depends on the number of tablets taken from the second pack. Breakthrough bleeding or spotting may occur during this period. Regular use of Leveret mini can be resumed after the usual 7-day break.

To accelerate the onset of menstrual bleeding, shorten the 7-day drug-free interval by the desired number of days. The shorter the drug-free interval, the less likely withdrawal bleeding will occur, and breakthrough or spotting bleeding may occur during intake of tablets from the next pack. It is important to emphasize that the drug-free interval cannot be extended.

Children

The drug is not intended for use in children.

Overdose

Symptoms of oral contraceptive overdose have been reported in adults, adolescents, and children up to 12 years of age.

Symptoms that may occur in overdose include: nausea, vomiting, breast tenderness, dizziness, abdominal pain, somnolence/weakness, and vaginal bleeding in young girls.

There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

Adverse reactions reported with concomitant use of ethinylestradiol and levonorgestrel are listed below.

The most serious adverse reactions, such as venous and arterial thromboembolism, cervical cancer, breast cancer, and malignant liver tumors, are described in the section "Special precautions for use".

In women who used COCs, the following serious adverse reactions have been reported, as described in the section "Special Warnings and Precautions for Use":

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Arterial hypertension;
• Liver tumors;
• Crohn’s disease, ulcerative colitis, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, hemolytic uremic syndrome, cholestatic jaundice.

The frequency of breast cancer diagnosis among women taking COCs is slightly increased. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer in women who are currently using or have recently used COCs is small relative to the overall risk of breast cancer. The relationship to COC use is unknown. For detailed information, see sections "Contraindications" and "Special Warnings and Precautions for Use".

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

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives.

Post-marketing data (Warning issued by the Center for Drug Evaluation and Research (CDER) FDA).

Five studies comparing the risk of breast cancer between women who had ever used (currently or in the past) COCs and women who had never used COCs reported no association between any use of COCs and the risk of breast cancer, with effect estimates ranging from 0.90 to 1.12.

In three studies, the risk of breast cancer was compared between women currently using COCs, those who recently used COCs (<6 months since last use), and those who had never used COCs. 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 observed an increased risk of breast cancer with current long-term 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 COC use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep the medicinal product out of the reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Laboratorios León Farma, S.A.

Manufacturer's address and place of business.

Ctra. La Valldina s/n, Polígono Industrial Navatejera, Villacambres, 24193 León, Spain.