Leya^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Cyndea Pharma S.L. (Spain)

ATC Code

G03AA12 (Drospirenone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Dosage Form

Leya®

Film-coated tablets, 3 mg + 0.02 mg: 28, 56, 84, or 168 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink in color, round, biconvex (24 pcs. in a blister).

Excipients: lactose monohydrate – 68.18 mg, potassium polacrilin – 4 mg, povidone K30 – 4 mg, magnesium stearate – 0.8 mg.

Film coating composition Opadry II pink 85F34048 (macrogol 3350 – 0.404 mg, titanium dioxide – 0.496 mg, polyvinyl alcohol – 0.8 mg, talc – 0.296 mg, iron oxide red dye – 0.0036 mg, iron oxide yellow dye – 0.0004 mg) – 2 mg.

Film-coated tablets (placebo) white in color, round, biconvex (4 pcs. in a blister).

Excipients: lactose monohydrate – 73.4 mg, potassium polacrilin – 1.6 mg, povidone K30 – 4 mg, colloidal silicon dioxide – 0.2 mg, magnesium stearate – 0.8 mg.

Film coating composition Opadry II white 85F18422 (macrogol 3350 – 0.8 mg, titanium dioxide – 0.5 mg, polyvinyl alcohol – 0.404 mg, talc – 0.296 mg) – 2 mg.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (2) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.
28 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Combined hormonal contraceptive with antimineralocorticoid and antiandrogenic action

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

Monophasic combined oral contraceptive (COC), containing Ethinylestradiol and the progestogen Drospirenone.

The contraceptive effect of the drug Leya^® is based on the interaction of various factors, the most important of which are suppression of ovulation and changes in the properties of cervical secretion, making it less permeable to spermatozoa. In therapeutic doses, Drospirenone also has antiandrogenic and moderate antimineralocorticoid properties, giving drospirenone a pharmacological profile similar to that of natural progesterone. Drospirenone helps reduce symptoms of acne (pimples), oily skin and hair, prevents weight gain and the appearance of edema associated with estrogen-induced fluid retention, which ensures very good tolerability of the drug Leya^®. A positive effect and clinical efficacy of drospirenone in alleviating symptoms of severe premenstrual syndrome (PMS), such as pronounced psychoemotional disorders, breast tenderness, headache, muscle and joint pain, weight gain and other symptoms associated with the menstrual cycle, have been shown. In combination with ethinylestradiol, Drospirenone demonstrates a favorable effect on the lipid profile, characterized by an increase in HDL content in blood plasma.

In women taking COCs, the menstrual cycle becomes more regular, painful menstruation is less common, bleeding intensity decreases, which reduces the risk of anemia. Furthermore, according to epidemiological studies, the use of COCs reduces the risk of endometrial cancer and ovarian cancer.

Pharmacokinetics

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed. After a single oral dose, C_max in plasma, approximately 38 ng/ml, is reached in about 1-2 hours. Bioavailability is 76-85%. Food intake does not affect the bioavailability of drospirenone.

Distribution

After oral administration, the plasma concentration of drospirenone decreases biphasically, with a T_1/2 in the second phase of 31 hours. Drospirenone binds to plasma albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3-5% of the total plasma concentration of the substance is present as free steroid. Ethinylestradiol-induced increase in SHBG does not affect the binding of drospirenone to plasma proteins. The mean apparent V_d is 3.7±1.2 L/kg.

Steady-state concentration. During cyclic treatment, C_ss^max of drospirenone in plasma is reached after 8 days of drug administration and is approximately 70 ng/ml. An increase in drospirenone plasma concentration by about 2-3 times (due to accumulation) was observed, which was determined by the ratio of T_1/2 in the terminal phase and the dosing interval. Further increase in plasma concentration of drospirenone is noted between the 1st and 6th cycles of administration, after which no increase in concentration is observed.

Metabolism

After oral administration, Drospirenone is extensively metabolized. Most metabolites in plasma are represented by acidic forms of drospirenone.

Excretion

The metabolic clearance rate of drospirenone in plasma is 1.5±0.2 ml/min/kg. Drospirenone is excreted unchanged only in trace amounts. Drospirenone metabolites are excreted via the intestine and kidneys in a ratio of approximately 1.2:1.4. T_1/2 for metabolite excretion is approximately 24 hours.

Pharmacokinetics in special clinical cases

Patients with renal impairment. C_ss of drospirenone in plasma in women with mild renal impairment (CrCl 50-80 ml/min) were comparable to those in women with normal renal function (CrCl > 80 ml/min). In women with moderate renal impairment (CrCl 30-50 ml/min), the plasma concentration of drospirenone was on average 37% higher than in women with normal renal function. Treatment with drospirenone was well tolerated in all groups. Drospirenone intake did not have a clinically significant effect on plasma potassium concentration. Pharmacokinetics in severe renal impairment has not been studied.

Patients with hepatic impairment

Drospirenone is well tolerated by patients with mild or moderate hepatic impairment (Child-Pugh class B). Pharmacokinetics in severe hepatic impairment has not been studied.

Ethinylestradiol

Absorption

After oral administration, Ethinylestradiol is rapidly and completely absorbed. The peak plasma concentration after a single oral dose is reached in 1-2 hours and is about 33 pg/ml. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant food intake reduces the bioavailability of ethinylestradiol in about 25% of the subjects, whereas no such changes were noted in other patients.

Distribution

The plasma concentration of ethinylestradiol decreases biphasically; T_1/2 is approximately 24 hours. Ethinylestradiol is largely and non-specifically bound to plasma albumin (approximately 98.5%) and causes an increase in SHBG concentrations in plasma. The mean apparent V_d is about 5 L/kg.

Metabolism

Ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and in the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation, producing various hydroxylated and methylated metabolites, present both as free metabolites and as conjugates with glucuronic and sulfuric acids. Ethinylestradiol is completely metabolized; the metabolic clearance rate is about 5 ml/min/kg.

Excretion

Ethinylestradiol is practically not excreted unchanged. Ethinylestradiol metabolites are excreted via the kidneys and intestine in a ratio of 4:6; T_1/2 is approximately 1 day.

Steady-state concentration

Steady-state concentration is reached during the second half of the drug administration cycle, and the plasma concentration of ethinylestradiol increases by approximately 1.4-2.1 times.

Preclinical safety data

Preclinical data obtained from standard studies on toxicity after repeated dose administration, as well as genotoxicity, carcinogenic potential, and reproductive toxicity, do not indicate a special risk for humans. However, it should be remembered that sex hormones can promote the growth of some hormone-dependent tissues and tumors.

Indications

• Contraception;
• Contraception and treatment of moderate acne (acne vulgaris);
• Contraception and treatment of severe premenstrual syndrome (PMS).

ICD codes

Dosage Regimen

The drug Leya^® is intended for oral administration daily for 28 days without breaks, approximately at the same time, with a small amount of water, in the order indicated on the blister pack. Taking tablets from a new pack starts on the day after taking the last tablet from the previous pack.

How to take the drug Leya^®

If no hormonal contraceptives were used in the previous month

Administration of the drug Leya^® starts on the first day of the menstrual cycle (i.e., on the first day of menstrual bleeding). It is permissible to start on days 2-5 of the menstrual cycle, but in this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking tablets from the new pack.

Withdrawal bleeding usually begins on the 2nd-3rd day after starting the inactive tablets and may not have ended before starting the tablets from the new pack.

When switching from other combined oral contraceptives (COC, vaginal ring or transdermal patch)

It is preferable to start taking the drug Leya^® on the day after taking the last active tablet from the previous pack, but in no case later than the next day after the usual 7-day break (for preparations containing 21 active tablets) or after taking the last inactive tablet (for preparations containing 28 tablets per pack). Taking the drug Leya^® should be started on the day of removal of the vaginal ring or contraceptive patch, but no later than the day when a new ring should be inserted or a new patch applied.

When switching from contraceptives containing only progestogens (“mini-pill”, injectable forms, implant or intrauterine contraceptive)

A woman can switch from the “mini-pill” to taking the drug Leya^® on any day (without a break), from an implant or an intrauterine therapeutic system releasing a progestogen – on the day of its removal, from an injectable contraceptive – on the day when the next injection is due. In all cases, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets.

After an abortion in the first trimester of pregnancy

A woman can start taking the drug Leya^® from the first day after the abortion. If this condition is met, the woman does not need additional contraceptive measures.

After childbirth or abortion in the second trimester of pregnancy

It is recommended to start taking the drug Leya^® on day 21-28 after childbirth, in the absence of breastfeeding, or abortion in the second trimester of pregnancy. If administration is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if the woman has already been sexually active, pregnancy must be excluded before starting Leya^®.

Taking missed tablets

Missing inactive tablets can be ignored. However, they should be discarded so as not to accidentally prolong the period of taking inactive tablets. The following recommendations refer only to missing active tablets

• If the delay in taking the drug is less than 24 hours, contraceptive protection is not reduced. The woman should take the missed tablet as soon as possible, and take the next ones at the usual time.
• If the delay in taking the tablets is more than 24 hours, contraceptive protection may be reduced. The more tablets are missed, and the closer the missed tablets are to the phase of taking inactive tablets, the higher the likelihood of pregnancy.

In this case, the following basic rules can be followed:

• Drug administration should never be interrupted for more than 7 days (the recommended interval for taking inactive tablets is 4 days);
• 7 days of continuous tablet intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Thus, if the delay in taking active tablets is more than 24 hours, the following can be recommended:

From day 1 to day 7

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She continues to take the next tablets at the usual time. Additionally, during the next 7 days, it is necessary to additionally use a barrier method of contraception (e.g., a condom). If sexual intercourse occurred within 7 days before missing the tablet, the possibility of pregnancy should be considered.

From day 8 to day 14

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. The next tablets should be taken at the usual time. Provided that the woman took the tablets correctly for 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, and also if two or more tablets are missed, it is necessary to additionally use barrier methods of contraception (e.g., a condom) for 7 days.

From day 15 to day 24

The risk of reduced reliability is inevitable due to the approaching phase of taking inactive tablets. The woman must strictly adhere to one of the following two options. In this case, if all tablets in the 7 days preceding the first missed tablet were taken correctly, there is no need to use additional contraceptive methods. Otherwise, she must use the first of the following schemes and additionally use a barrier method of contraception (e.g., a condom) for 7 days.

Option 1: the woman should take the last missed tablet as soon as possible, as soon as she remembers (even if this means taking two tablets at the same time). The next tablets are taken at the usual time until the active tablets in the pack are finished. The four inactive tablets should be discarded and the tablets from the next pack should be started immediately. Withdrawal bleeding is unlikely until the active tablets in the second pack are finished, but spotting and breakthrough bleeding may occur during tablet intake.

Option 2: the woman can also interrupt taking tablets from the current pack. Then she should take a break of no more than 4 days, including the days of missing tablets, and then start taking tablets from a new pack. If a woman missed active tablets and withdrawal bleeding did not occur during the intake of inactive tablets, pregnancy must be excluded.

Recommendations for gastrointestinal disorders

In severe gastrointestinal disorders, absorption of the drug may be incomplete, so additional contraceptive measures should be taken.

If vomiting occurs within 4 hours after taking an active tablet, one should be guided by the recommendations for missed tablets. If the woman does not want to change her usual regimen and shift the start of menstruation to another day of the week, an additional active tablet should be taken from another pack.

Changing the day of onset of menstrual-like bleeding

To delay the onset of menstrual-like bleeding, the woman should continue taking tablets from the next pack, skipping the inactive tablets from the current pack. Thus, the cycle can be extended, as desired, for any period until the active tablets from the second pack are finished. While taking tablets from the second pack, the woman may experience spotting or breakthrough uterine bleeding. Regular intake of the drug Leya^® is resumed after the end of the phase of taking inactive tablets.

To shift the day of onset of menstrual-like bleeding to another day of the week, the woman should shorten the next phase of taking inactive tablets by the desired number of days. The shorter the interval, the higher the risk that she will not have withdrawal bleeding and will subsequently have spotting and breakthrough bleeding while taking the second pack (just as in the case when she would like to delay the onset of menstrual-like bleeding).

How to delay withdrawal bleeding

To delay the onset of menstruation, the woman should proceed to taking tablets from a new pack of the drug Leya^®, skipping the placebo tablets. Such cycle extension can be continued until the active tablets of the second pack are finished. During this extension, the woman may experience breakthrough bleeding or spotting. Subsequently, regular intake of the drug Leya^® should be resumed after the usual tablet-free interval, which is 7 days.

To shift the onset of menstruation to another day, more suitable for the woman’s usual schedule, the second phase of taking placebo tablets can be shortened by as many days as needed. The shorter this phase, the higher the risk that withdrawal bleeding will not develop, and that breakthrough bleeding or spotting will appear while taking tablets from the second pack (as well as when delaying menstruation).

Special Patient Categories

Children and adolescents: the drug Leya^® is indicated only after menarche. Available data do not suggest a dose adjustment in this patient group.

Elderly patients not applicable. The drug Leya^® is not indicated after menopause.

The drug Leya^® is contraindicated in women with severe liver diseases until liver function tests return to normal.

The drug Leya^® is contraindicated in women with severe renal impairment or with acute renal failure.

Adverse Reactions

Clinical trial data

The frequency of adverse reactions is presented according to the classification (MedDRA): very common (>10%), common (≥1% <10%), uncommon (≥0.1% <1%), rare (≥0.01% <0.1%), very rare (<0.01%), frequency unknown (cannot be estimated from the available data).

Infections and infestations uncommon – oral candidiasis, vaginal candidiasis, herpes simplex.

Immune system disorders: uncommon – allergic reactions, rare – bronchial asthma; frequency unknown – hypersensitivity reactions.

Blood and lymphatic system disorders rare – anemia, thrombocytopenia.

Psychiatric disorders: common – emotional lability; uncommon – depression, nervousness, sleep disorder; rare – anorgasmia.

Nervous system disorders common – headache; uncommon – paresthesia, dizziness, migraine; rare – tremor.

Eye disorders uncommon – conjunctivitis, dry eye syndrome, visual disturbances.

Ear and labyrinth disorders rare – hearing impairment.

Cardiac disorders uncommon – extrasystoles, tachycardia, pulmonary embolism, increased blood pressure, decreased blood pressure, varicose veins; rare – arterial and venous thromboembolism, syncope.

Respiratory, thoracic and mediastinal disorders pharyngitis.

Gastrointestinal disorders common – nausea; uncommon – vomiting, gastroenteritis, diarrhea; rare – constipation, abdominal pain, abdominal distension.

Hepatobiliary disorders rare – cholecystitis.

Skin and subcutaneous tissue disorders uncommon – pruritus, rash, seborrhea, acne; rare – alopecia, dry skin, eczema, photodermatitis, acneiform dermatitis, hypertrichosis, striae, erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders uncommon – neck pain, pain in extremity, low back pain; muscle cramps.

Renal and urinary disorders uncommon – cystitis.

Reproductive system and breast disorders: common – breast pain, breast tenderness, metrorrhagia, absence of withdrawal bleeding; uncommon – breast neoplasms, galactorrhea, ovarian cyst, hot flush, leukorrhea, vaginal dryness, pelvic pain, abnormal Pap smear, decreased libido, breast enlargement, painful withdrawal bleeding, scanty withdrawal bleeding; rare – fibrocystic breast disease, vaginitis, cervical polyp, cervical neoplasia, endometrial atrophy, heavy withdrawal bleeding, dyspareunia, postcoital bleeding, withdrawal bleeding, uterine enlargement.

Endocrine disorders very rare – changes in glucose tolerance or effect on insulin resistance.

General disorders and administration site conditions common – weight increased; uncommon – increased appetite, weight decreased, anorexia, edema, asthenia, excessive thirst, hyperhidrosis.

Investigations uncommon – hyperkalemia, hyponatremia.

Postmarketing data

The following serious adverse reactions with unknown frequency have been reported in women using COCs: venous thromboembolic complications, arterial thromboembolic complications, increased blood pressure, liver neoplasms.

The association with COC use is not conclusive for the occurrence or worsening of the following conditions: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestations, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice, chloasma.

Acute and chronic liver function disorders may require discontinuation of COC use until markers of liver function return to normal.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

The frequency of diagnosing breast cancer is slightly increased in women who use COCs, although a causal relationship with COC use has not been established.

Contraindications

The use of the drug Leya^® is contraindicated in the presence of any of the conditions listed below; if any of these conditions occurs for the first time during COC treatment, their use should be discontinued immediately.

• Current or history of thrombosis (venous and arterial) and thromboembolism (including deep vein thrombosis, pulmonary embolism, myocardial infarction), cerebrovascular disorders (including history);
• Conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) current or history;
• Hereditary or acquired predisposition to venous or arterial thrombosis, such as resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Current or history of migraine with focal neurological symptoms;
• Multiple or severe risk factors for venous or arterial thrombosis, including complicated heart valve lesions, atrial fibrillation; cerebrovascular or coronary artery disease; uncontrolled arterial hypertension; severe dyslipoproteinemia, diabetes mellitus with vascular complications, major surgery with prolonged immobilization; smoking over the age of 35; obesity with BMI over 30 kg/m²; extensive trauma;
• Hepatic impairment, severe liver diseases (until liver function tests return to normal);
• Liver tumors (benign or malignant), including history;
• Severe renal impairment, acute renal failure;
• Adrenal insufficiency;
• Pancreatitis, including history, if associated with severe hypertriglyceridemia;
• Known hormone-dependent malignant diseases (including of the genital organs or breasts) or suspicion thereof;
• Vaginal bleeding of unknown etiology;
• Pregnancy or suspected pregnancy;
• Breastfeeding period;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (contains lactose monohydrate);
• Hypersensitivity to any component of the drug Leya^®.

With caution

If the patient has any of the conditions/risk factors listed below, the potential risk and expected benefit of using COCs, including the drug Leya^®, should be carefully weighed.

• Risk factors for thrombosis and thromboembolism: smoking, thrombosis (including history), myocardial infarction or cerebrovascular accident at a young age in any first-degree relative; obesity with BMI less than 30 kg/m²; dyslipoproteinemia; controlled arterial hypertension; migraine without focal neurological symptoms; uncomplicated heart valve diseases; cardiac arrhythmias;
• Other diseases in which peripheral circulatory disorders may be noted: diabetes mellitus; systemic lupus erythematosus; hemolytic-uremic syndrome; Crohn’s disease and ulcerative colitis; sickle cell anemia; as well as superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• Liver diseases;
• Diseases that first occurred or worsened during pregnancy or during previous use of sex hormones (e.g., jaundice, cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestations, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

The drug Leya^® is contraindicated for use during pregnancy. If pregnancy occurs while taking the drug Leya^®, it is necessary to discontinue its use immediately. Epidemiological studies have not revealed either an increased risk of birth defects in children born to mothers who took COCs before pregnancy, or a teratogenic effect when COCs were taken inadvertently in early pregnancy.

Available data on the use of the drug Leya^® during pregnancy are too limited and do not allow conclusions to be drawn about its negative impact on pregnancy or on the health of the fetus or newborn.

The drug Leya^® is contraindicated during breastfeeding. COCs may reduce the amount of breast milk and change its quality. A small amount of sex hormones and/or their metabolites may pass into breast milk and may possibly affect the child.

Use in Hepatic Impairment

The drug Leya^® is contraindicated in women with severe liver diseases until liver function tests return to normal.

Use in Renal Impairment

The drug Leya^® is contraindicated in women with severe renal impairment or with acute renal failure.

Pediatric Use

The drug Leya^® is indicated only after menarche. Available data do not suggest a dose adjustment in this patient group.

Geriatric Use

Not applicable. The drug Leya^® is not indicated after menopause.

Special Precautions

If any of the conditions/risk factors listed below are currently present, the potential risk and expected benefit of using COCs should be carefully weighed in each individual case and discussed with the patient before starting the drug. In case of worsening, intensification or first manifestation of any of these conditions or risk factors, the woman should consult her doctor, who may decide to discontinue the drug.

Cardiovascular diseases

Results of epidemiological studies indicate an association between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders) when taking COCs. These diseases are rare.

The risk of developing venous thromboembolism (VTE) is highest in the first year of taking such drugs. An increased risk is present after initial use of COCs or resumption of use of the same or different COCs (after a break in drug use of 4 weeks or more), mainly during the first 3 months.

The overall risk of VTE in patients taking low-dose COCs (< 50 mcg ethinyl estradiol) is 2-3 times higher than in non-pregnant patients who do not take COCs, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth. VTE can be life-threatening or fatal (in 1-2% of cases). Venous thromboembolism, manifesting as deep vein thrombosis, or pulmonary embolism, can occur with the use of any COCs.

Very rarely, thrombosis of other blood vessels occurs with the use of COCs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels. Symptoms of deep vein thrombosis (DVT) include the following: unilateral swelling of the lower limb or along a vein in the lower limb, pain or discomfort only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin on the lower limb.

Symptoms of pulmonary embolism (PE) are as follows: difficult or rapid breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep breathing; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., shortness of breath, cough) are non-specific and may be misinterpreted as signs of other more or less severe conditions (e.g., respiratory tract infection).

Arterial thromboembolism can lead to stroke, vascular occlusion or myocardial infarction.

Symptoms of stroke are as follows: sudden weakness or loss of sensation in the face, arm or leg, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden unilateral or bilateral loss of vision; sudden gait disturbance, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without an epileptic seizure. Other signs of vascular occlusion: sudden pain, swelling and slight blueness of the extremities, “acute abdomen” symptom complex.

Symptoms of myocardial infarction include: pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone; discomfort radiating to the back, jaw, left upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat. Arterial thromboembolism can be life-threatening or fatal.

The risk of developing thrombosis (venous and/or arterial) and thromboembolism increases

• With age;
• In smokers (with increasing number of cigarettes or increasing age the risk increases, especially in women over 35 years old);

In the presence of

• Obesity (BMI more than 30 kg/m²);
• Dyslipoproteinemia;
• Arterial hypertension;
• Migraine;
• Heart valve diseases;
• Atrial fibrillation;
• Family history (e.g., venous or arterial thromboembolism ever in close relatives or parents at a relatively young age). In case of hereditary or acquired predisposition, a woman should be examined by an appropriate specialist to decide on the possibility of taking COCs;
• Prolonged immobilization, major surgery, any surgery on the lower limbs, pelvic area, neurosurgical operations or extensive trauma. In these cases, COC use should be discontinued (in case of planned surgery, at least four weeks before it) and not resumed until two weeks after the end of immobilization. It should be taken into account that temporary immobilization (e.g., air travel lasting more than 4 hours) is also a risk factor for venous thromboembolism.

The risk of developing thrombosis and thromboembolism when several high-risk factors are combined is mutually reinforcing.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial. The increased risk of thromboembolism in the postpartum period should be taken into account.

Peripheral circulatory disorders may also be noted in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine during the use of COCs (which may precede cerebrovascular disorders) is grounds for immediate discontinuation of these drugs. Biochemical parameters indicating a hereditary or acquired predisposition to venous or arterial thrombosis include the following: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the corresponding condition may reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose oral contraceptives (< 0.05 mg ethinyl estradiol).

According to some data, drugs containing Drospirenone have a higher risk of developing thromboembolic complications compared to drugs containing levonorgestrel, norgestimate or norethindrone.

Tumors

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of cervical cancer with long-term use of COCs. The association with COC use has not been proven. Controversy remains as to the extent to which these findings are related to cervical pathology screening or to sexual behavior characteristics (less frequent use of barrier contraceptive methods).

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking or recently taking COCs is small relative to the overall risk of this disease. The observed increase in risk may be a consequence of earlier diagnosis of breast cancer in women using COCs, the biological effect of oral contraceptives, or a combination of both factors. In women who have used COCs, earlier stages of breast cancer are detected than in women who have never used them.

In rare cases, the development of benign, and in extremely rare cases, malignant liver tumors has been observed during the use of COCs, which in some cases led to life-threatening intra-abdominal bleeding. This should be taken into account when conducting a differential diagnosis in case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding. Tumors can be life-threatening or fatal.

Other conditions

Clinical studies have shown no effect of drospirenone on plasma potassium concentration in patients with mild to moderate renal impairment. There is a theoretical risk of developing hyperkalemia in patients with impaired renal function with an initial potassium concentration at the upper limit of normal, simultaneously taking drugs that lead to potassium retention in the body. However, in women at increased risk of developing hyperkalemia, it is recommended to determine plasma potassium concentration during the first cycle of taking the drug Leya^®.

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may be increased while taking COCs.

Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. However, if a persistent, clinically significant increase in blood pressure develops during COC use, these drugs should be discontinued and treatment for arterial hypertension should be initiated. COC use may be continued if normal blood pressure values are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and when taking COCs, but their association with COC use has not been proven: jaundice and/or itching associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestations; hearing loss associated with otosclerosis. Cases of Crohn’s disease and ulcerative colitis during the use of COCs have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver function disorders may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice that first developed during a previous pregnancy or previous use of sex hormones requires discontinuation of COCs. Although COCs may affect insulin resistance and glucose tolerance, there is generally no need to adjust the dose of hypoglycemic drugs in patients with diabetes using low-dose COCs (<0.05 mg ethinyl estradiol). However, women with diabetes should be under close supervision by an endocrinologist while taking COCs. Chloasma may sometimes develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma while taking COCs should avoid prolonged exposure to the sun and UV radiation.

Cases of depression and epilepsy during the use of COCs have been described.

Laboratory Tests

The use of COCs may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, and adrenal function, the level of transport proteins in plasma, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. The changes usually do not go beyond the normal range. Drospirenone increases plasma renin activity and aldosterone, which is associated with its antimineralocorticoid effect.

Medical Examinations

Before starting or resuming the use of the drug Leya^®, it is necessary to review the woman’s personal and family history, and perform a thorough medical (including measurement of BP, HR, determination of BMI) and gynecological examination (including breast examination and cytological examination of cervical mucus), and to rule out pregnancy. The frequency and nature of follow-up examinations should be determined individually for each woman, but not less than once every 6 months.

The woman should be warned that COCs do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced Efficacy

The efficacy of the drug Leya^® may be reduced in the following cases: if active (pink) tablets are missed, in case of vomiting, diarrhea, or as a result of drug interactions.

Insufficient Menstrual Cycle Control

While taking the drug Leya^®, irregular bleeding (“spotting” or “breakthrough” bleeding) may occur, especially during the first months of use. Therefore, the assessment of any irregular bleeding should be performed only after an adaptation period of approximately three cycles. If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant neoplasms or pregnancy.

In some women, withdrawal bleeding may not occur during the break in taking the active (pink) tablets. If the drug Leya^® was taken as directed, it is unlikely that the woman is pregnant. If the drug Leya^® was taken irregularly, or if two consecutive withdrawal bleedings are absent, then pregnancy must be ruled out before continuing to take the drug.

Effect on Ability to Drive and Operate Machinery

No effect of the drug Leya^® on the ability to drive vehicles and operate machinery has been established.

Overdose

To date, there has not been a single case of overdose of the drug Leya^®. Considering the clinical experience with COCs, the following symptoms may be observed in case of drug overdose: nausea, vomiting, “spotting” bleeding or metrorrhagia.

There is no antidote; treatment is symptomatic.

Drug Interactions

Interactions of oral contraceptives with other drugs may lead to “breakthrough” bleeding and/or reduced contraceptive reliability. Women taking these drugs should temporarily use barrier methods of contraception in addition to taking the drug Leya^® or choose another method of contraception.

The use of drugs that induce hepatic microsomal enzymes may lead to an increase in the clearance of sex hormones. Such drugs include: phenytoin, barbiturates, primidone, carbamazepine, rifampicin; there are also suggestions regarding oxcarbazepine, topiramate, felbamate, griseofulvin and preparations containing St. John’s wort.

HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and their combinations may also potentially affect hepatic metabolism.

According to some studies, certain antibiotics (e.g., penicillins and tetracycline) may reduce the enterohepatic recirculation of estrogens, thereby lowering the concentration of ethinylestradiol.

While taking drugs that affect microsomal enzymes and for 28 days after their discontinuation, an additional barrier method of contraception should be used.

While taking antibiotics (such as ampicillins and tetracyclines) and for 7 days after their discontinuation, an additional barrier method of contraception should be used. If during these 7 days of using a barrier method the active (pink) tablets run out, then the placebo (white) tablets from the current package should be skipped and the tablets from the next package of the drug Leya^® should be started. The main metabolites of drospirenone are formed in plasma without the involvement of cytochrome P450 isoenzymes. Therefore, an influence of cytochrome P450 isoenzyme inhibitors on the metabolism of drospirenone is unlikely.

COCs may affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations.

Based on in vitro interaction studies, as well as an in vivo study in female volunteers taking omeprazole, simvastatin, and midazolam as markers, it can be concluded that an influence of drospirenone at a dose of 3 mg on the metabolism of other drugs is unlikely.

There is a theoretical possibility of an increase in plasma potassium concentration in women receiving Leya^® concurrently with other drugs that may increase plasma potassium concentration. These drugs include ACE inhibitors, angiotensin II receptor antagonists, some non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone with ACE inhibitors or indomethacin, no significant difference in plasma potassium concentration compared to placebo was detected. Nevertheless, in women taking drugs that may increase plasma potassium concentration, it is recommended to determine the plasma potassium concentration during the first cycle of taking the drug Leya^®.

To determine possible interactions with drugs taken concurrently with the drug Leya^®, the prescribing information for these drugs should be consulted.

Storage Conditions

The drug should be stored out of the reach of children in a dry place at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.