Tri-Regol^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

G03AB03 (Levonorgestrel and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Levonorgestrel (Rec.INN registered by WHO)

Dosage Form

Tri-Regol®

Coated tablets: 21 pcs. in a blister, 1 or 3 blisters in a pack, incl.: tab. I pink 0.05 mg+0.03 mg: 6 pcs. in a blister; tab. II white 0.075 mg+0.04 mg: 5 pcs. in a blister; tab. III dark yellow 0.125 mg+0.03 mg: 10 pcs. in a blister

Dosage Form, Packaging, and Composition

Coated tablets, three types.

Tablets I, coated, pink, round, biconvex, with a glossy surface; white on the cross-section.

Excipients: anhydrous colloidal silicon dioxide, magnesium stearate, talc, corn starch, lactose monohydrate.

Coating composition: sucrose, talc, calcium carbonate, titanium dioxide (E171), copovidone, macrogol 6000, anhydrous colloidal silicon dioxide, povidone, sodium carboxymethylcellulose, iron oxide red (E172).

Tablets II, coated, white, round, biconvex, with a glossy surface; white on the cross-section.

Excipients: anhydrous colloidal silicon dioxide, magnesium stearate, talc, corn starch, lactose monohydrate.

Coating composition: sucrose, talc, calcium carbonate, titanium dioxide (E171), copovidone, macrogol 6000, anhydrous colloidal silicon dioxide, povidone, sodium carboxymethylcellulose.

Tablets III, coated, dark yellow, round, biconvex, with a glossy surface; white on the cross-section.

Excipients: anhydrous colloidal silicon dioxide, magnesium stearate, talc, corn starch, lactose monohydrate.

Coating composition: sucrose, talc, calcium carbonate, titanium dioxide (E171), copovidone, macrogol 6000, anhydrous colloidal silicon dioxide, povidone, sodium carboxymethylcellulose, iron oxide yellow (E172).

21 pcs. (tablets I, II and III*) – blisters (1) – cardboard packs^×.
21 pcs. (tablets I, II and III*) – blisters (3) – cardboard packs^×.

* tablets I pink – 6 pcs.; tablets II white – 5 pcs.; tablets III dark yellow 10 pcs.
^× a flat cardboard case for blister storage is included in the pack.

Clinical-Pharmacological Group

Three-phase oral contraceptive

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; systemic hormonal contraceptives; progestogens and estrogens, sequential preparations (for sequential administration)

Pharmacological Action

Levonorgestrel + Ethinylestradiol is a combined three-phase oral low-dose contraceptive drug (COC).

The contraceptive effect is achieved through complementary mechanisms: suppression of ovulation, increased viscosity of cervical secretion (making it difficult for sperm to pass through the cervical canal), proliferation and secretory transformation of the endometrium (preventing implantation of a fertilized egg).

When used correctly, the Pearl index (an indicator reflecting the pregnancy rate in 100 women during one year of contraceptive use) is less than 1. If the dosage regimen is violated, including missed tablets, the Pearl index may increase. In women taking COCs, the cycle becomes more regular, the pain and intensity of menstrual-like bleeding decrease, thereby reducing the risk of iron deficiency anemia.

Pharmacokinetics

Levonorgestrel

Absorption

After oral administration, Levonorgestrel is rapidly and completely absorbed, its C_max in blood plasma (about 2.3 ng/ml) is reached in approximately 1.3 hours. Bioavailability is almost 100%.

Distribution

Levonorgestrel binds to blood plasma albumin and to sex hormone-binding globulin (SHBG). Only about 1.1% of the total levonorgestrel concentration is free in blood plasma; about 64% is specifically bound to SHBG and about 35% is non-specifically bound to albumin. The induction of SHBG synthesis by ethinylestradiol affects the binding of levonorgestrel to plasma proteins, causing an increase in the fraction bound to SHBG and a decrease in the fraction bound to albumin. The apparent V_d after a single dose is about 129 L.

Metabolism

Levonorgestrel is completely metabolized via known pathways of sex hormone metabolism. The main metabolites in blood plasma are unconjugated and conjugated forms of 3α-, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, the main enzyme involved in the metabolism of levonorgestrel is the CYP3A4 isoenzyme. Plasma clearance is about 1.0 ml/min/kg.

Excretion

The decrease in levonorgestrel plasma concentration is biphasic, T_1/2 in the terminal phase is about 25 hours. It is not excreted unchanged from the body. Levonorgestrel metabolites are excreted by the kidneys and through the intestine in a 1:1 ratio with T_1/2 of about 24 hours.

Steady-state concentration

With daily administration of the drug, the concentration of levonorgestrel in blood plasma increases approximately 3 times, reaching a steady-state concentration in the second half of the drug administration cycle. The pharmacokinetics of levonorgestrel is influenced by the concentration of SHBG in blood plasma, which increases with the co-administration of levonorgestrel and ethinylestradiol by approximately 1.6 times. At steady-state concentration, the clearance rate decreases to approximately 0.7 ml/min/kg.

Ethinylestradiol

Absorption

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max in blood plasma, equal to approximately 50 pg/ml, is reached in 1-2 hours. During the “first pass” through the liver, Ethinylestradiol is metabolized, resulting in an average bioavailability of about 45% (individual values within 20-65%).

Distribution

Ethinylestradiol is almost completely (98%), although non-specifically, bound to blood plasma albumin. Ethinylestradiol induces the synthesis of SHBG. The apparent V_d is 2.8-8.6 L/kg.

Metabolism

Ethinylestradiol undergoes presystemic conjugation, both in the small intestinal mucosa and in the liver. The primary metabolism of ethinylestradiol occurs via aromatic hydroxylation. This produces a wide range of hydroxylated and methylated metabolites, which are present both as free metabolites and as conjugates (glucuronides and sulfates). The metabolic clearance rate from blood plasma is 2.3-7 ml/min/kg.

Excretion

The decrease in ethinylestradiol plasma concentration is biphasic: the first phase is characterized by T_1/2 of about 1 hour, the second – 10-20 hours. It is not excreted unchanged from the body. Ethinylestradiol metabolites are excreted by the kidneys and through the intestine in a 4:6 ratio with T_1/2 of about 24 hours.

Steady-state concentration

With daily administration of the Levonorgestrel + Ethinylestradiol combination, the concentration of ethinylestradiol in blood plasma increases approximately 2 times. Given the variable T_1/2 in the terminal phase and daily oral administration, steady-state concentration is reached after approximately 1 week.

Indications

• Oral contraception.

ICD codes

Dosage Regimen

Orally. The tablets should be taken in the order indicated on the package, every day at approximately the same time, with a small amount of water, 1 tablet per day for 21 days. Taking tablets from the next package should be started 7 days after the end of the previous one. During these 7 days, menstrual-like bleeding occurs. It usually starts on the 2nd-3rd day after taking the last tablet and may not stop until starting the tablets from the next package.

How to start taking Tri-Regol^®

If no hormonal contraceptive drugs were taken in the previous month

Taking Tri-Regol^® should be started on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding), then the tablets are taken in order. Starting on the 2nd-5th day of the menstrual cycle is allowed, but in this case, during the first 7 days of taking tablets from the first package, it is recommended to additionally use a barrier method of contraception (for example, a condom).

When switching from other combined hormonal contraceptive drugs (COC, vaginal ring or transdermal patch)

It is preferable to start taking Tri-Regol^® on the day after taking the last hormone-containing tablet of the previous COC, but in no case later than the next day after the usual 7-day break (if the woman was taking a COC containing 21 tablets per package) or after taking the last hormone-free tablet (if the woman was taking a COC containing 28 tablets per package). Taking the drug should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch applied. The recommended hormone-free interval of the previous contraceptive method should not be exceeded under any circumstances.

When switching from contraceptives containing only progestogens (“mini-pills”, injectable forms, implant), or from an intrauterine therapeutic system releasing a progestogen

Switching from “mini-pills” to Tri-Regol^® can be done on any day (without a break), from an implant or intrauterine contraceptive with a progestogen – on the day of its removal, from an injectable form – from the day when the next injection should be given. In all cases, during the first 7 days of taking the tablets, it is necessary to additionally use a barrier method of contraception (for example, a condom).

After abortion, including spontaneous, in the first trimester of pregnancy

Taking Tri-Regol^® can be started immediately. In this case, there is no need to use additional methods of contraception.

After childbirth (in the absence of breastfeeding) or termination of pregnancy (including spontaneous) in the second trimester

It is recommended to start taking Tri-Regol^® on the 21st-28th day after childbirth (in the absence of breastfeeding) or immediately after termination of pregnancy in the second trimester of pregnancy. If the drug is started later, it is necessary to additionally use a barrier method of contraception (for example, a condom) during the first 7 days of taking the contraceptive. If sexual intercourse occurred before starting the drug, pregnancy must be excluded.

Recommendations in case of a missed dose

If the delay in taking the drug was less than 12 hours, contraceptive reliability is not reduced. The woman should take the tablet as soon as she remembers, the next tablet is taken at the usual time.

If the delay in taking the tablet was more than 12 hours, contraceptive reliability may be reduced. In this case, the following two rules should be followed

1. Taking the drug should never be interrupted for more than 7 days.
2. To achieve adequate suppression of the hypothalamic-pituitary-ovarian system, tablets must be taken for 7 consecutive days. Accordingly, if the delay in taking the tablets was more than 12 hours (the interval from the moment of taking the last tablet is more than 36 hours), depending on the week when the tablet was missed, the following recommendations should be followed

First week of taking the drug

The woman should take the missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. Then she should continue taking the drug according to the usual schedule. Additionally, a barrier contraceptive method (for example, a condom) should be used for the next 7 days. If the woman had sexual contacts during the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer the break in taking the drug is to the moment of sexual contact, the higher the risk of pregnancy.

Second week of taking the drug

It is necessary to take the missed tablet as soon as the woman remembers, even if this means taking 2 tablets at the same time. Then she should continue taking the drug according to the usual schedule. Provided that the woman took the drug correctly for the 7 days preceding the first missed tablet, there is no need to use additional (non-hormonal) contraceptive methods. Otherwise, or in case of missing 2 or more tablets, additional contraceptive methods should be used for the next 7 days.

Third week of taking the drug

The risk of reduced contraceptive reliability increases due to the upcoming break in taking the drug. If during the 7 days preceding the first missed tablet the woman took the drug on time, there is no need to use additional contraceptive measures. If during the 7 days preceding the first missed tablet there were violations in taking the drug, then during the next 7 days it is necessary to additionally use a barrier method of contraception (for example, a condom), in this case, one of the recommendations below should be followed.

1. It is necessary to take the missed tablet as soon as possible, as soon as the woman remembers (even if this means taking 2 tablets at the same time). The next tablets are taken at the usual time until the tablets from the current package are finished. Taking tablets from a new package should be started immediately, without the usual 7-day break. “Withdrawal” bleeding is unlikely until the tablets from the new package are finished, but “spotting” bloody discharge and/or “breakthrough” bleeding may be noted on the days of taking the drug.
2. You can also interrupt taking the tablets from the current package, take a break for 7 or fewer days (including the days of missed tablets), and then start taking tablets from a new package of the contraceptive.

If a woman missed taking tablets and then during the break in taking the drug she does not have “withdrawal” bleeding, pregnancy must be excluded.

Do not take more than 2 tablets within 1 day!

Recommendations in case of gastrointestinal disorders

In severe gastrointestinal disorders, the absorption of the drug may be incomplete, so additional methods of contraception should be used. If vomiting occurred or severe diarrhea was present within 3-4 hours after taking the tablet, one should be guided by the recommendations for missed tablets indicated above. It is necessary to take the tablet(s) of the corresponding color from another package

Changes in the day of onset of menstrual-like bleeding

To delay the onset of “withdrawal” bleeding, it is necessary to continue taking the drug; for this, the last 10 tablets (dark yellow) from a new package of the drug should be used without the usual 7-day break. Tablets from a new package can be taken for as long as necessary until the dark yellow tablets run out. While taking the drug from the second package, “spotting” vaginal bleeding and/or “breakthrough” bleeding may be noted. Resumption of taking the drug from the next package should be after the usual 7-day break.

To move the day of onset of “withdrawal” bleeding to another day of the week, the next break in taking the tablets should be shortened by the desired number of days. The shorter the interval, the higher the likelihood of “spotting” or “breakthrough” bleeding while taking tablets from the second package.

Special patient groups

Elderly women. Not applicable. Tri-Regol^® is not indicated after menopause.

Patients with impaired liver function. The use of Tri-Regol^® is contraindicated in patients with hepatic insufficiency or severe liver diseases until liver function tests normalize.

Patients with impaired renal function. The efficacy and safety of Tri-Regol^® in women with renal failure have not been studied. No dose adjustment is required in such patients.

Children and adolescents under 18 years of age. The use of Tri-Regol^® in adolescent girls under 18 years of age is contraindicated due to the lack of clinical data on the efficacy and safety of this combination in this age population.

Adverse Reactions

The most frequent adverse reactions during administration of the Levonorgestrel + Ethinylestradiol combination are headache, “spotting” bleeding and acyclic bleeding.

Possible adverse reactions when using the Levonorgestrel + Ethinylestradiol combination are distributed by system-organ classes with an indication of their frequency of occurrence according to WHO recommendations: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000).

*Estimated frequency based on epidemiological studies covering the group of combined oral contraceptives.

Venous and arterial thromboembolic complications combine the following nosological forms: peripheral deep vein occlusion, thrombosis and thromboembolism / pulmonary vessel occlusion, thrombosis, embolism and infarction / myocardial infarction / cerebral infarction and stroke, not classified as hemorrhagic.

Description of selected adverse reactions

The following are serious adverse reactions reported in women taking COCs.

Tumors

• Women using COCs have a very slightly increased frequency of breast cancer detection. Since breast cancer is rare in women under 40 years of age, the increase in its frequency relative to the overall risk of breast cancer is very slight. A causal relationship with COC use is unknown.
• Liver tumors (benign and malignant).

Other conditions

• Hypertriglyceridemia (increased risk of pancreatitis when using COCs);
• Increased blood pressure;
• Effect on peripheral insulin resistance and impaired glucose tolerance;
• Impaired liver function;
• Chloasma;
• Crohn’s disease, ulcerative colitis;
• Epilepsy;
• Endometriosis, uterine fibroids;
• Porphyria;
• Systemic lupus erythematosus;
• Hemolytic-uremic syndrome;
• Gestational herpes;
• Sydenham’s chorea;
• Otosclerosis;
• Cholestatic jaundice.

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

Interaction

Due to the interaction of other drugs (enzyme inducers) with oral contraceptives, “breakthrough” bleeding and/or a decrease in contraceptive effect may occur (see section “Drug interactions”).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

The use of the Levonorgestrel + Ethinylestradiol combination, like other COCs, is contraindicated in the presence of any of the following diseases/conditions or risk factors

• Hypersensitivity to levonorgestrel, ethinylestradiol and/or any of the excipients;
• Venous thrombosis or venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), currently or in history;
• Arterial thrombosis or arterial thromboembolism (ATE), including myocardial infarction, stroke or prodromal conditions (including transient ischemic attack, angina), currently or in history;
• Identified hereditary or acquired predisposition to VTE or ATE, including activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of multiple high-risk factors for VTE or ATE (see section “Special Precautions”) or one serious risk factor, such as:
  • Diabetes mellitus with diabetic angiopathy;
  • Severe dyslipoproteinemia;
  • Uncontrolled arterial hypertension (BP 160/100 mm Hg and above).
• Migraine with focal neurological symptoms in history;
• Major surgery with prolonged immobilization;
• Hepatic failure or severe liver diseases currently or in history (until liver function tests normalize);
• Liver tumors (benign and malignant), including in history;
• Hormone-dependent malignant neoplasms of the genital organs or breast (including suspected);
• Amenorrhea of unclear etiology;
• Genital bleeding of unclear etiology;
• Pregnancy (including suspected);
• Breastfeeding period;
• Age under 18 years (due to lack of data on efficacy and safety in adolescent girls under 18 years);
• Concomitant use with direct-acting antiviral drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections “Drug interactions” and “Special Precautions”).

If any of these diseases/conditions or risk factors occur during contraceptive use, the administration of Tri-Regol^® should be immediately discontinued.

With caution

If any of the conditions/diseases or risk factors listed below are currently present, a thorough assessment of the expected benefit to possible risk of using Tri-Regol^® should be conducted for each woman individually and discussed before starting the drug

• Risk factors for thrombosis and thromboembolism (smoking, age, presence of thrombosis and thromboembolic complications in any first-degree relative under 50 years of age, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve diseases, cardiac arrhythmias);
• Other diseases in which peripheral circulation disorders may be noted: diabetes mellitus without vascular complications; systemic lupus erythematosus; hemolytic-uremic syndrome; Crohn’s disease and ulcerative colitis; sickle cell anemia; superficial phlebitis;
• Hypertriglyceridemia;
• Diseases that first occurred or worsened during a previous pregnancy or previous use of sex hormones, for example: jaundice and/or pruritus associated with cholestasis, gallbladder diseases, otosclerosis with hearing impairment, porphyria, gestational herpes, Sydenham’s chorea;
• Epilepsy;
• Depression;
• In women with hereditary forms of angioedema.

Use in Pregnancy and Lactation

Pregnancy

The use of the Levonorgestrel + Ethinylestradiol combination during pregnancy is contraindicated. If pregnancy is diagnosed during drug use, it should be discontinued immediately. Numerous epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy, nor a teratogenic effect when sex hormones were taken inadvertently in early pregnancy.

Breastfeeding period

The use of the Levonorgestrel + Ethinylestradiol combination, like other COCs, may reduce the amount of breast milk and change its composition, therefore, until breastfeeding is discontinued, the drug is contraindicated. A small amount of sex hormones and/or their metabolites passes into breast milk and may affect the newborn.

Use in Hepatic Impairment

Contraindicated in severe liver diseases, liver tumors.

The use of Tri-Regol^® is contraindicated in patients with hepatic failure or severe liver diseases until liver function tests normalize.

Use in Renal Impairment

The efficacy and safety of Tri-Regol^® in women with renal impairment have not been studied. No dose adjustment is required in such patients.

Pediatric Use

The use of Tri-Regol^® in adolescent girls under 18 years of age is contraindicated due to the lack of clinical data on the efficacy and safety of this combination in this age population.

Geriatric Use

Not applicable. Tri-Regol^® is not indicated after menopause.

Special Precautions

In the presence of any of the conditions/diseases/risk factors listed below, the potential risk and expected benefit of using COCs, including the Levonorgestrel + Ethinylestradiol combination, should be carefully assessed in each individual case and discussed with the woman before starting the drug. In case of exacerbation of diseases, worsening of the condition, or appearance of the first symptoms of any of these conditions/diseases or risk factors, the woman should consult her doctor to decide on discontinuing the drug.

Risk of developing VTE and ATE

Epidemiological studies have established a connection between the use of COCs and an increased risk of arterial and venous thrombosis and thromboembolism, such as myocardial infarction, stroke, DVT and PE. These diseases are observed extremely rarely.

The use of any COC is associated with an increased risk of developing VTE, manifested as DVT and/or PE. The increased risk of developing VTE while using COCs is due to the presence of estrogen in its composition.

The choice of the Levonorgestrel + Ethinylestradiol combination for contraception can only be made after consultation with the woman, allowing to ensure that she fully understands the risk of VTE associated with taking this contraceptive, the effect of the drug on her existing risk factors, and that the risk of developing VTE is highest in the first year of taking COCs. An increased risk is also noted when resuming COC use – after a break in drug use of 4 weeks or more.

VTE can be fatal in 1-2% of cases.

Very rarely, while taking COCs, thrombosis occurs in other blood vessels (for example, in the veins and arteries of the liver, mesentery, kidneys, brain or retina).

DVT symptoms unilateral swelling or along the 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 of the affected lower limb.

PE symptoms difficult or rapid breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep inspiration; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (for example, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions/diseases (for example, respiratory tract infection).

ATE can lead to stroke, vascular occlusion or myocardial infarction.

Stroke symptoms sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, one- or two-sided loss of vision, gait disturbance, dizziness, loss of balance or coordination, severe or prolonged headache for no apparent reason; problems with speech and understanding, loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion: sudden pain, swelling and slight bluish discoloration of the limbs, “acute” abdomen symptom complex.

Myocardial infarction symptoms pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone, with radiation to the back, jaw, upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat.

ATE can be life-threatening or fatal.

In women with a combination of several risk factors for VTE and ATE or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than with simple summation of factors. In this case, the use of the Levonorgestrel + Ethinylestradiol combination is contraindicated.

The risk of developing venous and/or arterial thrombosis, or thromboembolism or cerebrovascular disorders increases

• With age;
• In smokers (the risk increases to a greater extent in women over 35 years of age);
• In the presence of a family history of venous or arterial thrombosis, or thromboembolism in siblings or parents under 50 years of age (if a hereditary predisposition is suspected, consultation with a specialist is recommended before starting COCs);
• With obesity (BMI over 30 kg/m²);
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation;
• In case of prolonged immobilization, major surgical intervention, any surgery on the lower limbs, neurosurgical operations or extensive trauma; in these situations, COC use should be discontinued (in case of planned surgery, at least 4 weeks before it) and resumed no earlier than 2 weeks after the woman’s full mobility is restored.

Temporary immobilization (for example, air travel lasting more than 4 hours) may also be a risk factor for developing VTE, especially in the presence of other risk factors.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

The increased risk of thromboembolic complications in the postpartum period should be taken into account.

Peripheral circulation 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 while taking COCs (which may precede cerebrovascular disorders) is grounds for immediate discontinuation of the contraceptive.

Biochemical indicators indicating a hereditary or acquired predisposition to the development of venous or arterial thrombosis include: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the “benefit-risk” ratio, it should be taken into account that therapy for these conditions/diseases may reduce the associated risk of thrombosis or thromboembolism.

Tumors

The most significant risk factor for cervical cancer (CC) is persistent papillomavirus infection. There are reports of a slight increase in the risk of developing CC with long-term use of COCs. However, a connection with COC use has not been proven. The question of to what extent these data are related to screening for cervical diseases or to the characteristics of a woman’s sexual behavior (less frequent use of barrier contraception methods, a larger number of sexual partners) remains open.

According to a meta-analysis of the results of 54 epidemiological studies, a small increase (1.24 times) in the risk of breast cancer (BC) was detected in women taking COCs. The increased risk gradually disappears within 10 years after discontinuation of COCs. Since BC is rare in women under 40 years of age, the increase in the number of BC cases in women currently taking COCs or who have taken them recently is insignificant relative to the overall risk of this disease. A connection with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of BC in women taking COCs (they are diagnosed with earlier clinical forms of BC than women who have not taken COCs), the biological effect of COCs, or a combination of both these factors.

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

Other conditions

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

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

The following diseases, according to available data, develop or worsen both during pregnancy and when taking COCs, but their connection with COC use has not been proven: cholestatic jaundice and/or pruritus associated with cholestasis; gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea, gestational herpes; hearing loss due to otosclerosis.

Cases of Crohn’s disease and ulcerative colitis have been reported while using COCs.

While taking COCs, the course of endogenous depression and epilepsy may worsen. Depressed mood and depression are well-known adverse reactions when using hormonal contraceptives. Depression can be serious and cause suicidal behavior and suicide. A woman should consult her doctor in case of mood swings and the appearance of symptoms of depression, including shortly after starting the Levonorgestrel + Ethinylestradiol combination.

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

Acute or chronic liver diseases 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 in patients with diabetes taking low-dose COCs, adjustment of the dose of hypoglycemic drugs is usually not required. However, women with diabetes should be carefully monitored while taking COCs.

Chloasma may sometimes develop, especially in women with a history of chloasma gravidarum. While taking COCs, women prone to chloasma should avoid prolonged sun exposure and ultraviolet radiation.

Effect on Liver Function Parameters

During clinical trials involving patients receiving a course of therapy for viral hepatitis C (a combination of medicinal products containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin), an increase in ALT activity of more than 5 times the ULN was registered more frequently in patients taking COCs containing Ethinylestradiol. If it is necessary to undergo a course of therapy with this combination of drugs, a patient taking the Levonorgestrel + Ethinylestradiol combination should be switched to alternative methods of contraception (non-hormonal or progestogen-only contraceptives) before starting treatment. Resumption of the Levonorgestrel + Ethinylestradiol combination can be no earlier than 2 weeks after the end of the course of antiviral therapy.

Medical Examinations

Before starting or resuming the Levonorgestrel + Ethinylestradiol combination, it is necessary to review the woman’s personal and family history, conduct a thorough general medical (including measurement of BP, determination of BMI) and gynecological examination (with mandatory examination of the mammary glands and cytological examination of the cervical epithelium), and rule out pregnancy.

The scope of additional tests and the frequency of follow-up examinations are determined individually. Typically, follow-up examinations should be performed at least once every 6 months.

It must be remembered that the drug does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced Efficacy

The efficacy of the Levonorgestrel + Ethinylestradiol combination may decrease in case of missed tablets, gastrointestinal disorders, or as a result of drug interactions.

Inadequate Cycle Control

While taking COCs, especially during the first months of use, irregular bleeding (“spotting” and/or “breakthrough” bleeding) may occur. Therefore, the assessment of any irregular bleeding should be performed only after an adaptation period of approximately 3 treatment 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 tablet-free interval. If the drug was taken as recommended, it is unlikely that the woman is pregnant. However, if the drug regimen was violated, or if 2 consecutive withdrawal bleedings are absent, pregnancy must be ruled out before continuing its use.

Laboratory Tests

The use of drugs such as the Levonorgestrel + Ethinylestradiol combination may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, kidney, and adrenal function, the concentration of transport proteins in plasma (e.g., corticosteroid-binding globulin), lipid/lipoprotein fractions, parameters of carbohydrate metabolism, coagulation, and fibrinolysis. These changes generally remain within normal physiological limits.

Excipients

This drug contains lactose (in the form of lactose monohydrate) and sucrose. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, glucose-galactose malabsorption syndrome, fructose intolerance, or sucrase-isomaltase deficiency should not take this drug.

Effect on the Ability to Drive Vehicles and Operate Machinery

The use of the Levonorgestrel + Ethinylestradiol combination has no or negligible influence on the ability to drive and use machines.

Overdose

No serious adverse reactions have been observed following overdose with the Levonorgestrel + Ethinylestradiol combination.

Symptoms: nausea, vomiting, and in adolescent girls upon accidental ingestion – vaginal bleeding.

Treatment: There is no specific antidote; symptomatic treatment should be administered.

Drug Interactions

In case of concomitant use with other medicinal products, to identify possible drug interactions, one should also refer to the information presented in the prescribing information of those drugs.

Pharmacodynamic Interaction

In clinical trials of patients receiving therapy for viral hepatitis C with medicinal products containing ombitasvir, paritaprevir, ritonavir, and dasabuvir (with or without ribavirin), an increase in ALT activity of more than 5 times the ULN was observed significantly more often in women using COCs containing Ethinylestradiol, compared to the ULN in healthy and hepatitis C virus-infected women.

Pharmacokinetic Interaction

Effect of Other Medicinal Products on the Levonorgestrel + Ethinylestradiol Combination

Interaction of COCs with medicinal products that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, which, in turn, can lead to breakthrough uterine bleeding and/or a decrease in the contraceptive effect.

Women who are being treated with microsomal enzyme inducers concomitantly with the Levonorgestrel + Ethinylestradiol combination are advised to temporarily use a barrier method of contraception (e.g., a condom). The barrier method of contraception should be used throughout the entire period of taking the concomitant drugs and for another 28 days after their discontinuation. If the use of the inducer drug continues after taking the last tablet of the Levonorgestrel + Ethinylestradiol combination from the current package, the intake of tablets from a new package of the contraceptive should be started without the usual 7-day break. Induction of hepatic microsomal enzymes may be observed as early as a few days after co-administration and may persist for up to 4 weeks after discontinuation of the inducer therapy. Maximum enzyme induction is usually observed within several weeks.

During long-term therapy with drugs that induce hepatic microsomal enzymes, it is advisable to consider the choice of an alternative non-hormonal method of contraception.

Substances Increasing the Clearance of the Levonorgestrel + Ethinylestradiol Combination (Reduced Efficacy by Enzyme Induction)

Such medicinal products include drugs containing phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin; and also possibly oxcarbazepine, topiramate, felbamate, griseofulvin; some HIV protease inhibitors (e.g., ritonavir, nevirapine) and non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz); herbal preparations containing St. John’s wort (Hypericum perforatum).

Accidental pregnancies and breakthrough bleeding have been reported during concomitant use of the contraceptive with herbal preparations containing St. John’s wort. The effect on the clearance of the Levonorgestrel + Ethinylestradiol combination may persist for another 2 weeks after stopping the preparations of St. John’s wort.

Substances with Variable Effects on the Clearance of the Levonorgestrel + Ethinylestradiol Combination

When the Levonorgestrel + Ethinylestradiol combination is used concomitantly, many inhibitors of HIV or hepatitis C virus protease and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogen or progestogen. In some cases, this effect may be clinically significant.

Substances Decreasing the Clearance of the Levonorgestrel + Ethinylestradiol Combination (Enzyme Inhibitors)

Strong and moderate inhibitors of the CYP3A4 isoenzyme, such as azole antifungals (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase plasma concentrations of estrogen and/or progestogen.

Etoricoxib at doses of 60 and 120 mg/day, when co-administered with COCs containing 0.035 mg of ethinylestradiol, increases the plasma concentration of ethinylestradiol by 1.4 and 1.6 times, respectively.

Effect of COCs on Other Medicinal Products

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. In vitro, Ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, as well as an irreversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, the use of a hormonal contraceptive containing Ethinylestradiol resulted in no increase or only a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam), while plasma concentrations of CYP1A2 substrates may increase weakly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine). When the Levonorgestrel + Ethinylestradiol combination is used concomitantly with troleandomycin, the risk of developing intrahepatic cholestasis increases.

Impaired Absorption

Reduced absorption: Drugs that increase gastrointestinal motility, for example, metoclopramide, may reduce the absorption of sex hormones.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 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.