Tri-regol

INSTRUCTIONS for medical use of the medicinal product TRI-REGOL (TRI-REGOL)

Composition:

Active substances: ethinylestradiol, levonorgestrel;

1 pink tablet contains: ethinylestradiol 0.03 mg, levonorgestrel 0.05 mg;

1 white tablet contains: ethinylestradiol 0.04 mg, levonorgestrel 0.075 mg;

1 dark-yellow tablet contains: ethinylestradiol 0.03 mg, levonorgestrel 0.125 mg;

Excipients:

1 pink tablet contains: colloidal anhydrous silicon dioxide, magnesium stearate, talc, corn starch, monohydrate lactose, sodium carmellose, povidone, polyethylene glycol (macrogol 6000), iron oxide red (E 172), copovidone, titanium dioxide (E 171), calcium carbonate, sucrose;

1 white tablet contains: colloidal anhydrous silicon dioxide, magnesium stearate, talc, corn starch, monohydrate lactose, sodium carmellose, povidone, polyethylene glycol (macrogol 6000), copovidone, titanium dioxide (E 171), calcium carbonate, sucrose;

1 dark-yellow tablet contains: colloidal anhydrous silicon dioxide, magnesium stearate, talc, corn starch, monohydrate lactose, sodium carmellose, povidone, polyethylene glycol (macrogol 6000), iron oxide yellow (E 172), copovidone, titanium dioxide (E 171), calcium carbonate, sucrose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink, round, biconvex, film-coated tablets with a glossy surface.

White, round, biconvex, film-coated tablets with a glossy surface.

Dark-yellow, round, biconvex, film-coated tablets with a glossy surface.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Sequential preparations containing progestogens and estrogens. ATC code G03A B03.

Pharmacological Properties

Pharmacodynamics

The contraceptive effect of oral contraceptives is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in the cervical mucus and endometrium. In addition to protection against pregnancy, oral contraceptives have many other beneficial effects. Menstrual cycles become more regular, menstruation is less painful in most cases, and bleeding is reduced. The latter reduces the frequency of iron deficiency. It has also been shown that high-dose oral contraceptives (50 micrograms of ethinylestradiol) reduce the risk of fibrocystic breast disease, ovarian cysts, vulvovaginal infections, ectopic pregnancy, and cancers of the endometrium and ovaries. It has not yet been established whether this also applies to low-dose oral contraceptives.

Pharmacokinetics

Levonorgestrel

Absorption

According to scientific publications, levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability is practically 100%) and does not undergo presystemic metabolism.

Distribution

Levonorgestrel binds to plasma proteins, primarily to sex hormone-binding globulin.

Biotransformation

Metabolism primarily involves the removal of the ∆4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most metabolites circulating in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel. The drug is excreted mainly in the form of glucuronides. A certain amount of the parent levonorgestrel also circulates as 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 is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are excreted in urine (40–68%) and feces (16–48%).

Ethinylestradiol

Absorption

Ethinylestradiol is rapidly and completely absorbed. Maximum serum concentration is reached within 1.5 hours.

Absolute bioavailability, due to presystemic conjugation and first-pass metabolism, is 60%. The area under the curve (AUC) and Cmax may slightly increase over time.

Distribution

Ethinylestradiol binds strongly but non-specifically to plasma albumin (98.5%), resulting in an increase in sex hormone-binding globulin concentration. The apparent volume of distribution of ethinylestradiol is approximately 5–18 L/kg.

Biotransformation

Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver. Hydrolysis of direct ethinylestradiol conjugates by intestinal flora regenerates ethinylestradiol, which can be reabsorbed, thereby completing the enterohepatic circulation loop. The main metabolic pathway of ethinylestradiol is hydroxylation, mediated by cytochrome P450, resulting in the formation of primary metabolites—2-OH-ethinylestradiol and 2-methoxyethinylestradiol. 2-OH-ethinylestradiol is further metabolized to chemically reactive metabolites.

Elimination

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

Steady State

Steady state is achieved after 3–4 days of administration, when serum ethinylestradiol levels are 20% higher compared to a single dose.

Clinical characteristics.

Indications. Oral contraception.

Contraindications.

Combined oral contraceptives (COCs) should not be used in the presence of any of the following conditions or disorders listed below. If any of these disorders or conditions develops for the first time during COC use, COC administration should be discontinued immediately.

• Current or past history of venous thrombosis (deep vein thrombosis, pulmonary embolism), with or without risk factors (see section "Special precautions");
• 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 acute cerebrovascular accident;
• past history of migraine with focal neurological symptoms;
• diabetes mellitus with vascular complications;
• severe degree or presence of multiple risk factors for venous or arterial thrombosis (see section "Special precautions");
• severe arterial hypertension;
• severe dyslipoproteinemia;
• ophthalmological disorders of vascular origin;
• hereditary or acquired tendency 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 (anti-cardiolipin antibodies, lupus anticoagulant);
• pancreatitis associated with severe hypertriglyceridemia, current or in history;
• current or past history of severe liver disease, if liver function tests have not returned to normal range;
• diagnosed or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breast);
• current or past history of liver tumors (benign or malignant);
• vaginal bleeding of unknown etiology;
• pregnancy or suspected pregnancy, breastfeeding period;
• hypersensitivity to the active substances levonorgestrel and ethinylestradiol or to any of the excipients.

Tri-Regol is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Note: Information regarding concomitantly administered medicinal products should be reviewed to identify potential interactions.

Pharmacodynamic interactions.

Concomitant use of medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir (with or without ribavirin), glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir may increase the risk of elevated alanine aminotransferase (ALT) (see sections "Contraindications" and "Special precautions"). Therefore, women taking Tri-Regol should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with these agents. Tri-Regol may be resumed 2 weeks after completion of treatment with these regimens.

Pharmacokinetic interactions

Effect of other medicinal products on Tri-Regol.

Interactions may occur with medicinal products that induce microsomal enzymes, potentially increasing the clearance of sex hormones, which in turn may lead to "breakthrough" bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may occur within a few days of starting treatment. Maximum enzyme induction generally occurs within a few 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 contraceptive method in addition to COCs. The barrier method should be used throughout the entire period of treatment with the inducing agent and for an additional 28 days after discontinuation of the agent.

If therapy with an enzyme-inducing agent is initiated during the period of taking the last tablets from the current COC pack, the next pack of COC tablets should be started immediately after finishing the previous pack, without any tablet-free interval.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use an alternative non-hormonal contraceptive method.

The following interactions have been documented according to published scientific data.

Substances that increase COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV treatments ritonavir, nevirapine, efavirenz, possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal medicinal products containing St. John’s wort (Hypericum perforatum).

Substances with variable effects on COC clearance

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

Therefore, information regarding the medical use of HIV/HCV treatment agents 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 Tri-Regol on other medicinal products.

Oral contraceptives may affect the metabolism of certain other active substances, thereby altering their plasma and tissue concentrations.

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

Cyclosporine. Oral contraceptives may inhibit hepatic metabolism of cyclosporine, leading to an increase in its adverse effects.

Lamotrigine. COCs have been shown to induce lamotrigine metabolism, resulting in subtherapeutic plasma concentrations of lamotrigine.

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

Laboratory tests.

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

Special precautions for use.

Medical examination/consultation

A complete medical examination, taking into account contraindications (see section "Contraindications") and special considerations described in this section, must be performed before initiating or resuming use of the medicinal product. Regular medical check-ups are also necessary, as contraindications (e.g., transient ischemic attack) or risk factors (e.g., personal or family history of venous or arterial thrombosis) may first appear during use of COCs. The frequency and nature of medical examinations should be based on current standards of medical practice and the individual characteristics of each woman. The medical examination should include measurement of blood pressure, examination of the breasts, abdomen, and internal and external genital organs, including cytological smear testing.

Patients should be informed that combined oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Special warnings

If any of the conditions/risk factors listed below are present, the benefits and potential risks of COCs should be evaluated for the individual woman and discussed with her before she decides to use the product. If any of these conditions or risk factors appear for the first time, worsen, or recur, the woman should consult her physician. The physician should then decide whether COC use should be discontinued.

Circulatory disorders

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in women using low-dose estrogen oral contraceptives (< 50 μg ethinylestradiol) is 20–40 cases per 100,000 women per year, although this risk depends on the type of progestogen. In women not using COCs, this risk is 5–10 cases per 100,000 women per year.

The risk of VTE is highest during the first year of oral contraceptive use. However, this risk is lower than the risk of venous thromboembolic disorders observed during pregnancy, which is 60 cases per 100,000 pregnancies. Venous thromboembolism is fatal in 1–2% of cases.

The overall absolute risk (incidence) of developing VTE with COCs containing levonorgestrel and 30 μg ethinylestradiol is 20 cases per 100,000 women per year.

Epidemiological studies have associated COC use with an increased risk of arterial thromboembolic complications such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism.

Rarely, thrombosis of other blood vessels (e.g., hepatic, mesenteric, renal veins, cerebral veins, retinal veins and arteries) has been reported in women taking oral contraceptives.

Symptoms of venous or arterial thrombotic/thromboembolic disorders or cerebrovascular disorders may include:

• Unilateral leg pain and/or swelling;
• Sudden acute chest pain, with or without radiation to the left arm;
• Sudden shortness of breath;
• Sudden cough without apparent cause;
• Any unusual, sudden, or persistent headache;
• Sudden partial or complete loss of vision;
• Diplopia;
• Slurred speech or aphasia;
• Vertigo;
• Collapse with or without focal epileptic seizure;
• Sudden weakness or severe numbness affecting one side or one part of the body;
• Motor disturbances;
• "Acute abdomen".

The risk of venous thromboembolic complications with COC use increases:

• With age;
• With a family history of such events (e.g., venous or arterial thromboembolism in parents or siblings at a young age). If there is a hereditary predisposition to thromboembolic disorders, the woman should consult a specialist before deciding to use any COC;
• With obesity (body mass index > 30 kg/m²);
• With prolonged immobilization, major surgery, surgery on the lower limbs, or severe trauma. Since the risk of thromboembolic disorders increases in the postoperative period, it is recommended to discontinue the drug 4 weeks before planned surgery and to restart 2 weeks after full mobilization. There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the development or progression of venous thrombosis.

The risk of arterial thromboembolic complications and cerebrovascular disorders with COC use increases:

• With age;
• With smoking (heavy smoking and age over 35 years are additional risk factors);
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve disorders;
• With atrial fibrillation.

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 reactions 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 oral contraceptive use (which may be a prodromal or cerebrovascular event) may necessitate immediate discontinuation of the drug.

Biochemical factors that may indicate inherited or acquired predisposition to venous or arterial thrombosis include: activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, and presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

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

When assessing benefit/risk, the physician should consider that there are ways to reduce the risk of thrombosis and that the risk of thrombosis during pregnancy is higher than the risk associated with the use of low-dose COCs (< 50 μg ethinylestradiol).

Tumors

The most significant risk factor for cervical cancer in women is human papillomavirus infection. Some epidemiological studies have suggested that long-term use of combined oral contraceptives increases this risk. However, results are inconsistent, as it is unclear to what extent other factors (e.g., cervical screening, sexual behavior) influence the findings.

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 disappears within 10 years after stopping COC use. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs compared to those who have never used COCs is small relative to the overall risk of breast cancer. These study results do not confirm a causal relationship.

The higher frequency of breast cancer detection may be due to earlier diagnosis in women using COCs, a biological effect of COCs, or a combination of both. Breast cancer is diagnosed at an earlier stage in women using oral contraceptives compared to those who have not used COCs.

Rarely, benign and even more rarely malignant liver tumors have been observed in women using COCs. In individual cases, these tumors have caused life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of liver tumor should be considered in differential diagnosis in women taking COCs.

Other conditions

Depressed mood and depression are known adverse effects of hormonal contraceptives (see section "Adverse reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to consult their physician if they experience mood changes or depressive symptoms, including shortly after starting treatment.

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

A slight increase in blood pressure has been observed in many women taking COCs; clinically significant increases are rare. If a marked increase in blood pressure occurs during COC use, the physician should discontinue COCs immediately. COC use may be resumed if normal blood pressure values are achieved with antihypertensive therapy.

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

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

In acute or chronic liver dysfunction, COC use may need to be discontinued until liver function tests return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice that first occurred during pregnancy or previous use of sex steroid hormones. Steroids may be poorly metabolized in patients with hepatic insufficiency.

Although exogenous estrogens 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 COC use, especially at the beginning of treatment.

Exacerbation of Crohn’s disease and ulcerative colitis has been reported during COC use.

Melasma may rarely develop, particularly in women with a history of melasma of pregnancy. Women predisposed to melasma should avoid direct sunlight or ultraviolet radiation while taking COCs.

Women with hyperlipidemia who choose to use oral contraceptives should be under close supervision.

Medicinal products of herbal origin containing Hypericum perforatum (St. John’s wort) should not be taken concomitantly with Tri-Regol, as there is a risk of reduced plasma concentrations of the active substances in Tri-Regol and, consequently, reduced efficacy (see section "Interaction with other medicinal products and other forms of interaction").

Reduced efficacy

The efficacy of COCs may be reduced in case of missed tablet intake, gastrointestinal disturbances (vomiting or diarrhea) (see section "Method of administration and dosage") or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Reduced cycle control

Intermenstrual bleeding (spotting or breakthrough bleeding) may occur during COC use, especially during the first 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. These measures may include curettage. After non-hormonal causes have been excluded, use of contraceptives with higher hormone content may be considered.

In some women, menstruation may not occur during the usual pill-free interval. If COCs have been taken according to the instructions in section "Method of administration and dosage", pregnancy is unlikely. However, if the instructions in section "Method of administration and dosage" were not followed before the first missed period, or if menstruation is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

Elevated ALT levels

During clinical trials in patients receiving medications for hepatitis C virus infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT levels more than 5 times the upper limit of normal were observed. This occurred more frequently in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Elevated ALT levels were also observed with antiviral medications containing glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Excipients

The medicinal product contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance or fructose intolerance, complete lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy.

Tri-Regol is contraindicated during pregnancy (see section "Contraindications").

If a woman becomes pregnant while taking the tablets, further intake 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 or teratogenic effects from unintentional use of oral contraceptives in early pregnancy.

Breastfeeding.

Oral hormonal contraceptives may affect lactation, as they may reduce the quantity and alter the composition of breast milk. Therefore, the use of combined oral contraceptives is not recommended until breastfeeding has ceased. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk. These amounts may affect the infant.

Ability to drive and use machines. The medicinal product does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

How to take Tri-Regol

Orally, in the order indicated on the packaging, approximately at the same time each day, 1 tablet daily, taken with a small amount of liquid.

Tri-Regol should be taken daily, 1 tablet per day for 21 days. Treatment with the tablets from each subsequent pack should begin after a 7-day break, during which withdrawal bleeding usually occurs. This bleeding typically starts on days 2–3 after taking the last tablet from the pack and may continue until the start of tablets from the next pack.

How to start taking Tri-Regol

If hormonal contraceptives were not used in the previous month

Tablet intake should begin on day 1 of the woman's menstrual cycle (i.e., on the first day of menstruation). Starting on days 2–7 is also possible; however, during the first cycle, it is recommended to additionally use a non-hormonal method of contraception (such as condoms or spermicides) for the first 7 days of tablet intake.

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

Treatment with Tri-Regol should begin the day after taking the last active tablet of the previous contraceptive (or after removal of the transdermal patch or vaginal ring), but no later than the day after the tablet-free interval (placebo tablets, interval after removal of the vaginal ring or transdermal patch) of the previous contraceptive.

Switching from a progestogen-only preparation (low-dose oral contraceptive, injection, implant, or intrauterine contraceptive device)

Switching from a low-dose oral contraceptive can be done at any time during the menstrual cycle (from an implant or intrauterine contraceptive device – the day after their removal; from an injection – on the day the next injection would have been due). In all cases, women are advised to additionally use a non-hormonal method of contraception for the first 7 days of tablet intake.

After first-trimester termination of pregnancy

Treatment should be started on the same day. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester termination of pregnancy

Regarding use during breastfeeding, see section "Use during pregnancy or breastfeeding."

For women who are not breastfeeding, treatment should begin on days 21–28 after childbirth or second-trimester termination of pregnancy, as the risk of thromboembolic disorders is increased during the postpartum period. If a woman starts taking the tablets later, it is recommended to additionally use a barrier method of contraception for the first 7 days of tablet intake. If sexual intercourse has already occurred, pregnancy should be ruled out before starting the tablets, or tablet intake should be delayed until the first menstrual bleeding.

Missed tablet intake

If less than 12 hours have passed since the scheduled tablet intake, contraceptive protection is not reduced – tablets should be taken at the usual time.

If more than 12 hours have passed since the scheduled tablet intake, contraceptive protection may be reduced.

In such cases, two main rules must be followed:

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

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

Week 1

The missed tablet should be taken as soon as the woman remembers, even if this means taking 2 tablets at the same time. Then continue taking tablets at the usual time. Additionally, barrier methods of contraception (e.g., condoms) should be used for the next 7 days. If sexual intercourse occurred within the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer the missed dose is to the 7-day treatment-free interval, the higher the risk of pregnancy.

Week 2

The missed tablet should be taken as soon as the woman remembers, even if 2 tablets must be taken simultaneously. Then continue taking tablets at the usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, no additional contraceptive methods are necessary. Otherwise, or if more than one tablet has been missed, it is recommended to additionally use barrier contraception for 7 days.

Week 3

There is a risk of reduced contraceptive protection due to the upcoming 7-day treatment-free interval. Therefore, additional contraceptive methods must be used, following one of the options described below, provided that tablets were taken correctly for the 7 days before the missed dose. If this is not the case, it is recommended to follow the first of the options below and use additional barrier methods of contraception (e.g., condoms) for the next 7 days.

The last missed tablet should be taken immediately upon remembering, even if 2 tablets must be taken simultaneously. Then continue taking tablets at the usual time. The patient should start taking tablets from the next pack the day after taking the last tablet from the current pack, meaning there should be no break between packs. It is unlikely that the woman will experience a withdrawal bleed before finishing the tablets from the second pack, although spotting or breakthrough bleeding may occur during tablet intake.

Alternatively, the woman may be advised to stop taking tablets from the current pack. In this case, she should take a treatment-free break of up to 7 days, including the days when she forgot to take the tablets, and then start taking tablets from the next pack.

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

In case of gastrointestinal disorders

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

In case of vomiting or acute diarrhea occurring within 3–4 hours after taking a tablet, refer to the section "Missed tablet intake."

The woman should take an active tablet(s) of the corresponding color (containing active ingredients) from another pack.

How to delay or shift withdrawal bleeding

To delay menstrual bleeding, start taking the tablets from a new pack the next day after finishing the current pack, beginning with the dark-yellow tablets (last phase), without a break. Bleeding can be delayed for the desired period until all dark-yellow tablets from the second pack are used up. Breakthrough bleeding or slight spotting may occur during this period. Regular use of Tri-Regol can be resumed after the usual 7-day break.

To shift the onset of menstruation to another day of the week, shorten the treatment-free interval by the desired number of days. The shorter the interval, the more likely it is that withdrawal bleeding will not occur, and breakthrough bleeding or spotting may occur during intake of tablets from the next pack. It is important to emphasize that the treatment-free interval must not be extended.

Children. Tri-Regol is not intended for use in children before puberty.

Overdose.

There is no information on serious harmful effects of the drug in case of overdose.

Symptoms: nausea, vomiting, and slight vaginal bleeding in young girls.

Treatment: there is no specific antidote; treatment is symptomatic.

Side effects

The most common side effects usually do not require discontinuation of treatment and include: depression, mood changes, headache, nausea, vomiting, abdominal pain, cholelithiasis, acne, chloasma, breast tenderness, breast pain, metrorrhagia, weight gain.

The frequency of adverse reactions is classified according to MedDRA [Medical Dictionary for Regulatory Activities]:

• Common: ≥ 1/100 to < 1/10
• Uncommon: ≥ 1/1000 to < 1/100
• Rare: ≥ 1/10,000 to < 1/1000
• Very rare: < 1/10,000
• Frequency not known: cannot be estimated from available data

Infections and infestations:
Common: vaginitis, including candidiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps):
Uncommon: breast cancer;
Rare: hepatic adenoma, hepatocellular carcinoma.

Immune system disorders:
Rare: hypersensitivity reactions;
Frequency not known: exacerbation of symptoms of hereditary and acquired angioedema.

Metabolism and nutrition disorders:
Uncommon: fluid retention, increased or decreased appetite;
Rare: impaired glucose tolerance, hyperlipidaemia;
Very rare: porphyria exacerbation;
Frequency not known: hypercholesterolaemia, hypertriglyceridaemia.

Psychiatric disorders:
Common: depression, mood changes;
Uncommon: decreased libido;
Rare: increased libido, decreased libido, loss of libido, nervousness;
Frequency not known: irritability.

Nervous system disorders:
Common: headache;
Uncommon: migraine;
Rare: cerebral circulation disorders, Sydenham's chorea;
Frequency not known: cerebrovascular disorders, exacerbation of epilepsy, dizziness.

Eye disorders:
Rare: intolerance to contact lenses;
Very rare: optic neuritis, retinal artery thrombosis, visual disturbances.

Ear and labyrinth disorders:
Rare: ear and balance organ disorders, otosclerosis.

Cardiac disorders:
Very rare: myocardial infarction.

Vascular disorders:
Uncommon: hypertension;
Rare: venous thromboembolism, complications of varicose vein disease;
Frequency not known: arterial thromboembolism, pulmonary artery embolism, phlebitis.

Gastrointestinal disorders:
Common: nausea, abdominal pain;
Uncommon: vomiting, diarrhoea;
Rare: ulcerative colitis, Crohn's disease;
Very rare: pancreatitis.

Hepatobiliary disorders:
Common: cholelithiasis;
Frequency not known: cholestatic jaundice.

Skin and subcutaneous tissue disorders:
Common: acne, chloasma;
Uncommon: skin rashes, urticaria, hirsutism, alopecia;
Rare: various skin lesions (e.g. exudative polymorphic erythema, nodular erythema);
Frequency not known: hypertrichosis, skin desquamation.

Musculoskeletal and connective tissue disorders:
Very rare: systemic lupus erythematosus;
Frequency not known: sensation of heaviness in the body.

Renal and urinary disorders:
Very rare: haemolytic-uraemic syndrome.

Reproductive system and breast disorders:
Common: breast pain, breast swelling, dysmenorrhoea, changes in cervical ectopy and cervical secretions, menorrhagia;
Uncommon: breast enlargement;
Rare: galactorrhoea, vaginal discharge;
Frequency not known: amenorrhoea, anovulatory cycles, oligomenorrhoea.

Investigations:
Common: weight gain;
Rare: weight loss, decreased serum folate levels.

The following serious adverse reactions have been reported in women taking combined oral contraceptives (see sections "Contraindications" and "Special warnings and precautions for use"):

• Venous thromboembolic complications, such as deep vein thrombosis or pelvic venous thrombosis, or pulmonary artery embolism;
• Arterial thromboembolic complications;
• Arterial hypertension;
• Liver tumours;
• Skin and subcutaneous tissue disorders; Crohn's disease, ulcerative colitis, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic-uraemic syndrome, cholestasis, cholestatic jaundice, chloasma, nodular erythema.

The incidence of breast cancer diagnosis is slightly higher in women taking combined oral contraceptives (COCs). 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 in relation to the overall risk of breast cancer. A causal relationship with COC use has not been established (see in detail sections "Contraindications" and "Special warnings and precautions for use").

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as patients' legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25°C.

Keep out of the reach and sight of children!

Packaging. Combination pack: 21 tablets per blister (6 pink tablets, 5 white tablets, 10 dark yellow tablets); 1 or 3 blisters with a cardboard blister holder in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Gedeon Richter", Hungary.

Manufacturer's name and address of the place of business.
H-1103 Budapest, Demréni utca 19-21, Hungary.