Regulon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REGULON®

Composition:

Active substances: desogestrel, ethinylestradiol;

One coated tablet contains 0.15 mg desogestrel and 0.03 mg ethinylestradiol;

Excipients: alpha-tocopherol (all-rac-α-tocopherol), magnesium stearate, colloidal anhydrous silicon dioxide, stearic acid, povidone, potato starch, lactose monohydrate;

Coating composition: propylene glycol, macrogol 6000, hypromellose.

Pharmaceutical form. Coated tablets.

Main physicochemical properties: white or almost white, round, biconvex coated tablets, approximately 6 mm in diameter, marked with "R8" on one side and "RG" on the other.

Pharmacotherapeutic group.

Hormonal contraceptives for systemic use, progestogens and estrogens.

ATC code G03A A09.

Pharmacological Properties

Pharmacodynamics

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several factors, the most important of which are the suppression of ovulation and changes in cervical secretion. In addition to preventing pregnancy, COCs have certain beneficial effects, which, like adverse effects (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"), may be considered when choosing a fertility control method. COCs promote regular menstrual cycles, less painful menstruation, and reduced menstrual blood loss. The latter may reduce the incidence of iron deficiency.

Furthermore, evidence indicates that high-dose COCs (0.05 mg ethinylestradiol) reduce the frequency of benign breast tumors, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, endometrial cancer, and ovarian cancer. However, it has not yet been confirmed whether this also applies to the use of low-dose COCs.

Pharmacokinetics

Desogestrel

Absorption. Desogestrel, when administered orally, is rapidly and completely absorbed and converted into etonogestrel. Peak serum concentrations are reached within approximately 1.5 hours. Bioavailability ranges from 62% to 81%.

Distribution. Etonogestrel binds to serum albumin and sex hormone-binding globulin (SHBG). Only 2–4% of the total drug concentration in serum exists as free steroid, while 40–70% is specifically bound to SHBG. Ethinylestradiol-induced elevation of SHBG affects the distribution among serum proteins, increasing the fraction bound to SHBG and decreasing the fraction bound to albumin. The volume of distribution of desogestrel is 5 L/kg.

Biotransformation. Etonogestrel is completely metabolized via known steroid metabolic pathways. The clearance rate of metabolites from serum is approximately 2 mL/min/kg. No interaction between etonogestrel and concomitantly administered ethinylestradiol has been observed.

Elimination. Serum levels of etonogestrel decline in two phases. The terminal elimination phase is characterized by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted in urine and bile in a ratio of 6:4.

Steady state. The pharmacokinetics of etonogestrel are influenced by serum SHBG levels, which increase threefold during ethinylestradiol administration. With daily dosing, steady state is reached in the second half of the cycle, when serum concentrations of etonogestrel increase two- to threefold.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and almost completely absorbed. Maximum plasma concentrations are reached within approximately 1–2 hours. Due to presystemic conjugation and first-pass effect, the absolute bioavailability of the drug is approximately 60%.

Distribution. Ethinylestradiol exhibits strong but non-specific binding to serum albumin (approximately 98.5%) and induces an increase in serum SHBG concentration. The expected volume of distribution is 5 L/kg.

Biotransformation. Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver. It is primarily metabolized via aromatic hydroxylation, but numerous other hydroxylated and methylated metabolites are also formed, appearing as free metabolites as well as conjugated sulfates and glucuronides. Metabolic clearance rate is approximately 5 mL/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and an irreversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Serum levels of ethinylestradiol decline in a biphasic manner; the terminal elimination phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is not excreted unchanged; its metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately one day.

Steady state. Steady state is achieved within 3–4 days, when serum drug concentrations are approximately 30–40% higher than after a single dose.

Clinical characteristics.

Indications.

Oral contraception.

Before prescribing Regulon®, the individual risk factors present in a woman should be assessed, particularly those related to the risk of venous thromboembolism (VTE), and the risk of venous thromboembolic complications associated with Regulon® should be compared with that of other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used in the conditions listed below. If any of these conditions occurs for the first time during CHC use, the CHC should be discontinued immediately.

• Established or suspected pregnancy.
• Presence or risk of venous thromboembolism (VTE).
  • Current venous thromboembolism, including patients receiving anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)).
  • Known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency.
  • Major surgery with prolonged immobilization (see section "Special precautions").
  • High risk of venous thromboembolism due to presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE).
  • Current or past arterial thromboembolism (e.g., myocardial infarction) or prodromal conditions (e.g., angina pectoris).
  • Cerebrovascular disorders – current or past stroke, or transient ischemic attack (TIA).
  • Established hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
  • History of migraine with focal neurological symptoms.
  • High risk of ATE due to presence of multiple risk factors (see section "Special precautions") or presence of any of the following serious risk factors:
• diabetes mellitus with vascular complications;
• severe arterial hypertension;
• severe dyslipoproteinemia.
• Current or past pancreatitis associated with severe hypertriglyceridemia.
• Current or past severe liver disease until liver function tests have returned to normal.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breast).
• Endometrial hyperplasia.
• Vaginal bleeding of unknown origin.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
• Regulon® is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Warning. To identify possible drug interactions, information contained in the prescribing information of other concurrently used medicinal products should be considered.

Pharmacodynamic interactions.

During clinical trials involving patients receiving treatment for hepatitis C virus (HCV) infection with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increases in alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Increases in ALT levels were also observed when glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir were used in women taking ethinylestradiol-containing medicinal products, such as CHCs (see section "Contraindications"). Therefore, women taking Regulon® should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) prior to initiating therapy with these combination medicinal products. Use of Regulon® may be resumed 2 weeks after completion of therapy with these combination regimens.

Pharmacokinetic interactions

Effect of other medicinal products on Regulon®

Interactions with medicinal products that induce microsomal enzymes are possible, leading to increased clearance of sex hormones, which may result primarily in breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction may occur within a few days of starting treatment. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the inducing agent, enzyme induction may persist for up to 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should use a barrier method of contraception or another contraceptive method in addition to the CHC. A barrier method should be used throughout the entire period of concomitant therapy and for an additional 28 days after its discontinuation. If the use of the enzyme-inducing agent continues beyond the last tablet of the current CHC pack, the next pack should be started without the usual break.

Long-term treatment

Women receiving long-term therapy with medicinal products that induce hepatic enzyme systems are advised to use another reliable non-hormonal method of contraception.

Interactions described in the literature.

Substances that increase CHC clearance (reducing CHC efficacy due to enzyme induction), e.g.: barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and the human immunodeficiency virus (HIV) drug ritonavir, nevirapine, and efavirenz; possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St. John's wort (Hypericum perforatum).

Substances with variable effects on CHC clearance: when used concomitantly with CHCs, 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 progestins. The effect of these changes may be clinically significant in some cases.

Therefore, to identify possible drug interactions and related recommendations, information contained in the prescribing information of concomitant medicinal products used for treatment of HIV infection/hepatitis C should be considered. In case of any doubts, women receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use an additional barrier method of contraception.

Active substances that reduce the clearance of Regulon® (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

Concomitant use with strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may lead to increased serum concentrations of estrogens or progestogens, including etonogestrel.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4–1.6-fold, respectively, when administered concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of Regulon® on other medicinal products

Oral contraceptives may affect the metabolism of other medicinal products. Consequently, their concentrations in plasma and tissues may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

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

Other interactions

Laboratory tests

The use of steroid contraceptives may influence the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function, as well as levels of plasma transport proteins such as corticosteroid-binding globulin, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Usually, changes remain within the normal laboratory reference ranges.

Special precautions.

Warning

If any of the conditions or risk factors listed below are present, the justification for using Regulon® should be discussed with the woman.

If there is an exacerbation or manifestation of any of the conditions or risk factors, women are advised to consult their physician and discuss the possibility of discontinuing the use of Regulon®.

1. Cardiovascular system disorders

Risk of venous thromboembolism (VTE)

The use of combined hormonal contraceptives (CHCs) increases the risk of venous thromboembolism (VTE) in patients taking them compared to those who do not use these drugs.

CHCs containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Other contraceptives, such as Regulon®, may double the risk of VTE. The decision to prescribe a contraceptive not belonging to the lowest-risk category regarding VTE should only be made after a consultation with the woman. It is essential to ensure that she fully understands the VTE risk associated with Regulon®, how her individual risk factors may influence this risk, and that the risk of VTE is highest during the first year of using the drug. Additionally, data indicate that the risk increases when restarting combined hormonal contraceptives after a break of 4 weeks or longer.

In a year, VTE occurs in approximately 2 out of 10,000 non-pregnant women who do not use CHCs. However, an individual woman's risk may be significantly higher depending on her specific risk factors (see below).

According to estimates¹, among 10,000 women using CHCs containing desogestrel, 9–12 will develop VTE within a year (compared to approximately 62 cases among women using CHCs containing levonorgestrel).

In both cases, the annual number of VTE events remains lower than the number expected during pregnancy or the postpartum period. VTE can be fatal in 1–2% of cases.

¹ These frequency estimates were derived by analyzing pooled data from epidemiological studies, using relative risks for different contraceptives compared to CHCs containing levonorgestrel.

² The median range of 5–7 per 10,000 woman-years is based on the relative risk of CHCs containing levonorgestrel compared to non-users, which is approximately 2.3–3.6.

Number of VTE cases per 10,000 women per year

In rare cases, thrombosis of other vessels (e.g., hepatic, mesenteric, renal, or retinal veins and arteries) has been reported in women taking COCs.

Risk factors for venous thromboembolism (VTE)

The risk of developing venous thromboembolic complications while taking COCs may increase substantially in women with additional risk factors, especially when multiple risk factors are present (see Table 1).

Regulon® is contraindicated in women who have multiple risk factors placing them at high risk for venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the individual risks associated with each factor; in such cases, the overall risk of VTE should be considered. COCs should not be prescribed if the benefit/risk balance is judged to be unfavorable (see section "Contraindications").

Table 1

Risk factors for venous thromboembolism (VTE)

There is no consensus regarding the potential impact of varicose veins and superficial thrombophlebitis on the development or progression of venous thrombosis.

It should also be noted that the risk of thromboembolic complications increases during pregnancy and in the first 6 weeks postpartum (see section "Use during pregnancy or breastfeeding").

Symptoms of venous thromboembolism (VTE)

Women should be informed that if symptoms of VTE occur, they should seek immediate medical attention and inform their healthcare provider about the use of COCs.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot or along a vein in the leg;
• Pain or increased sensitivity in the leg, which may occur only when standing or

walking;

• A sensation of warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden cough of unknown origin, possibly with blood;
• Acute chest pain;
• Pre-syncope or dizziness;
• Rapid or irregular heartbeat.

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

Other signs of vascular embolism may include: sudden pain, swelling, and mild cyanosis of a limb.

In the case of ocular vascular embolism, symptoms may range from blurred vision (without pain), which may progress to vision loss. Sometimes, complete vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have shown an association between the use of COCs and an increased risk of arterial thromboembolic events (myocardial infarction) or cerebrovascular disorders (e.g., transient ischemic attack, stroke). Cases of arterial thromboembolism may result in fatal outcomes.

Risk factors for arterial thromboembolism (ATE)

The risk of developing ATE or cerebrovascular events while using COCs increases in women with risk factors (see Table 2). Regulon® is contraindicated in women with a single serious risk factor or multiple risk factors that place them in a high-risk category for arterial thromboembolism (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor; therefore, the overall risk of ATE should be considered. COCs should not be prescribed if the benefit-risk ratio is considered unfavorable (see section "Contraindications").

Table 2

Risk factors for arterial thromboembolism (ATE)

Arterial Thromboembolic Symptoms (ATE)

Women should be informed that if any of the symptoms listed below occur, they should seek immediate emergency medical attention and inform their healthcare provider about the use of COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness of the face, weakness or numbness of extremities, especially on one side;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, speech or comprehension difficulties;
• sudden worsening of vision in one or both eyes;
• sudden severe or prolonged headache of unknown cause;
• loss of consciousness or syncope with or without seizures.

Transient symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction may include:

• pain, discomfort, pressure, heaviness, squeezing or fullness in the chest, arm, or behind the breastbone;
• discomfort radiating to the back, lower jaw, throat, arm, or stomach;
• sensation of stomach fullness, indigestion, or heartburn;
• excessive sweating, nausea, vomiting, or dizziness;
• severe weakness, restlessness, or shortness of breath;
• rapid or irregular heartbeat.

1. Tumors

Long-term use of oral contraceptives is known to be a risk factor for cervical cancer in women infected with human papillomavirus (HPV). However, this statement remains controversial, as it has not been definitively established to what extent study results account for the influence of confounding risk factors (e.g., differences in number of sexual partners or use of barrier contraceptive methods).

A meta-analysis of 54 international 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 discontinuation of 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 relative to the overall risk of breast cancer. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women using COCs, a biological effect of COCs, or a combination of both factors. A trend has been observed that malignant breast tumors detected in women who have ever taken COCs are generally less clinically advanced than in women who have never used COCs.

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

1. Other conditions

Depressed mood and depression are common adverse reactions associated with the use 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 informed of the need to consult a physician if mood swings or symptoms of depression occur, even shortly after initiation of treatment.

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

In women with hypertriglyceridemia or a family history of hypertriglyceridemia, the use of COCs may be associated with an increased risk of pancreatitis.

Although a slight increase in blood pressure has been observed in many women using COCs, clinically significant hypertension is rare. No causal relationship between COC use and clinically significant hypertension has been established. However, in cases of persistent clinically significant hypertension during COC use, discontinuation of COCs is advisable, and antihypertensive treatment should be initiated. COC use may be resumed if normal blood pressure values are achieved with antihypertensive therapy.

The occurrence or exacerbation of the following conditions has been reported during pregnancy and COC use, but their association with COC use has not been definitively proven: cholestatic jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice, which first occurred during pregnancy or previous use of sex steroid hormones, requires discontinuation of COCs.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating the need to alter therapeutic regimens in women with diabetes who take COCs. However, women with diabetes who use COCs should be under close medical supervision.

An increased risk of developing nonspecific ulcerative colitis and Crohn's disease has been associated with COC use.

Chloasma may occasionally develop (especially in women with a history of chloasma during pregnancy). Women predisposed to chloasma should avoid exposure to sunlight or ultraviolet radiation during COC use.

When selecting a contraceptive method(s), all the above information should be taken into account.

Medical examination/consultation

Before initiating or re-prescribing Regulon®, a thorough medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured, and a physical examination should be performed, guided by information on contraindications (see section "Contraindications") and special warnings and precautions (see section "Special Warnings and Precautions").

It is important to inform women about the risk of venous and arterial thrombosis, including the risk associated with Regulon® compared to other COCs, symptoms of VTE and ATE, established risk factors, and necessary actions in case of suspected thrombosis. Women should be advised to carefully read the package leaflet and follow the recommendations provided. The frequency and nature of follow-up examinations should be based on established medical practice guidelines, taking into account individual characteristics of each woman.

Women should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Reduced contraceptive efficacy

The effectiveness of COCs may be reduced in case of missed tablets, gastrointestinal disorders (see section "Dosage and Administration"), or concomitant use of other medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Due to the risk of reduced plasma concentration of Regulon® and diminished clinical effects, concomitant use with herbal preparations containing St. John's wort (Hypericum perforatum) should be avoided (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Menstrual cycle control

Irregular bleeding (spotting or breakthrough bleeding) may occur during use of any COCs, especially during the first months of use. Therefore, evaluation of any irregular bleeding is meaningful only after an adaptation period of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, non-hormonal causes of these conditions should be considered and malignancies or pregnancy should be excluded. Diagnostic curettage may be performed.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If a woman has used COCs according to the instructions described in the section "Dosage and Administration," the likelihood of pregnancy is low. However, if COCs have been used irregularly prior to the absence of the first withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

Regulon® contains lactose. Women with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

Regulon® should not be used during pregnancy. Before initiating Regulon®, pregnancy must be excluded. If pregnancy occurs during use of Regulon®, treatment should be discontinued immediately.

According to results of epidemiological studies, the frequency of congenital anomalies in newborns whose mothers took oral contraceptives before pregnancy does not exceed the normal rate. Furthermore, no teratogenic effects have been observed from the use of oral contraceptives in early pregnancy.

When re-prescribing Regulon®, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration" and "Special Warnings and Precautions").

Lactation period.

Oral contraceptives may reduce the quantity and alter the composition of breast milk. Moreover, this group of drugs passes into breast milk (although there is no evidence of adverse effects on infant health); therefore, the use of Regulon® is not recommended in breastfeeding women.

Small amounts of steroid hormones and/or their metabolites may pass into breast milk, but there is no evidence of adverse effects on infant health.

Ability to affect reaction speed when driving or operating machinery.

No effect of COCs on the ability to drive or operate machinery has been observed.

Method of Administration and Dosage.

Dosage

Begin tablet intake on the first day of the menstrual cycle, taking 1 tablet daily for 21 consecutive days without interruption, preferably at the same time each day. Then, a 7-day break should be taken, during which withdrawal bleeding usually occurs. On the day following the 7-day break (i.e., 4 weeks after the first tablet was taken, on the same day of the week), resume taking tablets from the next blister pack, which also contains 21 tablets, even if bleeding has not stopped. This regimen should be followed as long as contraception is needed. Provided the instructions are followed correctly, contraceptive protection remains effective during the 7-day tablet-free interval.

Tablets must be taken orally in the order indicated on the blister pack.

First use of Regulon®

If hormonal contraceptives have not been used in the previous month.

The first tablet of Regulon® should be taken on the first day of the menstrual cycle. In this case, no additional contraceptive methods are required.

Tablet intake may also begin between the 2nd and 5th day of menstruation; however, in this case, additional (barrier) contraceptive methods should be used during the first 7 days of tablet intake in the first cycle.

If more than 5 days have passed since the start of menstruation, the initiation of Regulon® should be postponed until the next menstrual period.

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

It is recommended that a woman start taking Regulon® tablets the day after taking the last active tablet of the previous COC. In such cases, Regulon® should not be started later than the day after the usual tablet-free interval or after the last inactive tablet of the previous COC. When switching from a vaginal ring or transdermal patch, it is recommended to start Regulon® on the day of removal of the previous method; in such cases, Regulon® should not be started later than the scheduled replacement date.

If the previous contraceptive method was used correctly and pregnancy is ruled out, switching to Regulon® can be done on any day of the cycle. The recommended tablet-free interval of the previously used contraceptive should not be exceeded.

Switching from progestogen-only contraceptives ("mini-pill", injections, implants) or a progestogen-releasing intrauterine system

A woman using a "mini-pill" (a preparation containing only progestogen) may start Regulon® on any day. For an implant or intrauterine system, start on the day of removal. For injectable contraceptives, start instead of the next scheduled injection. However, in all these cases, an additional contraceptive method is recommended during the first 7 days of tablet intake.

After first-trimester abortion

Regulon® should be started immediately on the same day as the procedure or miscarriage. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester abortion

For non-breastfeeding women, oral contraceptives should be started on days 21–28 after childbirth or second-trimester abortion. Additional contraceptive methods are not required in this case.

If Regulon® is started later, additional contraceptive methods should be used during the first 7 days of tablet intake.

If sexual intercourse has occurred after childbirth, tablet intake should be postponed until the first menstrual period.

Note: Women who are breastfeeding should not take COCs, as this may reduce the amount of breast milk (see section "Use in pregnancy or breastfeeding").

Missed tablets

If less than 12 hours have passed since a missed tablet, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, and then regular intake should continue at the usual time.

If more than 12 hours have passed since a missed tablet, contraceptive protection may be reduced. In case of a missed tablet, two main rules should be observed:

1. Do not interrupt tablet intake for more than 7 days.
2. Seven consecutive days of tablet intake are required to adequately suppress the hypothalamic-pituitary-ovarian system.

Accordingly, the following recommendations should be followed:

Week 1

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

Week 2

Take the missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue regular intake at the usual time. If tablets were taken correctly for the 7 days prior to the missed tablet, no additional contraceptive measures are needed. However, if more than one tablet was missed or if previous tablets were not taken correctly, an additional contraceptive method should be used for 7 days.

Week 3

The risk of reduced contraceptive efficacy is inevitable due to the proximity to the tablet-free interval. However, this can be prevented by adjusting the tablet intake schedule. If all tablets were taken correctly during the 7 days before the missed tablet, no additional contraceptive measures are needed if one of the two options below is followed. Otherwise, the woman should follow the first option and also use an additional contraceptive method for 7 days.

1. Take the missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue regular intake at the usual time. Immediately start a new blister pack after finishing the current one—i.e., do not take the usual 7-day break. Withdrawal bleeding before finishing the second pack is unlikely, but spotting or breakthrough bleeding may occur during tablet intake.
2. Alternatively, the woman may stop taking tablets from the current blister pack, observe a 7-day break (including the days when tablets were missed), and then start a new blister pack.

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

Recommendations in case of gastrointestinal disturbances

In cases of severe gastrointestinal disturbances, absorption of the drug may be incomplete, and additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking a tablet, follow the missed tablet recommendations outlined above. If the woman wishes to maintain her usual tablet-taking schedule, she should take an additional tablet(s) from another blister pack.

How to delay or shift the menstrual cycle

Delaying the menstrual cycle is not an approved indication for this drug. However, in exceptional cases when delaying menstruation is desired, the woman should continue taking tablets from a new Regulon® blister pack without the scheduled break. This delay can continue as long as desired, until the second blister pack is finished. During the delay, spotting or breakthrough bleeding may occur. After a planned 7-day break, regular intake of Regulon® can be resumed.

To shift the onset of menstruation to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. The shorter the break, the higher the risk that withdrawal bleeding will not occur, and spotting or breakthrough bleeding may occur during the next pack (during the delayed menstruation period).

Children. The safety and efficacy of desogestrel in adolescents under 18 years of age have not been established. No data are available.

Overdose

No serious adverse reactions have been reported with overdose of oral contraceptives. Possible symptoms may include nausea, vomiting, and slight vaginal bleeding in young girls. Overdose does not require specific treatment. However, gastric lavage may be considered if overdose is recognized within 2–3 hours or if a large number of tablets have been ingested. There is no specific antidote; symptomatic treatment should be administered.

Side effects.

Description of individual side effects

An increased risk of arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism, has been observed in women using combined oral contraceptives. Further information is provided in the section "Special precautions".

In addition, other adverse events observed during the use of COCs include arterial hypertension, hormone-dependent neoplasms (e.g., liver tumors, breast tumors), and chloasma, as described in detail in the section "Special precautions".

As with the use of any COCs, changes in the pattern of menstrual bleeding may occur, particularly during the first month of use. Changes may include alterations in frequency of bleeding (complete absence, decreased or increased frequency), intensity (decreased or increased), or duration.

Possible side effects reported in women taking COCs containing 0.15 mg desogestrel and 0.03 mg ethinylestradiol (as in the product Regulon®), as well as general side effects associated with COCs, are listed in the table below³. All side effects are classified by organ systems and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and frequency not known (cannot be estimated from available data).

3The most appropriate MedDRA term has been used to describe specific adverse reactions. Synonyms or related conditions are not listed, but should be considered.

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions between oral contraceptives and other medicinal products that induce microsomal enzymes (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions. Store at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging. 21 (21×1) tablets in a blister; 1 (21×1) or 3 (21×3) blisters in a cardboard box. A flat cardboard case for storing the blister is included in the cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address and location of manufacturing site.

H-1103 Budapest, Demréti Street 19–21, Hungary.

Marketing Authorization Holder.

JSC "Gedeon Richter".

Address of the Marketing Authorization Holder.

H-1103 Budapest, Demréti Street 19–21, Hungary.