Siluette^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER JSC (Hungary)

ATC Code

G03AA16 (Dienogest and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Siluette®

Film-coated tablets, 2 mg+0.03 mg: 21 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with an engraving “G53” on one side.

Excipients: lactose monohydrate – 47.66 mg, corn starch, hypromellose-2910, talc, polacrilin potassium, magnesium stearate; coating (Opadry II white 85F18422): polyvinyl alcohol, titanium dioxide (E171), macrogol-3350, talc

21 pcs. – blisters (1) – cardboard packs with a case for blister storage.
21 pcs. – blisters (3) – cardboard packs with a case for blister storage.

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

The combination of Dienogest + Ethinylestradiol is a low-dose monophasic oral combined estrogen-gestagen contraceptive drug.

The contraceptive effect of the Dienogest + Ethinylestradiol combination is achieved through complementary mechanisms, the most important of which are the suppression of ovulation and an increase in the viscosity of cervical secretion, making it impermeable to sperm.

When the drug is used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for one year) is less than 1. If a dose is missed or the drug is used incorrectly, the Pearl index may increase.

The gestagenic component of the Dienogest + Ethinylestradiol combination – Dienogest – has antiandrogenic activity, which has been confirmed by the results of a number of clinical studies.

In women taking combined oral contraceptives (COCs), the cycle becomes more regular, painful menstruation is less common, and the intensity and duration of bleeding are reduced, thereby lowering the risk of iron deficiency anemia.

Preclinical safety data

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

Pharmacokinetics

Dienogest

Absorption

When taken orally, Dienogest is rapidly and completely absorbed. C_max in plasma is 51 ng/ml and is reached after approximately 2.5 hours. The bioavailability is approximately 96%.

Distribution

Dienogest binds to plasma albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). The fraction of free dienogest in plasma is 10%; about 90% is non-specifically bound to plasma albumin.

Induction of SHBG synthesis by estradiol does not affect the binding of dienogest to plasma proteins.

Metabolism

Dienogest is almost completely metabolized.

Plasma clearance after a single dose is approximately 3.6 L/h.

Excretion

T_1/2 of dienogest from plasma is about 8.5-10.8 hours. A small amount of dienogest is excreted unchanged by the kidneys. Its metabolites are excreted by the kidneys and through the intestine in a ratio of 3:1, T_1/2 – 14.4 hours.

Steady-state concentration

The pharmacokinetics of dienogest are not influenced by SHBG levels in plasma. As a result of daily intake, the plasma concentration of dienogest increases approximately 1.5-fold, reaching a steady state after approximately 4 days of administration.

Ethinylestradiol

Absorption

Ethinylestradiol is rapidly and completely absorbed in the small intestine after oral administration. C_max in plasma is 67 pg/ml and is reached within 1.5-4 hours. During the “first pass” through the liver, a significant portion of ethinylestradiol is metabolized. The absolute bioavailability is approximately 44%.

Distribution

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

Metabolism

Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. The main pathway of ethinylestradiol metabolism is aromatic hydroxylation. Plasma clearance is approximately 2.3-7 ml/min/kg.

Excretion

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

Steady-state concentration

C_ss is reached during the second half of the treatment cycle.

Indications

• For adult women and adolescent girls after menarche for oral contraception.

ICD codes

Dosage Regimen

The drug Siluette^® should be taken orally, 1 tablet/day, daily, at approximately the same time, with a small amount of water.

How to take the drug Siluette^®

The calendar pack of Siluette^® contains 21 tablets. Each tablet in the pack is marked with the day of the week on which it should be taken.

Tablets should be taken in the direction of the arrow on the blister until all tablets (21 tablets) have been taken. For the next 7 days, the drug is not taken. Withdrawal bleeding should begin during these 7 days. It usually starts on the 2nd-3rd day after taking the last tablet and may not have finished before starting the tablets from the next pack. After the 7-day break, start taking tablets from the next pack, even if the bleeding has not yet stopped. This means that starting a new pack must be on the same day of the week and that withdrawal bleeding will occur on approximately the same day each month.

Taking tablets from the first pack of Siluette^®

When hormonal contraceptives were not used in the previous month

Siluette^® intake is started on day 1 of the menstrual cycle (i.e., on the first day of menstrual bleeding). The tablet marked with the corresponding day of the week should be taken. Then the tablets should be taken in the direction of the arrow on the blister. It is permissible to start taking the drug on days 2-5 of the menstrual cycle, but in this case, during the first 7 days of taking tablets from the first pack, it is recommended to additionally use a barrier method of contraception (e.g., a condom).

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

It is preferable to start taking Siluette^® the day after taking the last active tablet from the previous pack, but in no case later than the next day after the usual 7-day break (for drugs containing 21 tablets) or after taking the last inactive tablet (for drugs containing 28 tablets per pack). When switching from contraceptives with an extended dosing regimen, Siluette^® should be started after the usual break in taking active tablets. Siluette^® 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.

When switching from contraceptives containing only gestagens (“mini-pills”, injectable forms, implant), or from an intrauterine therapeutic system with gestagen release

Switching from “mini-pills” to Siluette^® can be done on any day (without a break), from an implant or intrauterine contraceptive with gestagen – on the day of their removal, from an injectable form – on the day when the next injection is due. In all these cases, during the first 7 days of taking the drug, an additional barrier method of contraception (e.g., a condom) must be used.

After termination of pregnancy (including spontaneous) in the first trimester of pregnancy

The drug can be started immediately. If this condition is met, no additional contraceptive measures are required.

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

It is recommended to start taking the drug on day 21-28 after childbirth (in the absence of breastfeeding) or termination of pregnancy in the second trimester. If the drug is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. If sexual intercourse occurred before starting Siluette^®, pregnancy must be ruled out.

Taking missed tablets

If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, and the next tablet should be taken at the usual time.

If the delay in taking the drug was more than 12 hours, contraceptive protection may be reduced. In this case, it is necessary to remember

• Drug intake should never be interrupted for more than 7 days;
• 7 days of continuous drug intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking the drug was more than 12 hours (the interval since taking the last tablet is more than 36 hours), depending on the week in which the tablet was missed, the following measures are necessary.

First week of taking the drug

The last missed tablet must be taken as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablets must be taken at the usual time. For the next 7 days, an additional barrier method of contraception (e.g., a condom) must be used. If sexual intercourse occurred during the week before missing the drug, the possibility of pregnancy must be considered. The more tablets missed and the closer they are to the break in taking the drug, the higher the risk of pregnancy.

Second week of taking the drug

The last missed tablet must be taken as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablets must be taken at the usual time.

Provided that the drug was taken correctly for the 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, and also if two or more tablets are missed, it is necessary to additionally use barrier methods of contraception (e.g., a condom) for the next 7 days.

Third week of taking the drug

The risk of reduced contraceptive reliability is inevitable due to the upcoming break in taking the drug. In this case, the following recommendations should be followed

• If all tablets were taken correctly during the 7 days preceding the first missed tablet, there is no need to use additional contraceptive methods. When taking missed tablets, follow points 1 or 2;
• If the drug was taken incorrectly during the 7 days preceding the first missed tablet, then for the next 7 days it is necessary to additionally use a barrier method of contraception (e.g., a condom), and in this case, follow point 1 for taking missed tablets.

1. The missed tablet must be taken as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablets are taken at the usual time until the tablets from the current pack are finished. Tablets from the next pack should be started immediately without the usual 7-day break. Withdrawal bleeding is unlikely until the tablets from the second pack are finished, but spotting and/or breakthrough bleeding may occur on the days of taking the drug.
2. Alternatively, the intake of tablets from the current pack can be interrupted, a break of 7 days or less can be taken ( including the day of missing the tablet), after which the intake of tablets from a new pack should be started.

If a woman missed taking tablets and then did not experience withdrawal bleeding during the break, pregnancy must be ruled out.

It is permissible to take no more than two tablets in one day.

Recommendations for gastrointestinal disorders

In case of severe gastrointestinal disorders, absorption may be incomplete, so additional contraceptive methods should be used. If vomiting or diarrhea occurs within 3-4 hours after taking the tablet, the recommendations for missed tablets should be followed. If a woman does not want to change her usual regimen and shift the start of withdrawal bleeding to another day of the week, an additional tablet should be taken from another pack.

Discontinuation of Siluette^®

Siluette^® can be discontinued at any time. If pregnancy is not planned, other methods of contraception should be considered. If pregnancy is planned, it is recommended to discontinue the drug and wait for a natural menstrual bleed.

Delaying the onset of withdrawal bleeding

To delay the onset of withdrawal bleeding, it is necessary to continue taking tablets from a new pack of Siluette^® immediately after all tablets from the previous pack have been taken, without a break in intake. Tablets from the new pack can be taken for as long as needed, including until the tablets in the pack run out. While taking the drug from the second pack, spotting and/or breakthrough bleeding may occur. Resumption of Siluette^® from the next pack should be after the usual 7-day break.

Changing the day of onset of withdrawal bleeding

To change the day of onset of withdrawal bleeding to another day of the week, the nearest 7-day break in taking tablets should be shortened (but not extended) by as many days as the woman wishes. For example, if the cycle usually starts on Friday, and in the future the woman wants it to start on Tuesday (3 days earlier), the intake of tablets from the next pack should be started 3 days earlier than usual. The shorter the interval, the higher the likelihood that withdrawal bleeding will not occur and that spotting and/or breakthrough bleeding will be observed while taking tablets from the second pack.

Special patient groups

Elderly patients over 65 years of age

Siluette^® is not used after menopause.

Liver function impairment

Siluette^® is contraindicated in patients with hepatic failure and severe liver diseases until liver function tests normalize.

Renal function impairment

Clinical studies of the dienogest and ethinylestradiol combination in patients with renal failure have not been conducted. Available data do not suggest a dosage adjustment in such patients.

Children

Siluette^® is indicated only after menarche.

Adverse Reactions

When taking COCs, irregular bleeding (“spotting” or “breakthrough” bleeding) may occur, especially during the first months of use.

Data on the frequency of adverse reactions reported during clinical studies of the ethinylestradiol and dienogest combination are presented in the table below.

Undesirable adverse reactions are distributed by system-organ class with an indication of their frequency of occurrence according to WHO recommendations: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), and frequency unknown (cannot be estimated from the available data).

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

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

Description of selected adverse reactions

The following are adverse reactions with a very low frequency of occurrence or with a delayed onset of symptoms that are considered to be associated with the group of combined oral contraceptives.

Tumors

• In women using combined oral contraceptives, the frequency of detection of breast cancer is very slightly increased. Since breast cancer is rare in women under 40 years of age, the increase in cancer frequency in women using combined oral contraceptives is insignificant in relation to the overall risk of breast cancer. A causal relationship with the use of combined oral contraceptives is unknown;
• Liver tumors (benign and malignant).

Other conditions

• Women with hypertriglyceridemia (increased risk of pancreatitis when using combined oral contraceptives);
• Increased blood pressure;
• Onset or worsening of conditions for which the association with the use of combined oral contraceptives is not indisputable: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes during pregnancy; hearing loss associated with otosclerosis;
• In women with hereditary angioedema, exogenous estrogens may cause or worsen symptoms of angioedema;
• Liver function disorders;
• Impaired glucose tolerance or effect on peripheral insulin resistance;
• Crohn’s disease, ulcerative colitis;
• Chloasma.

Interaction

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration in order to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged 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 combination of Dienogest + Ethinylestradiol is contraindicated in the presence of any of the conditions/diseases/risk factors listed below. If any of these conditions/diseases/risk factors develop for the first time while taking the combination of Dienogest + Ethinylestradiol, its use should be discontinued immediately.

• Hypersensitivity to dienogest and/or ethinylestradiol or to any of the excipients included in the drug;
• Venous thrombosis or thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), currently or in history;
• Arterial thrombosis or thromboembolism (ATE), including myocardial infarction, stroke; cerebrovascular disorders or prodromal conditions, including transient ischemic attack, angina, currently or in history;
• Identified acquired or hereditary predisposition to venous or arterial thrombosis, including activated protein C resistance, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of a pronounced high-risk factor or multiple high-risk factors for the development of VTE or ATE (see section “Special Precautions”) or the presence of such a serious risk factor as:
  • Diabetes mellitus with diabetic angiopathy;
  • Uncontrolled arterial hypertension;
  • Severe dyslipoproteinemia;
• Migraine with focal neurological symptoms currently or in history;
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Hepatic failure and severe liver diseases currently or in history (until liver function tests normalize);
• Liver tumors (benign or malignant) currently or in history;
• Identified hormone-dependent malignant diseases (including of the genital organs or mammary glands) or suspicion of them;
• Vaginal bleeding of unknown origin;
• Major surgical interventions with prolonged immobilization or extensive trauma;
• Pregnancy (including suspected);
• Breastfeeding period;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (the drug contains lactose monohydrate);
• Concomitant use with direct-acting antiviral drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Drug Interactions”).

With caution

The potential risk and expected benefit of using combined oral contraceptives should be carefully weighed in each individual case in the presence of the following diseases/conditions and risk factors.

• Risk factors for the development of thrombosis and thromboembolism:
  • Smoking;
  • Obesity;
  • Dyslipoproteinemia;
  • Controlled arterial hypertension;
  • Migraine without focal neurological symptoms;
  • Heart valve diseases, including uncomplicated heart valve diseases;
  • Hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident under the age of 50 in any of the immediate relatives);
• Other diseases in which peripheral circulatory disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis);
• Hereditary angioedema;
• Hypertriglyceridemia;
• Liver diseases not classified as contraindications;
• Diseases that first occurred or worsened during pregnancy or against the background of 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);
• Postpartum period;
• Epilepsy;
• Depression.

Use in Pregnancy and Lactation

Pregnancy

The use of the combination Dienogest + Ethinylestradiol during pregnancy is contraindicated. If pregnancy is diagnosed while using the contraceptive, its use 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, or a teratogenic effect when sex hormones were taken inadvertently in early pregnancy.

Breastfeeding period

The use of the combination Dienogest + Ethinylestradiol, like other combined oral contraceptives, may reduce the amount of breast milk and change its composition, therefore the use of the combination Dienogest + Ethinylestradiol is contraindicated until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites can penetrate into breast milk and affect the child’s health.

Use in Hepatic Impairment

The drug Siluette^® is contraindicated in hepatic failure and severe liver diseases (until liver function tests normalize); liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

The drug Siluette^® has not been specifically studied in patients with renal impairment. Available data do not suggest a change in treatment in such patients.

Pediatric Use

The drug Siluette^® is indicated only after menarche.

Geriatric Use

The drug Siluette^® is not used after menopause.

Special Precautions

If any of the conditions, diseases or risk factors listed below are currently present, a thorough assessment of the expected benefit versus the possible risk of using the combination Dienogest + Ethinylestradiol should be carried out for each woman individually before starting the drug. In case of worsening, intensification or first manifestation of any of these conditions, diseases or risk factors, the woman should consult her doctor, who may decide on the need to discontinue the drug.

Risk of developing VTE and ATE

Results of epidemiological studies indicate a relationship between the use of combined oral contraceptives and an increased incidence of venous and arterial thrombosis and thromboembolism (such as DVT and PE, myocardial infarction, stroke, cerebrovascular disorders). These diseases are rare. The increased risk is present after initial use of combined oral contraceptives or resumption of use after a break of 4 weeks or more. The greatest risk of developing VTE is observed in the first year of using combined oral contraceptives, mainly during the first 3 months.

Combined oral contraceptives containing levonorgestrel, norgestimate or norethisterone as the progestogenic component have the lowest risk of developing VTE. Other combined oral contraceptives, such as the combination of dienogest and ethinylestradiol, may have an increased risk of their development compared to levonorgestrel-containing drugs (1.6 times). The choice in favor of the combination Dienogest + Ethinylestradiol can only be made after consulting the woman, which will ensure her full understanding of the risk of developing VTE associated with the use of the drug, and the effect of the drug on her existing risk factors and that the risk of developing VTE is maximum in the first year of using combined oral contraceptives.

VTE can be life-threatening or fatal (in 1-2% of cases).

Very rarely, when using combined oral contraceptives, thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.

Symptoms of deep vein thrombosis unilateral swelling or swelling along the vein, pain or discomfort in the lower limb only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin of the lower limb.

Symptoms of pulmonary embolism 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 (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions/diseases (e.g., respiratory tract infections).

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

Symptoms of stroke include: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden unilateral or bilateral loss of vision; sudden gait disturbance, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion sudden pain, swelling and slight cyanosis of the extremities, “acute” abdomen.

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

Arterial thromboembolism can be life-threatening or fatal.

In women with a combination of several risk factors or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the degree of increased risk of thrombosis may be higher than with simple summation of risk factors. In this case, the use of the combination of dienogest and ethinylestradiol is contraindicated.

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

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

In the presence of

• Obesity (body mass index 30 kg/m² and above);
• Family history (for example, venous or arterial thromboembolism ever in close relatives or parents under the age of 50); in case of hereditary or acquired predisposition, a woman should be examined by an appropriate specialist to decide on the possibility of taking the contraceptive;
• Dyslipoproteinemia;
• Arterial hypertension;
• Migraine;
• Heart valve diseases;
• Atrial fibrillation;
• Prolonged immobilization, major surgery, any surgery on the lower extremities or extensive trauma; in these cases, the drug should be discontinued (in the case of planned surgery, at least 4 weeks before it) and not resumed for 2 weeks after the end of immobilization.

Temporary immobilization (for example, an air flight lasting more than 4 hours) may also be a risk factor for the development of venous thromboembolism, 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 developing thromboembolism in the postpartum period should be taken into account.

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

An increase in the frequency and severity of migraine during the use of the drug (which may precede cerebrovascular disorders) is a reason for immediate discontinuation of the contraceptive.

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

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

Tumors

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of cervical cancer with long-term use of COCs, but the association with COC use has not been proven. To date, there are controversies regarding the extent of the influence of various factors on these data, in particular, cervical screening examinations or features of a woman’s sexual behavior (number of sexual partners or less frequent use of barrier contraceptive methods), as well as the cause-and-effect relationship of these factors.

According to a meta-analysis of 54 epidemiological studies, a small increase (1.24-fold) in the risk of breast cancer was detected in women using COCs. The increased risk gradually disappears within 10 years after stopping COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking COCs or having taken them recently is insignificant relative to the overall risk of developing this disease. Its association with COC use has not been proven. The observed increase in breast cancer risk may be due not only to earlier diagnosis of breast cancer but also to the biological effects of sex hormones or a combination of these two factors. In women who have ever used COCs, earlier clinical stages of breast cancer are detected compared to women who have never used them.

In rare cases, the development of benign, and in extremely rare cases, malignant liver tumors has been observed during the use of COCs, which in some cases led to life-threatening intra-abdominal bleeding. In case of severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding, this should be considered during differential diagnosis.

Other Conditions

Depressed mood and depression are known adverse reactions when using hormonal contraceptives (see section “Adverse Reactions”). Depression can be a serious disorder and is a known risk factor for suicidal behavior and suicide. Women should be advised to consult their doctor if mood changes and depressive symptoms occur, including shortly after starting the contraceptive.

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

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

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

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

Although COCs can affect insulin resistance and glucose tolerance, adjustment of the dose of hypoglycemic drugs in patients with diabetes using low-dose COCs (<0.05 mg ethinylestradiol) is generally not required. However, patients with diabetes should be carefully monitored while taking COCs.

Chloasma may sometimes develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma while taking the Dienogest + Ethinylestradiol combination should avoid prolonged sun exposure and ultraviolet radiation.

Laboratory Tests

Taking the Dienogest + Ethinylestradiol combination may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal function, the concentration of transport proteins in plasma, parameters of carbohydrate metabolism, and parameters of blood coagulation and fibrinolysis. The changes usually do not exceed the normal range.

Reduced Efficacy

The efficacy of the Dienogest + Ethinylestradiol combination may be reduced in the following cases: when a tablet is missed, in case of gastrointestinal disorders, or as a result of drug interactions.

Frequency and Severity of Menstrual-like Bleeding

Irregular bleeding (“spotting” and/or “breakthrough” uterine bleeding) may occur while taking the Dienogest + Ethinylestradiol combination, especially during the first months of use. Therefore, the assessment of any irregular bleeding should be performed only after an adaptation period of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant neoplasms or pregnancy.

Absence of Scheduled Menstrual-like Bleeding

In some women, withdrawal bleeding may not occur during the tablet-free interval. If the Dienogest + Ethinylestradiol combination was taken as recommended, it is unlikely that the woman is pregnant. However, if the drug was previously used irregularly or if two consecutive withdrawal bleedings are absent, the drug should not be continued until pregnancy is ruled out.

Medical Examinations

Before starting or resuming the use of the Dienogest + Ethinylestradiol combination, it is necessary to review the woman’s medical history, family history, perform a thorough medical (including measurement of blood pressure, heart rate, determination of BMI) and gynecological examination, including breast examination and cervical cytology (Pap test), and rule out pregnancy. When resuming the Dienogest + Ethinylestradiol combination, the scope of additional tests and the frequency of follow-up examinations is determined individually, but not less than once every 6 months.

It must be borne in mind that the Dienogest + Ethinylestradiol combination does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Conditions requiring medical consultation

• Any changes in health status, especially the occurrence of conditions listed in the “Contraindications” section and the “Use with caution” subsection.
• A localized lump in the breast.
• Concomitant use of other medications (see also the “Drug Interactions” section).
• If prolonged immobilization is expected (e.g., a cast on a lower limb), hospitalization or surgery is planned (at least 4 weeks before the planned surgery).
• Unusually heavy vaginal bleeding.
• A tablet was missed in the first week of taking the pack, and sexual intercourse occurred seven or fewer days before that.
• Absence of scheduled menstrual-like bleeding twice in a row or suspicion of pregnancy (the next pack of the drug should not be started before consulting a doctor).

Tablet intake should be stopped and a doctor should be consulted immediately if there are possible signs of thrombosis, myocardial infarction, or stroke: unusual cough; unusually severe pain behind the breastbone radiating to the left arm; sudden onset of shortness of breath; unusual, severe, and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell, or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in a lower limb or sudden swelling of any of the lower limbs.

Excipients

The drug contains 47.66 mg of lactose monohydrate in each tablet. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on the Ability to Drive Vehicles and Machinery

No effect on the ability to drive vehicles and machinery has been identified.

Overdose

No serious disorders due to overdose have been reported.

Symptoms nausea, vomiting, and withdrawal bleeding. Vaginal bleeding may occur in girls who have not reached menarche if the drug is taken accidentally.

Treatment there is no specific antidote; symptomatic treatment should be carried out.

Drug Interactions

Effect of other medicinal products on the combination of dienogest and ethinylestradiol

Interaction 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.

Induction of hepatic microsomal enzymes may be observed within a few days of concomitant use. Maximum induction of hepatic microsomal enzymes is usually observed within a few weeks. After discontinuation of the drug, induction of hepatic microsomal enzymes may persist for up to 4 weeks.

Short-term therapy

Women who are treated with such drugs in addition to the Dienogest + Ethinylestradiol combination are advised to use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method of contraception should be used throughout the period of taking the concomitant drugs and for 28 days after their discontinuation. If the use of the hepatic microsomal enzyme inducer continues after taking the last Dienogest + Ethinylestradiol combination tablet from the current pack, a new pack of the Dienogest + Ethinylestradiol combination should be started without the usual 7-day break.

Long-term therapy

Women on long-term treatment with hepatic microsomal enzyme inducers are advised to use another reliable non-hormonal method of contraception.

Agents that increase the clearance of the active substances of the dienogest and ethinylestradiol combination (weakening efficacy by enzyme induction)

Phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort (Hypericum perforatum).

Agents with varying effects on the clearance of the active substances of the dienogest and ethinylestradiol combination

When used concomitantly with the dienogest and ethinylestradiol combination, many HIV or hepatitis C virus protease inhibitors (glecaprevir/pibrentasvir) and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogen or progestin. In some cases, this effect may be clinically significant.

Agents that reduce COC (enzyme inhibitors)

Dienogest is a substrate of the CYP3A4 isoenzyme. Strong and moderate CYP3A4 inhibitors, 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 or progestin, or both.

Etoricoxib at doses of 60 and 120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4 and 1.6 times, respectively, when co-administered with COCs containing 0.035 mg ethinylestradiol.

Effect of the dienogest and ethinylestradiol combination 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 administration of a hormonal contraceptive containing Ethinylestradiol did not lead to any increase or led only to 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).

In clinical studies involving patients receiving therapy for viral hepatitis C with direct-acting antiviral drugs containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin, an increase in ALT activity of more than 5 times the upper limit of normal was observed in women who were also taking ethinylestradiol-containing combined hormonal contraceptive drugs, compared to healthy and hepatitis C virus-infected women.

An increase in ALT activity was also noted in women taking ethinylestradiol-containing drugs, e.g., CHCs, and receiving therapy with the glecaprevir/pibrentasvir combination or sofosbuvir/velpatasvir/voxilaprevir (see section “Contraindications”).

Therefore, women taking the Dienogest + Ethinylestradiol combination should be switched to alternative contraceptive methods (non-hormonal or progestogen-only contraceptives) before starting treatment. The Dienogest + Ethinylestradiol combination can be resumed no earlier than 2 weeks after the end of the course of antiviral therapy.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, in the original packaging (blister in a carton), at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

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.