Siluet®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SILET® (SILET®)

Composition:

Active substances: dienogest, ethinylestradiol;

One film-coated tablet contains 2 mg of dienogest and 0.03 mg of ethinylestradiol;

Excipients: lactose monohydrate, corn starch, hypromellose (type 2910), talc, potassium polyacrylate, magnesium stearate;

Coating: Opadry II 85F18422 white (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white or almost white, round, biconvex film-coated tablets with "G53" engraved on one side and no engraving on the other side. Diameter approximately 5.5 mm.

Pharmacotherapeutic group. Sex hormones and modulators of the genital system. Progestogens and estrogens, fixed combinations. ATC code G03AA16.

Pharmacological Properties.

Pharmacodynamics.

All hormonal contraceptive methods are characterized by a very low rate of contraceptive failure when used according to instructions. The rate of contraceptive failure may be higher if the drug is not used in accordance with the instructions (e.g., missed tablet).

In clinical trials with Cilest®, the Pearl Index was calculated as follows:

• Unadjusted Pearl Index – 0.454 (upper 95% confidence interval (CI): 0.701);
• Adjusted Pearl Index – 0.182 (upper 95% confidence interval: 0.358).

Cilest®, film-coated tablets, is a combined oral contraceptive (COC) with antiandrogenic effect, containing ethinylestradiol and dienogest as the progestogen.

The contraceptive effect of Cilest® tablets is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

The antiandrogenic effect of the combination of ethinylestradiol and dienogest is primarily based on the reduction of androgen levels in blood plasma.

Dienogest is a derivative of nortestosterone with an in vitro affinity for progesterone receptors that is 10–30 times lower compared to other synthetic progestogens. In vivo data in animals indicate strong progestogenic and antiandrogenic activity. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

The dose of dienogest that leads to suppression of ovulation is 1 mg/day.

When high-dose COCs (0.05 mg ethinylestradiol) are used, the risk of endometrial and ovarian cancer is reduced. Whether this also applies to low-dose COCs remains unclear.

Pharmacokinetics.

Ethinylestradiol.

Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. Maximum serum concentration is approximately 67 pg/mL and is reached within 1.5–4 hours. During absorption and first-pass metabolism in the liver, ethinylestradiol undergoes extensive metabolism, resulting in an average oral bioavailability of approximately 44%.

Distribution. Ethinylestradiol binds strongly, but non-specifically, to serum albumin (approximately 98%) and induces an increase in serum concentrations of sex hormone-binding globulin (SHBG). The apparent volume of distribution of ethinylestradiol is approximately 2.8–8.6 L/kg.

Biological transformation. Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver. Ethinylestradiol is metabolized mainly via aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are also formed, including both free metabolites and conjugates with glucuronides and sulfates. Clearance is 2.3–7 mL/min/kg.

Elimination. Serum levels of ethinylestradiol decline in a biphasic manner, with half-lives of approximately 1 hour and 10–20 hours, respectively. Ethinylestradiol is not excreted unchanged; its metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is approximately 1 day.

Steady state. Steady state is achieved during the second half of the cycle of use, when the serum concentration of ethinylestradiol is approximately twice as high compared to a single dose.

Dienogest.

Absorption. After oral administration, dienogest is rapidly and completely absorbed. Maximum plasma concentration (51 ng/mL) is reached 2.5 hours after taking one tablet. Absolute bioavailability when co-administered with ethinylestradiol is 96%.

Distribution. Dienogest binds to serum albumin and does not bind to SHBG or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum is present as free steroid, while 90% is non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG levels does not affect the binding of dienogest to serum proteins. The apparent volume of distribution of dienogest ranges from 37 to 45 L.

Biological transformation. Dienogest is metabolized primarily by hydroxylation and conjugation, forming mainly endocrinologically inactive metabolites. These metabolites are rapidly eliminated from plasma, so no active metabolites are observed in plasma, only unchanged dienogest. Total clearance (CL/F) is 3.6 L/h after single administration.

Elimination. Plasma levels of dienogest decline with a half-life of approximately 9 hours. Only a negligible amount of dienogest is excreted unchanged by the kidneys. After an oral dose of 0.1 mg/kg body weight, excretion in feces and urine has a ratio of approximately 3:2. After oral administration, about 86% of the administered dose is excreted within 6 days, with the majority (42%) excreted in urine within the first 24 hours.

Steady state. The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, plasma concentration increases 1.5-fold, reaching steady state after 4 days of use.

Clinical characteristics.

Indications.

Oral contraception.

Before prescribing Silhouette®, the presence of individual risk factors in women, particularly regarding venous thromboembolism (VTE), should be assessed, and the risk of VTE with Silhouette® should be compared to the risk associated with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

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

• Presence or risk of venous thromboembolism (VTE):

• current venous thromboembolism (on anticoagulant therapy) or history thereof (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));

• known hereditary or acquired predisposition to VTE, such as activated protein C resistance (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency;

• major surgery with prolonged immobilization (see section "Special precautions");

• high risk of VTE due to the presence of multiple risk factors (see section "Special precautions");

• presence or risk of arterial thromboembolism (ATE):

  • current arterial thromboembolism, including history (e.g., myocardial infarction), or presence of prodromal symptoms (e.g., angina pectoris);
  • cerebrovascular disorders, including history of stroke or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high likelihood of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to the presence of any of the following serious risk factors:

• diabetes mellitus with vascular complications;

• severe arterial hypertension;

• severe dyslipoproteinemia;

• current or past pancreatitis, if associated with severe hypertriglyceridemia;

• current or past severe liver disease, until liver function tests return to normal;

• current or past liver tumors (benign or malignant);

• known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breasts);

• confirmed or suspected pregnancy;

• vaginal bleeding of unknown etiology;

• hypersensitivity to the active substances or to any of the excipients of the drug.

Concomitant use of Silhouette® with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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

Pharmacodynamic interactions

During clinical studies in patients receiving antiviral treatments for hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased alanine aminotransferase (ALT) levels exceeding 5 times the upper limit of normal (ULN) were observed. This occurred more frequently in women using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, increased ALT levels were also observed in women receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir who were taking ethinylestradiol-containing medicinal products such as CHCs (see section "Contraindications").

Therefore, women using Silhouette® must switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before initiating therapy with the above-mentioned drug combinations. Use of Silhouette® may be resumed 2 weeks after completion of therapy with these combined drugs.

Pharmacokinetic interactions

Effect of other medicinal products on Silhouette®.

Interactions are possible with medicinal products that induce microsomal enzymes. This leads to increased clearance of sex hormones, which in turn may alter the pattern of menstrual bleeding and/or lead to contraceptive failure.

Therapy

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should use a barrier method or another contraceptive method in addition to the combined oral contraceptive (COC). The barrier method should be used throughout the entire duration of treatment with the enzyme-inducing drug and for an additional 28 days after discontinuation.

If treatment with an enzyme-inducing drug is initiated during the period of taking the last tablets in the current COC pack, the next pack of COC tablets should be started immediately after finishing the previous pack, without the usual break.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another reliable non-hormonal contraceptive method.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction), e.g.: barbiturates, carbamazepine, phenytoin, primidone, rifampicin; also possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and medicinal products containing St John's wort (Hypericum perforatum).

Substances with variable effects on CHC clearance

When used concomitantly with COCs, many combinations of HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the medicinal product used for HIV/HCV treatment should be reviewed to identify potential interactions. 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.

Substances decreasing COC clearance (enzyme inhibitors)

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

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both components.

Etoricoxib at doses of 60 to 120 mg/day has demonstrated a 1.4–1.6-fold increase in ethinylestradiol plasma concentrations when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of Silhouette® on other medicinal products.

Oral contraceptives may affect the metabolism of other medicinal products. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). However, in vitro data indicate that inhibition of CYP enzymes by dienogest at therapeutic doses is unlikely.

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 types of interactions

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, as well as levels of plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Such changes are usually within normal limits.

Special precautions.

Warning. If any of the conditions or risk factors listed below are present, the appropriateness of using Siluet® should be discussed with the woman.

If any of the conditions or risk factors listed below worsen or occur for the first time, the woman should consult her physician, who may decide that Siluet® should be discontinued.

Combined oral contraceptives (COCs) should be discontinued if venous thromboembolism (VTE) or arterial thromboembolism (ATE) is suspected or confirmed. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (e.g., coumarins).

Circulatory disorders.

Risk of venous thromboembolism (VTE).

The use of any combined hormonal contraceptives (CHCs) increases the risk of venous thromboembolism (VTE) in women compared to non-users. Products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Other medicinal products, such as Siluet®, may increase this risk by up to 1.6 times. The decision to use a product other than those with the lowest VTE risk should only be made after thorough discussion with the woman. It is essential to ensure she fully understands the VTE risk associated with Siluet®, the impact of her individual risk factors, and the fact that VTE risk is highest during the first year of use. Some data suggest that the risk of VTE may increase when resuming CHC use after a break of 4 weeks or longer.

In women who do not use CHCs and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, in any individual woman, the risk may be significantly higher depending on her specific risk factors (see below).

Epidemiological studies indicate that among women using low-dose combined oral contraceptives (< 50 μg ethinylestradiol), 6–12 out of 10,000 users will develop VTE within one year.

It is estimated that among 10,000 women using CHCs containing levonorgestrel, approximately 61 will develop VTE within one year.

According to estimates², 8–11 out of 10,000 women using CHCs containing dienogest and ethinylestradiol will develop VTE within one year.

The annual number of VTE cases with CHC use is lower than that expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

Very rare cases of thrombosis in other vessels, including hepatic, mesenteric, renal veins or arteries, as well as retinal veins or arteries, have been reported in women using CHCs.

1 Based on average estimates of 5–7 cases per 10,000 woman-years, calculated from the relative risk of CHCs containing levonorgestrel compared to non-CHC users (approximately 2.3–3.6 cases).

2 According to meta-analysis data, the risk of VTE in women using dienogest and ethinylestradiol is slightly higher compared to women using COCs containing levonorgestrel (relative risk 1.57, range 1.07–2.30).

Risk factors for VTE development.

The risk of venous thromboembolic complications in women using CHCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see Table 1).

Siluet® is contraindicated in women with multiple risk factors that may increase the risk of 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 risks associated with each individual factor; therefore, the overall risk of VTE should be considered. CHCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 1. Risk factors for VTE development.

Risk factor	Comment
Obesity (body mass index over 30 kg/m2).	Risk increases significantly with increasing BMI of the patient. Particular attention is required when other risk factors are present.
Long-term immobilization, major surgery, any surgery on lower limbs or pelvic organs, neurosurgery, or extensive trauma. Note: temporary immobilization, including air travel longer than 4 hours, may also be a risk factor for VTE, especially in women with other risk factors.	In such situations, it is recommended to discontinue use of the drug/patch/ring (at least 4 weeks before elective surgery) and not resume use until at least 2 weeks after full resumption of mobility. Alternative contraceptive methods should be used to avoid unintended pregnancy. Antithrombotic treatment may be advisable if use of Siluet® was not discontinued in advance.
Family history (venous thromboembolism in a close relative or parent, especially at a relatively young age, e.g. before age 50).	If hereditary predisposition to VTE is suspected, women should consult a specialist before using any COCs.
Other medical conditions associated with VTE	Cancer, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), and sickle cell anemia.
Increasing age	Particularly over 35 years.

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the occurrence or progression of venous thrombosis.

Particular attention should be paid to the increased risk of thromboembolism during pregnancy and especially in the first 6 weeks postpartum (for information on pregnancy and lactation, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot, or swelling along a vein in the leg;
• Pain or tenderness in the leg, which may only be felt while standing or walking;
• Increased warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

• Sudden onset of unexplained shortness of breath or rapid breathing;
• Sudden cough, possibly with hemoptysis;
• Sudden chest pain;
• Severe dizziness or lightheadedness;
• Rapid or irregular heartbeat.

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

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

In cases of ocular vessel occlusion, initial symptoms may include blurred vision without pain, which may progress to vision loss. Sometimes, vision loss occurs almost instantaneously.

Risk of arterial thromboembolism (ATE).

Epidemiological studies indicate that the use of COCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic complications can be fatal.

Risk factors for ATE.

The risk of developing arterial thromboembolic complications or cerebrovascular events while using COCs increases in women with risk factors as described in Table 2. Siluet® is contraindicated if a woman has one serious or multiple risk factors for ATE that may increase the risk of arterial 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 risks associated with each individual factor, so the overall risk should be considered. COCs should not be prescribed if the benefit-risk ratio is unfavorable (see section "Contraindications").

Table 2. Risk factors for ATE

Risk factor	Comment
Increasing age	Especially over 35 years.
Smoking	Women should be advised to stop smoking if they wish to use COCs. Women aged 35 years and older who continue to smoke should be strongly advised to use another method of contraception.
Arterial hypertension
Obesity (body mass index exceeds 30 kg/m²)	Risk increases significantly with increasing body mass index. Particular attention is required if women have other risk factors.
Family history (arterial thromboembolism in a close relative or parent, especially at a relatively young age, e.g. before 50)	If hereditary predisposition to arterial thromboembolism is suspected, women should be advised to consult a specialist before using any COCs.
Migraine	An increase in frequency or severity of migraine during COC use (which may be a prodromal sign of cerebrovascular events) may require immediate discontinuation of the drug.
Other medical conditions associated with vascular adverse reactions	Diabetes mellitus, hyperhomocysteinemia, heart valve disorders and atrial fibrillation, dyslipoproteinemia, systemic lupus erythematosus.

ATE Symptoms

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision changes in one or both eyes;
• sudden, severe, or prolonged headache with no known cause;
• loss of consciousness or fainting, with or without seizures.

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

Symptoms of myocardial infarction (MI) may include:

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

Tumors.

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs (more than 5 years), although this observation remains controversial, as it is not fully established whether the study results adequately account for confounding risk factors such as sexual behavior and other factors, including human papillomavirus infection.

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 returns to the baseline level associated with age within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among current or recent users of COCs is small in relation to the overall risk of breast cancer.

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 differential diagnosis of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of liver tumor should be considered in women taking COCs.

Such neoplasms may be life-threatening or lead to fatal outcomes.

Other conditions.

Depressed mood and depression are common adverse reactions during 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 to contact their physician if they experience mood swings or symptoms of depression, even if these occur shortly after starting treatment.

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

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension is rare. However, if clinically manifest arterial hypertension develops during COC use, it is appropriate to discontinue COCs and treat the hypertension. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive therapy. COCs should be discontinued if persistently high blood pressure values remain during COC use despite adequate antihypertensive therapy in women with pre-existing hypertension diagnosed before starting COCs.

The occurrence or exacerbation of the following conditions has been reported during pregnancy and with use of COCs, but their causal relationship to COC use has not been definitively established: jaundice and/or pruritus associated with cholestasis; gallbladder stone 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 and acquired angioedema.

COC use may need to be discontinued in cases of acute or chronic liver dysfunction until liver function tests return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis that first occurred during pregnancy or previous use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating the need to alter therapy in women with diabetes mellitus who use low-dose COCs (< 0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use, especially at the beginning of treatment.

Exacerbations of endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have also been observed during COC use.

Chloasma may occasionally occur, particularly in women with a history of chloasma of pregnancy. Women predisposed to chloasma should avoid direct sunlight and ultraviolet radiation during COC use.

Medical examination/consultation.

Before initiating or resuming use of Siluet® a thorough medical and family history should be taken, a medical examination performed, and pregnancy excluded. Blood pressure should be measured and a medical examination conducted, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special Precautions"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Siluet® compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

Patients are advised to carefully read the package leaflet and follow the recommendations provided. The frequency and nature of medical check-ups should follow established treatment protocols and be adapted to each individual woman.

Patients should be warned that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted infections.

Reduced efficacy.

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

Cycling disturbances.

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

If irregular bleeding persists or occurs after several regular cycles, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures undertaken, including evaluation to exclude malignancy or pregnancy. Diagnostic procedures may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to the instructions in the section "Dosage and Administration," pregnancy is unlikely. However, if COC use was irregular before the first missed withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

This medicinal product contains 47.66 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated during pregnancy.

If pregnancy occurs during use of Siluet®, treatment should be discontinued immediately. Extensive epidemiological studies have not shown an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor evidence of teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation. Based on animal data, adverse effects due to hormonal influence of the active substances cannot be excluded. However, the overall experience with COC use during pregnancy does not indicate adverse effects in humans.

When resuming use of Siluet®, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration" and "Special Precautions").

Lactation period. COCs may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the infant. Therefore, Siluet® is not recommended until complete weaning.

Ability to influence reaction speed when driving or operating machinery.

Studies on the influence on the ability to drive or operate machinery have not been conducted. No effect on the ability to drive or operate machinery has been observed in women using COCs.

Method of Administration and Dosage.

Method of Administration.

For oral use.

Dosage.

How to take Siluet®

Tablets should be taken daily at approximately the same time, with a small amount of liquid if necessary, in the order indicated on the blister pack. One tablet should be taken daily for 21 consecutive days. The first tablet of each subsequent pack should be taken after a 7-day break, during which withdrawal bleeding usually occurs. This bleeding typically starts 2–3 days after taking the last tablet and may not have ended by the time the next pack is started.

How to Start Treatment with Siluet®

If hormonal contraceptives have not been used previously (last month). Begin taking tablets on the first day of menstrual bleeding.

Switching from another combined oral contraceptive (COC). It is recommended to start taking Siluet® tablets the day after taking the last active tablet of the previous COC, but no later than the day after the usual tablet-free interval or after placebo tablets of the previous COC.

Switching from a vaginal ring or transdermal patch.

It is recommended to start using Siluet® on the day of removal of the vaginal ring or transdermal patch, but no later than the day when the next application of these products would normally occur.

Switching from a progestogen-only method (‘mini-pill’, injections, implants) or intrauterine system containing progestogen.

Siluet® can be started at any time after discontinuation of the ‘mini-pill’ (in the case of an implant or intrauterine system – on the day of removal; in the case of an injection – instead of the next scheduled injection). However, in all cases, it is recommended to use an additional barrier method of contraception during the first 7 days of taking the drug.

After first-trimester abortion.

Treatment should begin immediately on the same day after the procedure. In this case, there is no need to use additional contraceptive methods.

After childbirth or second-trimester abortion.

It is recommended to start taking Siluet® on days 21–28 after childbirth or second-trimester abortion. If treatment is started later, an additional barrier method of contraception should be used during the first 7 days of tablet use. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting the COC, or the first menstrual period should be awaited.

For information regarding breastfeeding, see section «Use during pregnancy or breastfeeding».

Missed tablet.

If the delay in taking the tablet does not exceed 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible. The next tablet from the pack should be taken at the usual time.

If the delay in taking the tablet exceeds 12 hours, contraceptive protection may be reduced. In this case, two main rules should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous tablet intake for 7 days.

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

• Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. Additionally, use a barrier method of contraception (e.g., condom) for the next 7 days. If sexual intercourse occurred in the previous 7 days, consider the possibility of pregnancy. The greater the number of missed tablets and the closer to the 7-day tablet-free interval, the higher the risk of pregnancy.

• Week 2

Take the last missed tablet as soon as possible, even if two tablets have to be taken simultaneously. Then continue taking tablets at the usual time. If tablets were taken correctly during the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use an additional barrier method of contraception for 7 days.

• Week 3

The risk of reduced efficacy increases as the 7-day tablet-free interval approaches. However, following one of the regimens below can prevent a reduction in contraceptive protection. If one of the following options is followed, additional contraceptive methods are not required, provided tablets were taken correctly during the 7 days before the missed dose. Otherwise, the first option below should be followed, and additional contraceptive methods used for the next 7 days.

1. Take the last missed tablet as soon as possible, even if two tablets have to be taken at the same time. Then continue taking tablets at the usual time. Start the next pack immediately after finishing the current one, i.e., no tablet-free interval should occur. Withdrawal bleeding is unlikely to occur before finishing the second pack, although spotting or breakthrough bleeding may occur.
2. Alternatively, it is possible to stop taking tablets from the current pack. In this case, the tablet-free interval, including the days of missed tablets, should not exceed 7 days; tablet intake should resume with the next pack.

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

Recommendations in case of gastrointestinal disturbances.

In case of severe gastrointestinal disorders, incomplete absorption of the drug is possible; therefore, additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking a tablet, a new tablet should be taken as soon as possible. If more than 12 hours have passed, follow the instructions for missed tablets as described in the section «Method of Administration and Dosage», subsection «Missed tablet». If a woman does not wish to change her usual dosing schedule, she should take an additional tablet(s) from another blister pack.

Delaying withdrawal bleeding.

To delay withdrawal bleeding, continue taking Siluet® tablets from a new pack without a break. The duration of intake may be extended, if desired, up to the end of the second pack. Breakthrough bleeding or spotting may occur during this time. Normal Siluet® dosing should be resumed after the usual 7-day tablet-free interval.

To shift the timing of menstruation to another day of the week than that indicated by the current dosing schedule, it is recommended to shorten the tablet-free interval by the desired number of days. It should be noted that the shorter the interval, the more frequent the absence of menstruation-like bleeding and the higher the risk of breakthrough bleeding or spotting during the intake of tablets from the second pack (as in the case of delaying withdrawal bleeding).

Additional Information for Special Patient Groups

Geriatric Patients

Do not use. Siluet® is not indicated after menopause.

Patients with Hepatic Impairment

Siluet® is contraindicated in women with severe liver disease (see section «Contraindications»).

Patients with Renal Impairment

Siluet® has not been specifically studied in patients with renal impairment. Available data do not indicate the need for dosage adjustment in this patient group.

Children. The drug is indicated for use only after onset of menstruation.

Overdose.

Acute toxicity of dienogest and ethinylestradiol after oral administration is very low. For example, if a child takes several Siluet® tablets at once, symptoms of intoxication are unlikely. Possible symptoms in such cases include nausea, vomiting, and slight vaginal bleeding in young girls. Specific treatment is usually not required. Symptomatic therapy may be administered if necessary.

Adverse reactions.

Adverse reactions are listed in decreasing order of severity. Frequency is defined as follows: common (≥1/100 to ≤1/10), uncommon (≥1/1000 to <1/100), and rare (≥1/10,000 to <1/1000). Other adverse reactions observed only during the post-marketing period, for which frequency cannot be estimated, are listed under the column "Frequency unknown".

System Organ Classes	Common	Uncommon	Rare	Frequency not known
Infections and infestations		vaginitis/vulvovaginitis, vaginal candidiasis or other fungal vulvovaginal infections	salpingo-oophoritis, urinary tract infections, cystitis, mastitis, cervicitis, fungal infections, candidiasis, oral herpes, influenza, bronchitis, sinusitis, upper respiratory tract infections, viral infections
Benign, malignant and unspecified neoplasms (incl. cysts and polyps)			uterine leiomyoma, breast lipoma
Blood and lymphatic system disorders			anaemia
Immune system disorders			hypersensitivity	exacerbation of symptoms of hereditary and acquired angioedema
Endocrine disorders			virilization syndrome
Metabolism and nutrition disorders		increased appetite	anorexia
Psychiatric disorders		depressed mood	depression, mental disorders, insomnia, sleep disorders, aggression	mood changes, increased libido, decreased libido,
Nervous system disorders	headache	dizziness, migraine	ischaemic stroke, cerebral circulation disorder, dystonia
Eye disorders			dry eye, eye irritation, oscillopsia, visual disturbance	contact lens intolerance
Ear and labyrinth disorders			sudden hearing loss, tinnitus, vertigo, hearing impairment
Cardiac disorders			cardiovascular disorders, tachycardia3
Vascular disorders		hypertension, hypotension	VTE, ATE, PE, thrombophlebitis, diastolic hypertension, orthostatic circulatory disturbances, hot flushes, varicose veins, venous disorders, venous pain
Respiratory, thoracic and mediastinal disorders			asthma, hyperventilation
Gastrointestinal disorders		abdominal pain4, nausea, vomiting, diarrhoea	gastritis, enteritis, dyspepsia
Skin and subcutaneous tissue disorders		acne, alopecia, rash5, pruritus6	allergic dermatitis, atopic dermatitis/neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorders/hyperpigmentation, seborrhoea, dandruff, hirsutism, skin disorders, skin reactions, cellulite ("orange peel" skin), spider angioma	urticaria, nodular erythema, erythema multiforme
Musculoskeletal and connective tissue disorders			back pain, musculoskeletal discomfort, myalgia, limb pain
Reproductive system and breast disorders	breast pain7	withdrawal bleeding irregularities8, intermenstrual bleeding9, breast enlargement10, breast swelling, dysmenorrhoea, genital/vaginal discharge, ovarian cyst, pelvic pain	cervical dysplasia, adnexal cyst, adnexal tenderness, breast cyst, fibrocystic mastopathy, dyspareunia, galactorrhoea, menstrual disorders	breast discharge
Congenital, familial and genetic disorders			Manifestations of asymptomatic polymastia
General disorders and administration site conditions		increased fatigue11	chest pain, peripheral oedema, influenza-like illness, inflammation, pyrexia, irritability	fluid retention
Investigations		weight increased	elevated blood triglycerides, hypercholesterolaemia, weight decreased, weight changes

3including increased heart rate

4including upper and lower abdominal pain, abdominal discomfort/bloating

5including macular rash

6including generalized pruritus

7including breast discomfort and breast tension

8including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea

9including vaginal bleeding and metrorrhagia

10including breast tenderness and breast swelling

11including weakness and malaise

The most appropriate MedDRA term has been used to describe each adverse reaction.

Synonyms or related conditions are not listed but should be taken into consideration.

Description of individual adverse reactions

The following serious adverse reactions have been observed in women using combined oral contraceptives (COCs) (also see section "Special warnings and precautions for use").

Tumours

• A slightly increased incidence of breast cancer has been reported in women taking oral contraceptives. Since breast cancer is rare in women under 40 years of age, the frequency is low in relation to the overall risk of breast cancer. A causal relationship with COC use is not known.
• Liver tumours (benign and malignant).
• Cervical cancer.

Other conditions

• Hypertriglyceridaemia (increased risk of pancreatitis with COC use).
• Arterial hypertension.
• Development or worsening of conditions for which the relationship with COC use has not been definitively established: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
• Exogenous estrogens may cause or exacerbate symptoms of hereditary and acquired angioedema.
• Disorders of liver function.
• Changes in glucose tolerance or effects on peripheral insulin resistance.
• Crohn's disease, ulcerative colitis.
• Chloasma.

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions. This medicinal product does not require special temperature storage conditions. Store in the original packaging to protect from light.

Keep out of the reach and sight of children.

Packaging. 21 tablets in a blister; 1 or 3 blisters with a cardboard holder for blister storage in a carton.

Prescription classification. Prescription only.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address and place of business.

H-1103 Budapest, Demréni út 19-21, Hungary.