Sofiti

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOFITI®

Composition:

Active substances: ethinylestradiol, dienogest;

One film-coated tablet (white) contains: ethinylestradiol 0.03 mg, dienogest 2 mg;

Excipients: lactose monohydrate, corn starch, povidone K-30, magnesium stearate (vegetable); coating: hypromellose 2910, polyethylene glycol, titanium dioxide (E 171).

One film-coated placebo tablet (green) contains: lactose monohydrate, corn starch, povidone K-30, colloidal silicon dioxide (anhydrous), magnesium stearate; coating: hypromellose 2910, triacetin (E1518), polysorbate, titanium dioxide (E 171), FD&C Blue 2 Aluminium Lake (E 132), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, unmarked tablets; placebo: round, green tablets.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. Dienogest and ethinylestradiol.

ATC code G03A A16.

Pharmacological properties.

Pharmacodynamics.

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

The following Pearl Index was calculated during clinical studies:

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

Sofyti® is a combined oral contraceptive (COC) containing ethinylestradiol and the progestogen dienogest.

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

Dienogest is a derivative of nortestosterone with an in vitro affinity for progesterone receptors that is 10–30 times lower than that of 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 required to suppress ovulation is 1 mg/day.

The use of high-dose COCs (50 μg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. Whether this also applies to low-dose COCs remains unclear.

Pharmacokinetics.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Peak 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 concentration of sex hormone-binding globulin (SHBG). The apparent volume of distribution of ethinylestradiol is approximately 2.8–8.6 L/kg.

Metabolism. Ethinylestradiol undergoes extensive presystemic conjugation in the intestinal mucosa and in the liver. The primary metabolic pathway is 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 one day.

Steady state. Steady state is achieved during the second half of the treatment cycle, when serum concentrations of ethinylestradiol are approximately twice as high as after a single dose.

Dienogest.

Absorption. After oral administration, dienogest is rapidly and completely absorbed. Maximum serum concentration is reached within 2.5 hours after a single oral dose and is 51 ng/mL. The absolute bioavailability of dienogest in combination with ethinylestradiol is approximately 96%.

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

Metabolism. Dienogest is primarily metabolized via hydroxylation and conjugation, forming predominantly endocrinologically inactive metabolites. These metabolites are rapidly eliminated from plasma, so that no active metabolites are detectable in plasma—only unchanged dienogest. Total clearance is approximately 3.6 L/h after a single dose.

Elimination. Serum levels of dienogest decline with a half-life of approximately 9 hours. Only a small amount of dienogest is excreted unchanged by the kidneys. After administration of an oral dose of 0.1 mg/kg body weight, the ratio of renal to fecal excretion is 3.2. Approximately 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, serum concentrations increase 1.5-fold, reaching steady state after 4 days of treatment.

Preclinical safety data

Preclinical studies with ethinylestradiol and dienogest revealed expected estrogenic and progestogenic effects.

Results from standard preclinical studies on repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk for humans. However, it should be noted that sex steroids may promote the growth of pre-existing hormone-dependent tissues and tumors.

Environmental risk assessment studies have shown that ethinylestradiol and dienogest may potentially pose a risk to the aquatic environment (see section "Special precautions for disposal").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

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

• Presence of or risk of venous thromboembolism (VTE):
  • Current (during anticoagulant therapy) or history of venous thromboembolism (e.g., deep vein thrombosis (DVT), 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 the presence of multiple risk factors (see section "Special precautions").
• Presence of or risk of arterial thromboembolism (ATE):
  • Current or history of arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • Current or history of cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or one serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Acute or history of pancreatitis associated with severe hypertriglyceridemia.
• Severe liver disease currently or in history, until liver function tests return to normal limits.
• Current or history of liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breast).
• Established or suspected pregnancy.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Sofiti® is contraindicated when used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir ("Interaction with other medicinal products and other forms of interaction").

Special safety measures.

This medicinal product may pose a risk to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Note: Information regarding the medicinal product intended for concomitant use with Sofiti® should be reviewed to identify potential interactions.

Effect of other medicinal products on Sofiti®

Interactions may occur with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, which in turn may result in changes in the pattern of menstrual bleeding and/or loss of contraceptive efficacy.

Therapy

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

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to COCs. The barrier method should be used throughout the treatment period with the respective medicinal product and for an additional 28 days after discontinuation of its use. If treatment is initiated during the period of taking the last white tablets in the pack, the intake of white tablets from the next pack should begin immediately after completion of the previous pack, i.e., the green placebo tablets should be skipped.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to choose another reliable non-hormonal method of contraception.

Substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example: 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 COC 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 overall effect of such changes may be clinically significant in some cases.

Therefore, the package leaflet of the medicinal product for the treatment of HIV/HCV, which will be used concomitantly, 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 that decrease 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 plasma concentrations of ethinylestradiol when used concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of Sofiti® on other medicinal products

COCs 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.

Pharmacodynamic interactions

During clinical trials involving patients receiving treatment for hepatitis C virus (HCV) infection with regimens containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevations in transaminases (ALT) greater than 5 times the upper limit of normal (ULN) were observed. This occurs with significantly higher frequency in women who were using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, in patients receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were observed in women taking ethinylestradiol-containing medicinal products, such as CHCs (see section "Contraindications").

Therefore, women using Sofiti® must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the aforementioned combination of medicinal products. Use of Sofiti® may be resumed 2 weeks after completion of therapy with the aforementioned combination.

Other forms of interaction

Laboratory tests

Use of contraceptive steroids may influence the results of certain laboratory tests, including liver function, thyroid function, adrenal function, and renal function biochemical parameters; plasma concentrations of binding proteins such as SHBG, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Such changes are usually within normal limits.

Special precautions for use.

The decision to prescribe the medicinal product Sofiti® should be made taking into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with the use of Sofiti® compared to other COCs (see sections "Contraindications" and "Special precautions for use").

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

In case of exacerbation or at the first signs of any of these conditions or risk factors, women are advised to consult a physician and determine the need to discontinue Sofiti®.

In case of suspected or confirmed VTE or ATE, COCs should be discontinued. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effect of anticoagulants (coumarins).

• Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any COCs increases the risk of developing venous thromboembolism (VTE) in women using them compared to those who do not use COCs. Preparations containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. The use of other medicinal products, such as Sofiti®, may increase the risk of VTE by 1.6 times. The decision to use a product other than those with the lowest risk of VTE should be made only after discussion with the woman. It is necessary to ensure that she understands the risk of VTE associated with COC use, the extent of influence of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming COC use after a break of 4 weeks or longer.

VTE develops in 2 out of 10,000 women who do not use COCs and are not pregnant over a 1-year period. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

Epidemiological studies in women using low-dose (< 50 mcg ethinylestradiol) COCs have shown that 6 to 12 out of 10,000 women will develop VTE within 1 year.

It is estimated that among 10,000 women using COCs containing levonorgestrel, approximately 6 cases of VTE will occur per year.

It is estimated² that among 10,000 women using low-dose COCs containing dienogest and ethinylestradiol, 8–11 cases of VTE will occur per year.

The number of VTE cases per year reported was lower than that expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

1 On average, 5–7 cases per 10,000 woman-years based on the calculation of relative risk of using COCs containing levonorgestrel compared to women not using COCs (approximately 2.3–3.6 cases).

2 According to meta-analysis data, it is estimated that the risk of VTE in women using the medicinal product is slightly higher compared to women using COCs containing levonorgestrel (RR = 1.57 with a range from 1.07 to 2.30).

Number of VTE cases per 10,000 women per year

Rare cases of thrombosis in other blood vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, or retinal vessels, have been reported in women using COCs.

Risk factors for VTE

The risk of developing venous thromboembolic complications in women using COCs may be significantly higher in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Sofiti® 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 developing VTE should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1. Risk factors for VTE development

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

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

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

Women should be advised to seek immediate medical attention and inform their physician that they are taking a COC if any of the symptoms listed below occur.

Symptoms of DVT may include:

• unilateral swelling of the thigh, lower 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;
• sensation of warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include:

• sudden unexplained shortness of breath or rapid breathing;
• sudden cough, possibly with hemoptysis;
• sudden chest pain;
• severe dizziness or loss of balance;
• 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 manifestations of vascular occlusion may include sudden pain, swelling, and mild cyanosis of a limb.

Ocular vascular occlusion may initially present as painless blurred vision, which may progress to vision loss. In some cases, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

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

ATE risk factors

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The use of Sofití® is contraindicated in women who have 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. ATE risk factors

ATE Symptoms

Women should be advised to seek immediate medical attention and inform their physician if they are taking COCs should any of the following symptoms occur.

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 with or without seizures.

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

Symptoms of myocardial infarction may include:

• chest pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or below the sternum;

• discomfort radiating to the back, jaw, throat, arm, or stomach;

• feeling of fullness, indigestion, or heartburn;

• excessive sweating, nausea, vomiting, or dizziness;

• unusual 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; however, this remains controversial, as it has not been definitively established to what extent study results account for confounding risk factors such as sexual behavior and other factors, including human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer among women using COCs. This increased risk gradually returns to baseline levels associated with a woman's 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 minimal 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, which in some instances have led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a COC-related liver tumor should be considered during differential diagnosis. Such tumors may be life-threatening or lead to fatal outcomes.

• Other conditions

Women with hypertriglyceridemia or a family history of this disorder 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 persistent, clinically evident hypertension develops during COC use, it is advisable 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, despite adequate antihypertensive treatment, persistently high blood pressure values remain during COC use in women with pre-existing hypertension diagnosed before starting COCs. The following conditions have been reported to occur or worsen during pregnancy and with COC use, but their causal relationship to COC use has not been definitively established: cholestatic jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

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

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 is no evidence to suggest a need to alter the therapeutic regimen in diabetic women taking 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 reported during COC use.

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

Each tablet contains lactose monohydrate. This medicinal product is contraindicated in patients with rare hereditary conditions of galactose intolerance, fructose intolerance, total lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase deficiency. If you have been diagnosed with an intolerance to certain sugars, consult your physician before taking this medicinal product.

Psychiatric disorders

Depressed mood and depression are well-known adverse effects that may occur during use of hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to contact their physician if they experience mood changes or symptoms of depression, including soon after starting treatment.

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

Medical examination/consultation

Before initiating or resuming use of Sofiti® a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a medical examination performed, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Sofiti® compared to other COCs, as well as information on symptoms of VTE and ATE, known risk factors, and measures to take if thrombosis is suspected.

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

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

Reduced effectiveness

The effectiveness of COCs may be reduced in case of missed tablets (see section "Dosage and administration"), 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").

Cycle disturbances

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

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

Some women may not experience withdrawal bleeding during the tablet-free interval. If COCs have been taken according to the instructions in the "Dosage and administration" section, pregnancy is unlikely. However, if COCs were taken irregularly before the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be ruled out before continuing COC use.

Use during pregnancy or breastfeeding.

Pregnancy.

This medicinal product is not indicated during pregnancy.

If pregnancy occurs during use of Sofiti®, treatment should be discontinued immediately. Extensive epidemiological studies have not shown an increased risk of congenital anomalies in children born to women who used COCs prior to pregnancy, nor is there evidence of teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy (see section "Pharmacological properties"). Based on animal data, adverse effects due to the hormonal influence of the active substances cannot be excluded. However, overall clinical experience with COC use during pregnancy does not indicate any adverse effects in humans.

When resuming use of Sofiti®, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration" and "Special precautions for use").

Breastfeeding.

COCs may affect breastfeeding by reducing the quantity and altering 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, Sofiti® is not recommended until breastfeeding has completely ended.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted. No effect on the ability to drive or operate machinery has been observed in women using COCs.

Method of Administration and Dosage

Sofiti® tablets are intended for oral administration.

Dosing

Sofiti® should be taken as 1 tablet daily for 28 consecutive days. Tablets should be taken every day at approximately the same time, with liquid. Within 2–3 days after starting the green placebo tablets, withdrawal bleeding usually begins and may continue until the start of the white tablets from the next pack.

Each package includes a blister holder, which can be used to carry the blister when needed, and a calendar scale.

The blister contains 21 active tablets (white tablets) and 7 placebo tablets without active ingredients (green tablets).

How to Start Taking Sofiti®

• If hormonal contraceptives were not used previously (last month): start taking the white tablets on the first day of the natural cycle (i.e., the first day of menstrual bleeding).
• Switching from another combined oral contraceptive (COC): it is recommended to start taking the white Sofiti® tablet the day after the last active tablet of the previous COC, but no later than the day after the usual tablet-free interval or after taking the placebo tablets of the previous COC.
• Switching from a vaginal ring or transdermal patch: it is recommended to start taking the white Sofiti® tablets on the day of removal of the vaginal ring or transdermal patch, but no later than the day when the next application of these methods would normally occur.
• Switching from a progestogen-only method (‘mini-pill’, injections, implants) or an intrauterine system containing progestogen: the white Sofiti® tablets can be started on any day after stopping the ‘mini-pill’; switching from an implant or intrauterine system – on the day of removal; switching from an injectable preparation – instead of the next injection. However, in all these cases, a barrier method of contraception must be used additionally during the first 7 days of Sofiti® use.
• After first-trimester abortion: Sofiti® white tablets may be started immediately. In this case, additional contraceptive methods are not required.
• After childbirth or second-trimester abortion: it is recommended to start taking the white Sofiti® tablets between days 21–28 after childbirth or second-trimester abortion. If starting later, a barrier method of contraception should be used additionally for the first 7 days of tablet use. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting Sofiti®, or the first menstrual period should be awaited.

For breastfeeding women, see section "Use during pregnancy or breastfeeding".

What to do if a dose of active white Sofiti® tablets is missed

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

1. The interval between tablet intakes must never exceed 7 days.
2. Effective suppression of the hypothalamic-pituitary-ovarian system is achieved only with continuous tablet intake over 7 days.

Accordingly, follow the recommendations below:

• Missed tablet during the first week of Sofiti® use:

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, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred within the previous 7 days, the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer to the placebo tablet period, the higher the risk of pregnancy.

• Missed tablet during the second week of Sofiti® use:

Take the last missed tablet as soon as possible, even if two tablets must be taken at the same time. 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 required. However, if more than one tablet is missed, additional contraceptive methods are recommended for 7 days.

• Missed tablet during the third week of Sofiti® use:

The risk of reduced contraceptive effect increases as the placebo tablet period approaches. However, if the dosing schedule is followed, a reduction in contraceptive protection can be avoided. If one of the two options below is followed, no additional contraceptive methods are required, provided tablets were taken correctly during the 7 days before starting the green placebo tablets. Otherwise, it is recommended to follow the first option below and use additional contraceptive precautions for the next 7 days.

Option 1.

Take the last missed tablet as soon as possible, even if this means taking two white tablets at the same time. Then continue taking tablets at the usual time. Start taking white tablets from the next pack immediately after finishing the last white tablet from the previous pack, i.e., skip the green placebo tablets from the previous pack. Withdrawal bleeding is unlikely to occur before finishing the white tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.

Option 2.

You may stop taking tablets from the current pack, have a 7-day break (including the days when tablets were missed). For continued regular use, start a new pack.

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

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disturbances, incomplete absorption of the drug may occur; in such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, a new white tablet should be taken as soon as possible. If more than 12 hours have passed, apply the recommendations given above in the section "Method of Administration and Dosage" under "What to do if a dose of active white Sofiti® tablets is missed". If a woman does not wish to change her tablet-taking schedule, she should take an additional tablet(s).

How to delay withdrawal bleeding

To delay withdrawal bleeding, continue taking white Sofiti® tablets from a new pack without taking the green placebo tablets from the previous pack; that is, immediately start the white tablets from a new pack after finishing 21 white tablets. If desired, this period may be extended until all white tablets from the second pack are used. Breakthrough bleeding or spotting may occur during this time. Regular Sofiti® use should be resumed after a 7-day break (or 7-day use of green placebo tablets).

To shift the timing of withdrawal bleeding to another day of the week than the one currently scheduled, it is recommended to shorten the tablet-free interval by the desired number of days. Note that the shorter the interval, the more likely it is that withdrawal bleeding will not occur and the higher the risk of breakthrough bleeding or spotting during the intake of tablets from the second pack (as with delaying withdrawal bleeding).

What to do if placebo (green) tablets are missed: missing green tablets can generally be disregarded, but a 7-day interval must be maintained between the last white tablet of the previous pack and the first white tablet of the new pack.

Additional Information for Special Patient Groups

Elderly patients

Sofiti® is not indicated for use after menopause.

Patients with hepatic impairment

Sofiti® is contraindicated in women with severe liver disease (see section "Contraindications").

Patients with renal impairment

The use of Sofiti® in patients with impaired kidney function has not been specifically studied. Available data do not indicate the need for dosage adjustment in this patient group.

Children

This medicinal product is indicated for use only after the onset of menstruation.

Overdose.

Acute toxicity of ethinylestradiol and dienogest after oral administration is very low. For example, if a child accidentally takes several Sofiti® tablets at once, symptoms of intoxication are unlikely. Symptoms that may occur in such cases include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in girls before menarche following accidental/inadvertent use of the drug. Specific treatment is usually not required. If necessary, symptomatic therapy may be administered.

Adverse reactions

The frequency of adverse reactions reported during clinical studies (N=4942) in women taking the drug as an oral contraceptive is summarized in Table 3. Within each column, adverse reactions are listed in order of decreasing severity. Frequency is defined as 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 in post-marketing studies, for which frequency cannot be estimated, are listed in the column "Frequency not known".

Table 3. Frequency of adverse reactions reported during clinical studies

2 including increased heart rate

3 including upper and lower abdominal pain, abdominal discomfort/distension

4 including macular rash

5 including generalized pruritus

6 including breast discomfort and breast tension

7 including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea

8 including vaginal bleeding and metrorrhagia

9 including breast tenderness and breast swelling

10 including 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 considered.

Description of selected adverse reactions

The following serious adverse reactions have been observed in women using COCs (see also section "Special warnings").

Tumours

• A slightly increased frequency of breast cancer diagnosis has been reported among women using oral contraceptives. Since breast cancer is rare in women under the age of 40, the overall increase in frequency is small relative to the general risk of breast cancer. A causal relationship with COC use is not established.

• Liver tumours (benign and malignant).

• Cervical cancer.

Other conditions

• Hypertriglyceridaemia (increased risk of pancreatitis with COC use).
• Arterial hypertension.
• Development or exacerbation of disorders for which a definite association with COC use has not been established: cholestatic jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
• 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 medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach and sight of children.

Packaging.

Film-coated tablets, 0.03 mg/2 mg, pack of 28 (21 + 7) in a blister; 1 blister with calendar strip and blister holder in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Laboratorios Leon Farma, S.A.

Manufacturer's address.

Calle La Vallina S/N, Poligono Industrial Navatejera, Villaquilambre, 24193, Spain.

Marketing Authorisation Holder.

LLC "WORWARTS PHARMA".

Address of the Marketing Authorisation Holder.

4 Omelyana Prytsaka Street, Kyiv, 03142, Ukraine.