CERINTA

INSTRUCTIONS for medical use of the medicinal product CERINTA (CERINTA)

Composition:

Active substances: levonorgestrel, ethinylestradiol;

1 tablet contains levonorgestrel 0.15 mg and ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate; pregelatinized starch; pigment blend orange (RB-53652); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: light-orange, round, biconvex, uncoated tablets with embossing «708» on one side and smooth on the other side.

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

ATC code G03AA07.

Pharmacological Properties

Pharmacodynamics

The contraceptive effect of Cerinta tablets is achieved primarily by suppression of gonadotropins, resulting in inhibition of ovulation. Additional effects include changes in cervical mucus that impede sperm penetration into the uterus, and alterations in the endometrium that reduce the likelihood of implantation.

Pharmacokinetics

Levonorgestrel

Absorption. After oral administration, levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. Maximum concentration of the active substance in serum (approximately 3 ng/mL) is reached within one hour after administration of levonorgestrel in combination with ethinylestradiol. Subsequently, serum concentration decreases in a biphasic manner corresponding to a two-phase elimination process, with half-lives of approximately 0.5 hours and 20 hours. Bioavailability is nearly 100% due to the absence of first-pass metabolism.

Distribution. The majority of levonorgestrel is bound to plasma proteins, primarily to albumin and sex hormone-binding globulin (SHBG). The unbound fraction accounts for about 1.5% of the total plasma concentration, while approximately 65% of levonorgestrel is bound to SHBG. The relative proportions (free, albumin-bound, SHBG-bound) depend on SHBG concentration. Under conditions of induced SHBG synthesis, the fraction of levonorgestrel bound to this protein increases, while concentrations of the free form and the albumin-bound form decrease.

With daily administration, accumulation of levonorgestrel occurs, resulting in plasma concentrations approximately twice as high as those after a single dose. Steady-state levels are achieved during the second half of the treatment cycle. The pharmacokinetics of levonorgestrel depend on plasma SHBG concentration. After 1–3 cycles of use, serum levels of levonorgestrel no longer change significantly due to completion of SHBG synthesis induction. With long-term use, serum levels of levonorgestrel are 3–4 times higher than after a single dose.

Metabolism. Plasma clearance of levonorgestrel is approximately 1.5 mL/min/kg. The drug is hydroxylated in the liver, and metabolites are excreted as glucuronide conjugates. The main metabolites in plasma are unconjugated and conjugated forms of 3α,5β-tetrahydrolevonorgestrel. According to in vitro and in vivo studies, CYP3A4 is the primary enzyme involved in the metabolism of levonorgestrel.

Excretion. Levonorgestrel is excreted as metabolites with a half-life of approximately one day. Elimination occurs in roughly equal proportions via renal and biliary pathways: about 60% of levonorgestrel is excreted in urine and 40% in feces.

Ethinylestradiol

Absorption. Ethinylestradiol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum serum concentration is reached within 1–2 hours. Due to presystemic conjugation and first-pass metabolism, absolute bioavailability is 40–45%.

Distribution. The apparent volume of distribution is approximately 5 L/kg, and metabolic clearance is about 5 mL/min/kg. Ethinylestradiol is 98% bound to plasma proteins, primarily to albumin.

Metabolism. Ethinylestradiol undergoes presystemic conjugation. It passes through the intestinal wall (first phase of metabolism) and reaches the liver, where conjugation occurs (second phase of metabolism). These processes result in reduced and individually variable systemic bioavailability after oral administration. Both ethinylestradiol and its phase I metabolites are excreted as conjugates (sulfates and glucuronides) into bile, entering the enterohepatic circulation.

Other drugs may have either negative or positive effects on the systemic availability of ethinylestradiol. No interaction with vitamin C has been observed. With long-term use, ethinylestradiol induces hepatic synthesis of corticosteroid-binding globulin and SHBG; the degree of SHBG induction depends on the type and dose of the concomitantly administered progestogen.

Excretion. Ethinylestradiol is eliminated from plasma with a mean half-life of approximately 25 hours. Excretion of ethinylestradiol conjugates and its metabolites occurs via urine (60%) and feces (40%). In women with fully established lactation, approximately 0.02% of the administered dose may be transferred to the infant via breast milk.

Clinical Characteristics

Indications. Oral contraception.

Contraindications

Combined oral contraceptives (COCs) are contraindicated in the presence of the following diseases and pathological conditions. If any of these conditions develop during COC use, the drug should be discontinued immediately.

• Hypersensitivity to any component of the drug.
• Known or suspected pregnancy.
• Arterial or venous thromboembolic disorders (current or in history):
  • Venous thromboembolism (VTE): current VTE (while on anticoagulant therapy) or history of VTE (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]).
  • Known hereditary or acquired predisposition to venous thromboembolism, including activated protein C resistance (e.g., 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 multiple risk factors (e.g., smoking in women over 35 years of age, etc., see section "Special precautions").
  • Arterial thromboembolism (ATE): current ATE, history of arterial thromboembolism (e.g., myocardial infarction) or prodromal conditions (e.g., angina pectoris).
  • Cerebrovascular disorders: current stroke, history of stroke, or prodromal conditions (e.g., transient ischemic attack [TIA]).
  • Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
  • History of migraine with focal neurological symptoms.
  • High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or one serious risk factor such as:
    • diabetes mellitus with vascular complications (micro- or macroangiopathy);
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Cardiovascular diseases.
• Ophthalmological disorders of vascular origin.
• Hormone-sensitive malignant tumors of the genital organs and mammary glands — diagnosed, suspected, or with history.
• Severe liver disease — current or in history (e.g., active viral hepatitis or severe hepatic cirrhosis) — until normalization of liver function tests.
• Liver tumors (benign or malignant) — current or in history.
• Vaginal bleeding of unknown etiology.
• Pancreatitis associated with severe hypertriglyceridemia, or history thereof.
• Concomitant use of combination drugs containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

Interactions between COCs and other medicinal products may lead to reduced contraceptive efficacy and/or breakthrough bleeding and/or contraceptive failure. Therefore, information on concomitant medication should always be reviewed before initiating treatment.

Medicinal products that may affect the effect of COCs

Enzyme inducers

Medicinal products that induce microsomal enzymes (particularly cytochrome P450 3A4) may, when used concomitantly with COCs, increase the clearance of sex hormones, potentially leading to breakthrough bleeding and contraceptive failure. These include:

anticonvulsants: barbiturates (including phenobarbital, hydantoins), primidone, phenytoin, carbamazepine, oxcarbazepine, topiramate;

antibiotics / antifungal agents: griseofulvin, rifampicin;

herbal products: St. John’s wort (Hypericum perforatum);

antiretroviral agents: ritonavir, nelfinavir, nevirapine. Other antiretroviral drugs may also increase sex hormone plasma concentrations.

Other active substances that may reduce the efficacy of COCs: oxcarbazepine, topiramate, and griseofulvin.

The mechanism of action is based on the ability of these substances to increase hepatic enzyme activity. Enzyme induction may begin within a few days of concomitant use. Maximum enzyme induction is usually observed within 2–3 weeks after starting these drugs and may persist for approximately 4 weeks after discontinuation. Cases of contraceptive failure have also been reported with concomitant use of antibiotics such as ampicillin and tetracycline, although the mechanism of action remains unknown.

In case of short-term use of any of these enzyme-inducing agents, it is recommended to use additional barrier contraceptive methods from the start of treatment, throughout the treatment period, and for 28 days after discontinuation. If the current pack of Cerinta tablets is completed before the period requiring additional contraception ends, the next pack should be started immediately without a break. In this case, withdrawal bleeding should not be expected until after the second pack is completed. If no withdrawal bleeding occurs after finishing the second pack, the patient should consult a physician to exclude pregnancy.

For long-term use of enzyme inducers, alternative contraceptive methods are recommended.

Enzyme inhibitors

Strong and moderate inhibitors of CYP3A4, such as azole antifungals (e.g., itraconazole, voriconazole, fluconazole) and macrolides (e.g., erythromycin), may increase plasma concentrations of estrogen and/or progestin.

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

Effect of COCs on other medicinal products

COCs may affect the metabolism of other medicinal products. For example, they may increase plasma concentrations of cyclosporine, tizanidine, and theophylline, potentially leading to toxic effects. Concomitant use of lamotrigine and COCs may reduce lamotrigine plasma concentrations and impair seizure control in women initiating COC use.

Thyroid hormone replacement therapy or corticosteroid replacement therapy

Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure to thyroid hormone-binding globulin and cortisol-binding globulin. Dose adjustments of thyroid hormones or cortisol may be required.

Other medicinal products

Concomitant use of COCs may reduce systemic exposure to paracetamol, morphine, salicylic acid, and temazepam. Concomitant use with COCs containing ethinylestradiol may increase systemic exposure to other drugs, such as cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole. Dose adjustments of these medicinal products may be necessary.

Pharmacodynamic interactions

During clinical trials in patients receiving hepatitis C virus (HCV) treatment regimens containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir plus ribavirin, increased alanine aminotransferase (ALT) levels exceeding 5 times the upper limit of normal (ULN) were observed. This phenomenon occurred significantly more frequently in women using ethinylestradiol-containing drugs, including COCs. Additionally, increased ALT levels were also observed in women receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir who were concurrently using ethinylestradiol-containing drugs (including COCs) (see section "Contraindications").

Therefore, women using COCs should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the aforementioned medicinal products. Use of Cerinta may be resumed no earlier than 2 weeks after completion of treatment with the specified antiviral regimens.

Laboratory tests

Use of steroid contraceptives may affect the results of certain laboratory tests, including liver function biochemical parameters, thyroid and adrenal function, renal function, concentrations of transport proteins (e.g., corticosteroid-binding globulin and lipid/lipoprotein fractions), carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within normal laboratory limits.

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

St. John’s wort (Hypericum perforatum)

Herbal medicinal products based on St. John’s wort (Hypericum perforatum) should not be co-administered with this medicinal product, as they may potentially reduce the contraceptive efficacy of Cerinta tablets. Reports of breakthrough bleeding and unintended pregnancies have been received. Reduced contraceptive efficacy persists for at least 2 weeks after discontinuation of St. John’s wort.

Special precautions for use

Examination and clinical evaluation before prescribing COCs

Before initiating or resuming the use of COCs:

• A complete personal and family medical history should be obtained, a clinical examination performed, and pregnancy excluded;
• The presence of contraindications (see section "Contraindications") should be assessed and the warnings outlined in this section taken into account;
• An evaluation should be performed in case of undiagnosed vaginal bleeding;
• The potential risks associated with the use of the medicinal product and the factors contributing to their occurrence should be discussed with the woman;
• The patient must carefully read the package leaflet and strictly follow the recommendations provided therein;
• The physician must ensure that the woman fully understands all the risks involved.

If any of the diseases/factors listed below are present, the benefits of COCs and the potential risks associated with their use should be carefully evaluated for each individual woman, and the corresponding benefits and risks discussed with her before she decides to use such medications. If any of these conditions or risk factors appear for the first time, worsen, or recur, the woman should consult her physician. In such cases, the physician must decide whether to discontinue COC use.

During the entire period of oral contraceptive use, a clinical examination should be performed at least once a year. The frequency and nature of periodic check-ups should be individually determined for each patient.

Special warnings

General

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

Smoking increases the risk of serious cardiovascular side effects associated with the use of COCs. This risk increases with age (particularly high in women aged 35 years and older) and with the number of cigarettes smoked. All women using COCs should be strongly advised to stop smoking. For women aged 35 years and older who smoke, alternative contraceptive methods should be considered.

Disturbances of circulation

Risk of venous or arterial thromboembolism

The use of any combined oral contraceptive increases the risk of venous and arterial thromboembolic disorders. This risk is highest during the first year of COC use. There is also some evidence that the risk increases when a woman restarts COC use after a break of 4 weeks or more.

Overall, the incidence of thromboembolic disorders in non-pregnant women not using oral contraceptives is 2 cases per 10,000 women per year. However, the likelihood of thrombosis may vary significantly in individual women depending on their specific risk factors.

With COC use, the risk of venous and arterial thromboembolic disorders increases to 6 cases per 10,000 women per year (1–2% of these cases are fatal). However, this risk is still lower than that during pregnancy or the postpartum period.

Very rare cases of thrombosis in other blood vessels, such as hepatic, mesenteric, renal, cerebral, or retinal veins and arteries, have been reported in women using hormonal contraceptives. A causal relationship between the use of hormonal contraceptives and these events has not been established.

Risk factors for VTE and ATE

The risk of venous and/or arterial thromboembolism (myocardial infarction, cerebrovascular events such as TIA or acute ischemic stroke [AIS]) increases significantly when additional risk factors are present.

COCs are contraindicated if a woman has multiple risk factors for venous/arterial thrombosis. If more than one risk factor is present, their combined effect may exceed the sum of individual risks, so the overall risk of VTE should be assessed. If the benefit-risk ratio is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

There is no consensus regarding the possible role of varicose veins and superficial thrombophlebitis in the development or progression of venous thrombosis.

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

If symptoms of venous or arterial thrombotic/thromboembolic disorders occur, women should seek immediate medical attention and inform their healthcare provider that they are taking COCs.

Symptoms of VTE/ATE

• VTE

Deep vein thrombosis:

− unilateral swelling of the calf and/or foot or along a vein in the leg;

− pain or tenderness in the leg, which may only be felt while standing or walking;

− elevated temperature in the affected leg;

− red or discolored skin on the leg.

Pulmonary embolism:

− sudden onset of unexplained shortness of breath or rapid breathing;

− sudden cough, which may be accompanied by hemoptysis;

− sharp chest pain;

− severe dizziness or lightheadedness;

− rapid or irregular heartbeat.

Some of these symptoms (such as shortness of breath, cough) are nonspecific and may be misinterpreted as more common or less serious conditions (e.g., acute respiratory infection).

Ocular vein occlusion: symptoms may range from painless blurred vision to vision loss. Sometimes, vision loss may occur almost immediately.

Other signs of venous thrombosis include:

• sudden pain;

• swelling;

• slight cyanosis;

• discoloration of a limb.

• ATE

Cerebrovascular accident:

− sudden numbness or weakness of the arm, leg, or face, especially on one side of the body;

− sudden difficulty walking, dizziness, loss of balance or coordination;

− slurred speech, sudden speech disturbance or difficulty understanding speech;

− sudden worsening of vision in one or both eyes;

− sudden or severe headache without known cause;

− loss of consciousness or syncope, with or without seizures.

TIA: transient symptoms of cerebrovascular accident (see above).

Myocardial infarction:

− pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or substernal area;

− discomfort radiating to the back, jaw, throat, arm, or abdomen;

− feeling of fullness, indigestion, or suffocation;

− sweating, nausea, vomiting, or dizziness;

− extreme weakness, anxiety, or shortness of breath;

− rapid or irregular heartbeat.

During the postpartum period, the increased risk of VTE should be considered.

Conditions requiring close medical monitoring

The decision to prescribe COCs should be based on clinical evaluation and discussion with the woman.

Exacerbation or first occurrence of any of the following conditions or risk factors may indicate that the use of oral contraceptives should be discontinued. In each case, the woman should consult her physician, who will decide whether to discontinue COC use.

• Diabetes mellitus with mild vascular disease or mild nephropathy, retinopathy, or neuropathy
• Adequately controlled arterial hypertension, i.e., systolic pressure >140–159 mm Hg or diastolic pressure >90–94 mm Hg
• Porphyria
• Obesity
• Migraine
• Cardiovascular diseases

Indications for immediate discontinuation of COC use

When stopping oral contraception, non-hormonal contraceptive methods should be used to ensure continuous contraceptive protection.

• New onset or worsening of migraine or unusually frequent or unusually severe headaches
• Sudden visual, hearing, or other sensory disturbances
• First signs of thrombosis or clot formation (e.g., unusual pain or swelling in the leg(s), stabbing pain during breathing or coughing without apparent cause). Sensation of pain and tightness in the chest
• Need for planned major surgery (e.g., abdominal, orthopedic), any surgery on the legs, treatment of varicose veins, or prolonged immobilization, such as after accidents or surgeries. COC use should be discontinued at least four weeks before the procedure. Resumption of use is possible no earlier than two weeks after full remobilization. In case of emergency surgery, thrombosis prophylaxis is usually indicated, for example, subcutaneous administration of heparin
• Appearance of jaundice, hepatitis, or generalized pruritus
• Significant increase in blood pressure
• Severe pain in the upper abdomen or enlargement of the liver
• Obvious exacerbation of conditions that may worsen during oral contraception or pregnancy.

Tumors

Numerous epidemiological studies have assessed the risk of ovarian, endometrial, cervical, and breast cancer in women using COCs. Evidence suggests that high-dose COCs provide significant protection against both ovarian and endometrial cancer. However, it remains unclear whether low-dose COCs offer the same level of protective effect.

Breast cancer

Levonorgestrel; ethinylestradiol is contraindicated in women who currently have or have had breast cancer, as breast cancer may be hormone-sensitive (see section "Contraindications").

Epidemiological studies have not demonstrated a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not show a link between current or past use of COCs and the risk of breast cancer. However, some studies report a slight increase in the risk of breast cancer among women who currently or recently used (less than 6 months since last use) COCs, as well as among those currently taking COCs (see section "Adverse reactions").

Analysis of epidemiological studies shows that women who have used COCs have an increased relative risk of developing breast cancer. The additional risk of breast cancer is more commonly observed in women who are currently using or have used COCs within the last 10 years, compared to those who have never used COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer in women currently or previously using COCs is low compared to the lifetime risk of developing breast cancer. The most important risk factor for breast cancer in women using COCs is the age at which COC use is discontinued: the older the woman at the time of discontinuation, the higher the risk of breast cancer. Duration of use is less important, and the increased risk gradually disappears within 10 years after stopping COC use.

Causal relationship evidence is not provided in these studies. The increased risk may be related to earlier diagnosis of breast cancer in women using COCs, biological effects of COCs, or a combination of both factors.

In women using oral contraceptives, breast cancer is diagnosed at an earlier stage compared to women who did not use COCs.

Cervical cancer. The most important risk factor for cervical cancer is persistent infection with human papillomavirus.

Some studies have reported an increased incidence of cervical cancer among women who have used COCs for a long time, but the results are inconsistent. Sexual behavior and other factors, such as human papillomavirus, play a role in the development of cervical cancer; therefore, the relationship between cervical cancer and COC use is not clearly defined. The impact of, for example, cervical cancer screening, sexual behavior, including use of barrier contraceptives, remains unknown.

Liver tumors. Rarely, benign and very rarely malignant liver tumors have been observed with long-term use of sex hormones, which in some cases may lead to life-threatening intra-abdominal hemorrhage. Severe acute pain in the upper abdomen, enlargement of the liver, or signs of intraperitoneal hemorrhage may indicate the presence of a liver tumor. This should be considered in differential diagnosis.

Other conditions

During COC use, the risk of exacerbation of certain chronic diseases cannot be excluded.

Hyperlipidemia

Women with hypertriglyceridemia or a family history of this condition have an increased risk of pancreatitis when using COCs. Women with hyperlipidemia should be under careful medical supervision during COC use due to the increased risk of vascular diseases.

Blood pressure

Hypertension is a risk factor for myocardial infarction or stroke. A slight increase in blood pressure has been observed in many women using COCs, although clinically significant increases are rare. Antihypertensive therapy should usually be initiated at a level of 160/100 mm Hg in women without additional risk factors or 140/90 mm Hg in women with cardiovascular risk factors. If blood pressure increases during COC use in women with existing hypertension or if a significant increase in blood pressure does not respond adequately to antihypertensive treatment, COC use should be discontinued. In some cases, COC use may be resumed if normal blood pressure values can be achieved with antihypertensive therapy.

Conditions that may worsen during pregnancy or COC use:

• jaundice and/or pruritus associated with cholestasis;
• gallstone formation;
• systemic lupus erythematosus;
• herpes gestationis;
• hearing loss associated with otosclerosis;
• sickle cell anemia;
• renal dysfunction;
• porphyria;
• hemolytic uremic syndrome;
• Sydenham's chorea;
• in women with hereditary angioedema, exogenous estrogens may trigger or exacerbate symptoms of angioedema;
• any other condition whose exacerbation occurred in a woman during pregnancy or previous COC use.

Liver function disorders

Acute or chronic liver function disorders may necessitate discontinuation of COC use until liver function parameters normalize. Recurrence of cholestatic jaundice and/or pruritus associated with cholestasis, which occurred during pregnancy or previous use of sex steroids, requires discontinuation of COC use. Metabolism of steroid hormones may be slowed in patients with liver function disorders.

Diabetes mellitus (without vascular involvement)

COCs may affect peripheral insulin sensitivity and glucose tolerance. COCs may be used in women with insulin-dependent diabetes mellitus without vascular disease. There is no need to change the therapeutic regimen for diabetic patients taking low-dose COCs. However, it should be remembered that all individuals with diabetes have an increased risk of arterial disease, which should be considered when prescribing COCs. COC use is contraindicated in diabetic patients with angiopathy.

Mental disorders. Women who develop severe depression during COC use should discontinue use of these drugs and use alternative contraceptive methods until the causal relationship between depressive symptoms and COC use is evaluated. Close monitoring is required for women with a history of major depressive episodes, and COC use should be discontinued if depressive symptoms recur.

Chloasma. Chloasma may rarely develop, especially in women with a history of melasma of pregnancy. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during COC use.

Menstrual cycle changes. In some patients, a reduction in the duration or intensity of menstrual bleeding may occur, which is not abnormal and may be expected. This can be beneficial in cases of heavy menstruation.

Missed periods: In some women, withdrawal bleeding may not occur after a break in tablet use. If COCs were used according to the recommendations provided in the "Dosage and administration" section, pregnancy is unlikely. However, if the instructions for use before the first missed withdrawal bleeding were not followed or if two consecutive withdrawal bleedings are absent, pregnancy should be ruled out before continuing COC use.

Intermenstrual bleeding. Irregular bleeding (spotting or breakthrough bleeding) may occur during the first months of use. Evaluation of any irregular bleeding is meaningful only after an adaptation period of approximately three cycles. If irregular bleeding persists or develops after previously regular cycles, use of non-hormonal methods is recommended, along with appropriate diagnostic measures to exclude malignancy or pregnancy.

Women should be informed that amenorrhea or oligomenorrhea may occur after discontinuation of oral contraceptives, especially if these conditions existed prior to their use.

Reduced efficacy

The efficacy of COCs may be reduced in case of missed tablet intake, vomiting, or diarrhea (see section "Dosage and administration"), as well as due to concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction**"**).

The use of COCs has been associated with Crohn's disease and ulcerative colitis.

Cerinta tablets contain lactose monohydrate. Women with rare hereditary disorders related to galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use this medicinal product.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy. If pregnancy is established, use of the drug must be stopped immediately.

If a woman becomes pregnant while taking the tablets, further use of the drug should be stopped immediately.

Results from a large number of epidemiological studies have not shown an increased risk of congenital defects in children born to women who used COCs before pregnancy, nor teratogenic effects from unintentional use of contraceptive tablets in early pregnancy. When resuming COC use, the increased risk of VTE in the postpartum period should be considered.

Breastfeeding period. Hormonal contraceptives may reduce milk secretion and alter milk composition, and may pass into breast milk in small amounts. These amounts may affect the infant, especially during the first 6 weeks postpartum. Therefore, use of these products during breastfeeding is contraindicated. Breastfeeding women should use other contraceptive methods.

Ability to affect reaction speed when driving or operating machinery

The medicinal product generally does not affect the ability to drive or operate machinery, but due to certain adverse reactions (e.g., headache), it may have a minor influence.

Method of Administration and Dosage

Method of administration. Take orally, approximately at the same time each day, one tablet daily.

If a woman has not previously used a contraceptive, the first tablet should be taken on the first day of menstruation. One tablet should be taken daily for 21 consecutive days (preferably at the same time each day). Starting on days 2–7 of the cycle is also possible; however, during the first cycle, it is recommended to additionally use a non-hormonal contraceptive method (such as condoms or spermicides) for the first 7 days of tablet intake.

After completing the 21-day course of the medication, a 7-day break is taken, during which withdrawal bleeding usually occurs (typically on day 2 or 3). The next pack containing 21 tablets should be started on the 8th day after the 7-day break, even if bleeding has not yet stopped.

The medication may be continued using this regimen for as long as pregnancy prevention is desired. When Cerinta is used regularly, the contraceptive effect persists throughout the 7-day break.

Switching from another combined hormonal contraceptive (oral tablets, vaginal ring, or transdermal patch): Cerinta should be started the day after taking the last active tablet of the previous contraceptive (removal of the vaginal ring or transdermal patch), but no later than the day after the tablet-free interval (placebo tablets, removal of the vaginal ring or transdermal patch) of the previous contraceptive.

Switching to Cerinta from a progestogen-only contraceptive (low-dose oral contraceptive, injection, implant, or intrauterine device): Switching from a low-dose oral contraceptive can occur on any day of the menstrual cycle (from an implant or intrauterine device—on the day of removal; from an injection—on the day the next injection would have been due). In this case, it is recommended to additionally use a barrier method of contraception for the first 7 days of tablet intake.

After first-trimester abortion: Initiation of the medication should begin immediately on the same day as the procedure. In this case, there is no need to use additional contraceptive methods. If the medication is not started within 5 days after termination of pregnancy, the patient should use additional non-hormonal contraceptives (e.g., condoms or spermicides) for the first 7 days of the first cycle of COC use.

After childbirth or second-trimester abortion: The medication should be started on day 28 after childbirth or second-trimester abortion, due to the increased risk of thromboembolic disorders during the postpartum period. If the woman starts taking the tablets later, barrier contraceptive methods should be used additionally for the first 7 days of medication use. However, if sexual intercourse has already occurred, pregnancy should be ruled out or the woman should wait for the first menstrual period before starting COC use.

Lactation: see section "Use during pregnancy or breastfeeding".

Missed tablet

If a tablet is missed or taken incorrectly, the risk of pregnancy increases. If less than 12 hours have passed since the tablet should have been taken, contraceptive protection is not reduced. However, if more than 12 hours have passed, contraceptive protection may be reduced.

If a woman has missed taking tablets and then fails to experience a withdrawal bleed during the first usual tablet-free interval, pregnancy should be considered.

Gastrointestinal disorders. Vomiting or diarrhoea may reduce the effectiveness of the preparation due to incomplete absorption of the active ingredients.

If vomiting occurs within 3–4 hours after taking a tablet, the woman should follow the recommendations given in the section "Missed tablet intake".

If a woman wishes to continue her regular tablet-taking schedule during diarrhoea, she should take additional tablets from another pack for as many days as necessary.

Menstrual cycle control

To delay menstruation, the next pack of Cerinta tablets should be started the day after finishing the current pack, without any break. The duration of menstrual delay depends on the number of tablets taken from the second pack. Breakthrough bleeding or spotting may occur during this period. Regular use of Cerinta can be resumed after the usual 7-day tablet-free interval.

To bring on a withdrawal bleed earlier, the 7-day tablet-free interval may be shortened by the desired number of days. However, it should be noted that the shorter the tablet-free interval, the less likely a withdrawal bleed will occur. Instead, breakthrough bleeding or spotting may occur during the intake of tablets from the following pack.

Important: the tablet-free interval must not exceed 7 days.

Children. This medicinal product is not intended for use in children.

Overdose

Symptoms of accidental overdose: severe headache, gastrointestinal disturbances (nausea, vomiting). Vaginal bleeding may occur after discontinuation of the drug. Withdrawal bleeding may even occur in prepubertal girls following accidental ingestion of the medicinal product.

Treatment: discontinue use of the drug; treatment is symptomatic. There is no specific antidote.

Adverse Reactions

At the beginning of treatment, intermenstrual bleeding, nausea, abdominal pain, weight gain, breast pain, breast tenderness, headache, and depressed mood were very common (>1/10). These adverse effects are temporary and resolve spontaneously.

Serious adverse reactions include arterial and venous thromboembolism.

The following adverse reactions are listed by organ systems and frequency of occurrence (common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; frequency not known: cannot be estimated from available data).

Eye disorders:

common: visual disturbances;

rare: intolerance to contact lenses.

Immune system disorders:

uncommon: systemic lupus erythematosus;

rare: hypersensitivity reactions;

frequency not known: exacerbation of idiopathic angioedema.

Investigations:

common: weight gain;

uncommon: changes in serum lipid levels;

rare: weight loss.

Metabolism and nutrition disorders:

uncommon: fluid retention;

frequency not known: hypertriglyceridemia.

Nervous system disorders:

common: headache, increased irritability;

uncommon: migraine, chorea.

Cardiovascular disorders:

uncommon: arterial hypertension, venous thromboembolism, arterial thromboembolism.

Hepatobiliary disorders:

uncommon: cholelithiasis;

rare: cholestatic jaundice;

frequency not known: liver function abnormalities, increased transaminase levels.

Psychiatric disorders:

common: depressed mood, mood changes, nervousness;

uncommon: decreased libido;

rare: increased libido.

Reproductive system and breast disorders:

common: breast tenderness, breast pain, irregular bleeding, amenorrhea, hypomenorrhea;

uncommon: breast enlargement;

rare: galactorrhea; vaginal discharge, changes in vaginal secretion;

frequency not known: menstrual cycle changes, bloody discharge, breakthrough bleeding and withdrawal bleeding, amenorrhea after oral contraceptive use.

Skin and subcutaneous tissue disorders:

common: acne;

uncommon: rash, urticaria, chloasma;

rare: erythema nodosum, exudative polymorphic erythema.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

uncommon: breast cancer, hepatic adenoma, hepatocellular carcinoma, cervical cancer.

Ear and labyrinth disorders:

uncommon: otosclerosis.

Gastrointestinal disorders:

common: nausea, abdominal pain;

uncommon: vomiting, diarrhea;

very rare: pancreatitis.

The following adverse reactions (without frequency specified) have been reported by women using oral contraceptives:

Metabolism and nutrition disorders: hypercholesterolemia, hypertriglyceridemia.

Nervous system disorders: dizziness, worsening of epilepsy.

Vascular disorders: phlebitis.

Skin and subcutaneous tissue disorders: hirsutism, seborrhea.

Musculoskeletal and connective tissue disorders: sensation of heaviness.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic disorders, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis, phlebitis, and pulmonary embolism, has been observed in women using oral contraceptives. For further details, see section "Special precautions for use".

The following serious adverse events have been reported in women using oral contraceptives (described in section "Special precautions for use"):

• venous and arterial thromboembolic disorders;
• arterial hypertension;
• acute cerebrovascular disorders (e.g., transient ischemic attack, ischemic stroke, hemorrhagic stroke);
• arterial hypertension;
• liver tumors (benign and malignant).

A slightly increased incidence of breast cancer has been observed among women using oral contraceptives. Since breast cancer is rarely diagnosed in women under 40 years of age, the increase in cases among current or recent users of oral contraceptives is small compared to the overall risk of developing breast cancer.

A causal relationship with oral contraceptive use has not been established (see sections "Contraindications", "Special precautions for use").

Five studies comparing the risk of breast cancer between ever-users (current or past users) and never-users of oral contraceptives reported no association between any use of oral contraceptives and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

Three studies compared the risk of breast cancer between current or recent users (<6 months since last use) and never-users (Fig. 1). One of these studies reported no association between breast cancer risk and oral contraceptive use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both studies observed a higher risk with longer duration of current use, with relative risk ranging from 1.03 for less than one year of combined oral contraceptive (COC) use to approximately 1.4 for more than 8–10 years of oral contraceptive use.

Conditions reported to develop or worsen during pregnancy and with the use of oral contraceptives: Crohn’s disease, ulcerative colitis, cholestatic jaundice and/or pruritus; gallstone formation; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss associated with otosclerosis; sickle cell anemia; renal dysfunction; porphyria; cervical cancer; anovulatory cycles; metrorrhagia.

Changes in glucose tolerance and effects on peripheral insulin sensitivity have been observed in women using oral contraceptives (see section "Special precautions for use").

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in a light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

21 tablets per blister, 1 blister per cardboard box.

Prescription status

Prescription only.

Manufacturer

San Pharmaceuticals Industries Ltd.

Manufacturer's address and location of operations

Baroda Highway, Halol, Gujarat, 389350, India.