Gestarella^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Haupt Pharma Munster, GmbH (Germany)

Quality Control Release

ZENTIVA, k.s. (Czech Republic)

ATC Code

G03AA10 (Gestodene and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Gestodene (Rec.INN registered by WHO)

Dosage Form

Gestarella®

Film-coated tablets, 75 mcg+20 mcg: 21 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, shiny.

Excipients: sodium calcium edetate, lactose monohydrate, corn starch, povidone 25, magnesium stearate.

Shell composition sucrose, povidone 90 F, macrogol 6000, calcium carbonate, talc, glycol montan wax.

21 pcs. – blisters (1) – cardboard packs.
21 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Monophasic oral contraceptive

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

A monophasic low-dose combined gestagen-estrogen (Gestodene, a 19-nortestosterone derivative, and Ethinylestradiol) contraceptive drug. By acting on central and peripheral mechanisms, the drug inhibits the secretion of pituitary gonadotropic hormones, inhibits follicle maturation, prevents the process of ovulation, reduces the receptivity of the endometrium to the blastocyst and increases the viscosity of cervical secretion, making it difficult for sperm to penetrate into the uterine cavity.

The use of oral contraceptive drugs (COCs) with a high content of ethinylestradiol (50 mcg) reduces the risk of developing ovarian and endometrial cancer. For COC drugs with a lower content of ethinylestradiol, there is no data confirming this pharmacological effect. While using the drug, regular menstrual-like bleeding is established, pain sensations are less pronounced, the intensity of bleeding decreases, as a result of which one of the risk factors for the development of iron deficiency anemia is reduced.

Pharmacokinetics

Ethinylestradiol

Absorption

When taken orally, Ethinylestradiol is rapidly and completely absorbed. C_max is approximately 65 pg/ml and is reached after 1.7 h. During absorption and the “first pass” through the liver, Ethinylestradiol undergoes intensive metabolism, as a result, the bioavailability when taken orally averages 45% with high interindividual variability (about 20-65%).

Distribution

Ethinylestradiol is almost completely bound to blood plasma albumin (approximately 98%) and induces the synthesis of sex hormone-binding globulin (SHBG). V_d is about 2.8-8.6 l/kg.

Metabolism

Ethinylestradiol undergoes presystemic conjugation, both in the small intestinal mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation. The clearance of ethinylestradiol is 2.3-7 ml/min/kg.

Excretion

The decrease in ethinylestradiol concentration occurs in two phases, which are characterized by T_1/2 of about 1 h and 10-20 h, respectively. Ethinylestradiol is not excreted unchanged; its metabolites are excreted by the kidneys and through the intestines in a ratio of 4:6, respectively. T_1/2 is about 24 h.

Steady-state concentration

Taking into account the variability of T_1/2 in the terminal phase and daily administration, C_ss of ethinylestradiol in blood plasma is reached approximately after 1 week.

Gestodene

Absorption

When taken orally, Gestodene is rapidly and completely absorbed. C_max is about 4 ng/ml and is reached approximately 1 h after taking a single dose. Bioavailability is 99%.

Distribution

Gestodene binds to blood plasma albumin and SHBG. About 1.3% of the total drug concentration in blood plasma is in the form of free steroid, approximately 68% is specifically bound to SHBG.

Induction of SHBG synthesis by ethinylestradiol affects the binding of gestodene to blood plasma proteins, leading to an increase in the fraction bound to SHBG and a decrease in the fraction bound to albumin.

V_d is 0.7 l/kg.

Metabolism

Gestodene is almost completely metabolized. The metabolic clearance rate from blood plasma is about 0.8 ml/min/kg.

Excretion

The concentration of gestodene decreases in two phases. The terminal phase is characterized by T_1/2 of 12-15 h.

Gestodene is not excreted unchanged. Its metabolites are excreted by the kidneys and through the intestines in an approximate ratio of 6:4. T_1/2 of metabolites is about 24 h.

Steady-state concentration

The pharmacokinetics of gestodene depends on the concentration of SHBG in blood plasma, which increases 2-fold when administered together with ethinylestradiol. After repeated administration, the concentration of gestodene in blood plasma increases approximately 4-fold, and C_ss of the drug is reached during the second half of the therapeutic cycle.

Indications

• Oral contraception.

ICD codes

Dosage Regimen

The drug Gestarella^® is taken in a specific order indicated on the package, every day at approximately the same time. The tablets are taken orally with a small amount of water. One tablet is taken daily for 21 consecutive days.

Taking tablets from the next package should be started on the day after the 7-day break, during which menstrual-like bleeding occurs. Bleeding usually begins on the 2-3rd day after taking the last tablet and may not end before starting to take tablets from the new package.

How to start taking the drug Gestarella^®

If hormonal contraception was not used in the previous month

Tablet intake should be started on the first day of the natural menstrual cycle (i.e., on the first day of menstrual bleeding). It is also possible to start taking from the 2nd to the 5th day of the menstrual cycle, but in this case, it is necessary to use a barrier method of contraception during the first 7 days of the first cycle.

Switching from another combined oral contraceptive drug, vaginal ring, or transdermal patch

It is best to start taking the drug Gestarella^® immediately the day after taking the last active tablet (the last tablet containing the active substance) of the previous contraceptive drug, but in no case later than the next day after the usual 7-day break in taking tablets (for drugs with 21 tablets per package) or after taking placebo tablets of the previous contraceptive drug (for drugs with 28 tablets per package). In the case of using a transdermal patch, the woman should start taking the drug the day after its removal, but in no case later than the day when a new ring needs to be inserted or the next patch needs to be applied.

Switching from contraceptives containing only progestogens (“mini-pills”, injections, implant), or an intrauterine system (IUS) releasing progestogen

Switching from “mini-pills” is possible at any time, from an implant or IUS on the day of their removal, from injections on the day when the next injection should be given, but in all these cases, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the drug Gestarella^®.

Use after first trimester abortion

A woman can start taking the drug immediately. In this case, the use of additional contraceptive methods is not required.

Use after childbirth or second trimester abortion

The drug is started after childbirth, if the child is not breastfed, or after a second trimester abortion. Taking the drug Gestarella^® should be started between the 21st and 28th day after childbirth or abortion during the second trimester. If a woman starts taking it later, then it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if sexual intercourse occurred before starting the drug, it is necessary to exclude pregnancy before starting the contraceptive drug, or the woman should wait for her first menstrual-like bleeding.

Usually, the first menstrual cycle after stopping the drug is lengthened by 1 week. If a normal cycle is not restored within 2-3 months, it is necessary to consult a doctor.

Taking missed tablets

If the delay in taking the tablet is less than 12 hours, contraceptive protection is not impaired. The tablet must be taken immediately as soon as the woman remembers the missed tablet, the next tablet should be taken at the usual time. If the delay in taking the tablet is more than 12 hours, contraceptive protection may be reduced. In this case, it is necessary to be guided by the following basic rules and take appropriate measures.

1. Taking tablets should never be interrupted for more than 7 days.
2. A 7-day period of continuous tablet intake is required to achieve the necessary suppression of the hypothalamic-pituitary-ovarian system.

In accordance with the above rules, the following is recommended.

First week of taking the drug

The woman should take the last missed tablet immediately as soon as she remembers it, even if this means taking two tablets at the same time. After that, the tablets should be taken at the usual time. Additionally, during the next 7 days, it is necessary to use a barrier method of contraception, for example, a condom. If the woman had sexual intercourse in the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer the miss is to the break in taking the drug, the higher the risk of pregnancy.

Second week of taking the drug

The woman should take the last missed tablet immediately as soon as she remembers it, even if this means taking two tablets at the same time. After that, the tablets should be taken at the usual time. If the tablets were taken regularly for 7 days before the first missed tablet, additional contraceptive measures are not required. If the woman took the tablets irregularly or missed more than one tablet, additional contraceptive measures must be taken for 7 days.

Third week of taking the drug

Due to the upcoming break in taking the tablets, there is a high risk of reduced contraceptive reliability. However, despite this, by adjusting the drug regimen, a decrease in contraceptive protection can be prevented. When following one of the two instructions below, there is no need for other contraceptive measures, provided that the woman correctly took the tablets for 7 days before the first missed tablet. Otherwise, the woman should follow the first recommendation and take other additional contraceptive measures for 7 days.

1. The woman should take the last missed tablet immediately as soon as she remembers it, even if this means taking two tablets at the same time. After that, the tablets should be taken at the usual time. The woman should start taking from the next package immediately after finishing the tablets from the previous package. Thus, there will be no break between packages. Withdrawal bleeding is unlikely until the second package is finished, but scanty spotting or heavy vaginal bleeding may be noted.
2. The woman can also stop taking the tablets from the current package. In this case, it is necessary to take a break for 7 days, including the days of the miss, then start taking tablets from a new package.

If a woman forgot to take tablets and she does not have withdrawal bleeding during the tablet break, pregnancy must be excluded.

Intake in case of gastrointestinal disorders

If a woman had vomiting or diarrhea within 4 hours of taking the tablets, absorption may be incomplete and additional contraceptive measures should be taken. In these cases, one should be guided by the recommendations for a missed tablet.

Changing the day of the start of the menstrual cycle

If a woman wants to delay the day of the start of menstrual bleeding, she should start taking the drug Gestarella^® from the next package without a break. It is possible to continue taking the drug from the new package for as long as the woman wishes (up to the end of the tablets in the package). During this period, breakthrough bleeding or spotting may occur. After a 7-day break, the woman should resume regular intake of the drug.

If a woman wants to move the start of bleeding to another day of the week, then the nearest break in taking the tablets should be shortened by as many days as she wants. The shorter this interval, the higher the risk of withdrawal bleeding and the occurrence of breakthrough bleeding and spotting while taking the second package (as well as in the case of postponing the start of bleeding).

Adverse Reactions

The most frequently reported adverse reactions (AR) in clinical studies and post-marketing observations during the use of COCs are spotting/bleeding. Women taking COCs have been observed to have an increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis, and pulmonary embolism.

Adverse reactions are grouped according to MedDRA terminology. The frequency of side effects was determined in accordance with the WHO classification: very common (≥ 10%); common (≥ 1% and < 10%); uncommon (≥ 0.1% and < 1%); rare (≥ 0.01% and < 0.1%); very rare (< 0.01%); unknown frequency (it is not possible to determine the frequency of the side effect from the available data).

Immune system disorders: rare – hypersensitivity reactions; unknown frequency – exacerbation of systemic lupus erythematosus.

Metabolism and nutrition disorders common – weight increased, fluid retention; rare – weight decreased; unknown frequency – exacerbation of porphyria.

Psychiatric disorders common – depressed mood, mood swings; uncommon – decreased libido; rare – increased libido; unknown frequency – nervousness, depression.

Nervous system disorders common – headache, migraine; unknown frequency – dizziness, exacerbation of chorea.

Eye disorders rare – contact lens intolerance (discomfort when wearing them); unknown frequency – optic neuritis.

Vascular disorders rare – venous thromboembolism, arterial thromboembolism.

Gastrointestinal disorders common – nausea, vomiting; uncommon – abdominal pain, diarrhea; very rare – pancreatitis; unknown frequency – abdominal distension, colitis.

Hepatobiliary disorders rare – cholelithiasis.

Skin and subcutaneous tissue disorders uncommon – skin rash, incl. urticarial; rare – erythema nodosum, erythema multiforme; unknown frequency – acne, hirsutism, alopecia.

Reproductive system and breast disorders: common – breast tension, breast pain, vaginal discharge; uncommon – breast enlargement; rare – breast discharge; unknown frequency – painful menstrual-like bleeding, vaginitis, candidal vulvovaginitis, breast pain.

Investigations: uncommon – hyperlipidemia.

The following serious adverse events have been reported in women using COCs. Additional information on possible side effects is presented in the “Special Instructions” section.

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Cerebrovascular disorders;
• Increased blood pressure;
• Hypertriglyceridemia;
• Decreased glucose tolerance or effect on peripheral insulin resistance;
• Liver tumors (benign and malignant);
• Impaired liver function tests;
• Chloasma.

Onset or worsening of conditions for which the association with COC use is not proven: jaundice and/or itching associated with cholestasis; gallstone formation; hemolytic-uremic syndrome; herpes gestationis; hearing loss associated with otosclerosis; Crohn’s disease; ulcerative colitis; cervical cancer.

Contraindications

The drug Gestarella^® is contraindicated in the presence of any of the conditions/diseases listed below. If any of the listed conditions develops for the first time during its use, the drug should be immediately discontinued.

• Current or history of thromboses (venous and arterial) and thromboembolisms (including deep vein thrombosis, pulmonary embolism, myocardial infarction);
• Conditions preceding thrombosis (including angina pectoris);
• Cerebrovascular disease: current and history of stroke, transient ischemic attacks;
• Multiple or pronounced risk factors for venous or arterial thrombosis, including complicated lesions of the heart valves, atrial fibrillation, cerebrovascular or coronary artery disease, severe dyslipoproteinemia, uncontrolled arterial hypertension, major surgery, prolonged immobilization, air travel lasting more than 4 hours, surgical operations on the lower extremities and pelvic organs, neurosurgical interventions, smoking at the age of over 35 years;
• Congenital or acquired predisposition to arterial or venous thromboses (resistance to activated protein C (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin, lupus anticoagulant));
• Migraine with focal neurological symptoms currently or in history;
• Diabetes mellitus with vascular complications;
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Hepatic insufficiency and severe liver diseases, including Dubin-Johnson and Rotor syndromes (until liver enzyme parameters normalize);
• Liver tumors (benign or malignant) currently or in history;
• Identified hormone-dependent malignant neoplasms (including of the genital organs or breast) or suspicion thereof;
• Childhood and adolescent age (until menarche);
• Vaginal bleeding of unknown origin;
• Obesity (BMI over 30 kg/m²);
• Extensive trauma;
• Pregnancy or suspicion thereof;
• Period of breastfeeding;
• Galactose intolerance, lactase deficiency or glucose-galactose malabsorption, fructose intolerance or sucrase-isomaltase deficiency (the preparation contains lactose monohydrate and sucrose);
• Hypersensitivity to any component of the preparation Gestarella^®.

With caution

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

• Risk factors for thrombosis and thromboembolism: smoking, overweight (BMI≥25<30 kg/m²), dyslipoproteinemia, arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve defects, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives);
• Other diseases in which peripheral circulation disorders may be noted: diabetes mellitus, oncological diseases, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• Diseases that first occurred or worsened during pregnancy or during previous use of sex hormones (e.g., jaundice, cholestasis, gallbladder diseases, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea);
• Depression;
• Epilepsy;
• Postpartum period.

Use in Pregnancy and Lactation

Pregnancy

The preparation Gestarella^® must not be used during pregnancy. If pregnancy is detected during the use of the preparation Gestarella^®, it should be discontinued immediately and a physician should be consulted. However, extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy or who inadvertently took sex hormones in early pregnancy.

Breastfeeding period

COC use may reduce the amount of breast milk and change its composition, therefore the use of the preparation Gestarella^® is contraindicated during breastfeeding.

Use in Renal Impairment

Use with caution in renal impairment.

Pediatric Use

Contraindicated in childhood and adolescent age (until menarche).

Special Precautions

If there is any of the conditions or risk factors listed below, the possibility of using the preparation Gestarella^® should be discussed with the woman in advance. In case of worsening or first appearance of any of the conditions or risk factors, the woman should be advised to consult her physician to decide on the need to continue or discontinue the preparation.

Since the contraceptive effect of the preparation Gestarella^® mainly manifests by the 14th day from the start of use, it is recommended to additionally use non-hormonal (barrier) methods of contraception during the first 2 weeks of taking the preparation.

Cardiovascular diseases

Risk of venous thromboembolism (VTE)

The use of any COCs increases the risk of VTE compared to women not taking these preparations. Before starting the use of the preparation Gestarella^®, the higher (almost 2-fold) risk of developing VTE compared to other COCs containing levonorgestrel, norgestimate or norethisterone should be discussed with the woman. This risk is highest in the first year of use or upon resumption after a break of 4 weeks or more.

Results of an epidemiological study showed that among women who do not take COCs and are not pregnant, VTE occurs in approximately 2 out of 10,000 per year. However, in some women the risk may be significantly higher depending on the underlying risk factors they have (see below). According to expert estimates, VTE occurs in 9-12 out of 10,000 women per year taking COCs containing Gestodene. In both cases, the number of VTEs per year is less than the number of expected VTEs during pregnancy or in the postpartum period.

Risk factors for thromboembolic complications

The risk of venous and arterial thromboembolic complications in women taking COCs may significantly increase in the presence of additional risk factors, especially if the risk factors are multiple (see Table 1 and Table 2).

The preparation Gestarella^® is contraindicated if a woman has multiple risk factors for VTE or ATE. If a woman has more than one risk factor, the degree of risk of developing thromboembolic complications may be greater than the simple sum of individual factors. If the benefit-risk ratio is negative, the preparation Gestarella^® should not be prescribed.

VTE risk factors

Table No. 1. VTE risk factors

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

The increased risk of thromboembolism during the first 6 weeks of the postpartum period should be taken into account.

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

If symptoms of VTE occur, the woman should immediately seek emergency medical help and inform the physician that she is taking COCs.

DVT symptoms may include

• Unilateral swelling of the lower limb and/or foot or along a vein in the lower limb;
• Pain in the lower limbs or tenderness upon touch, which may be felt only when standing or walking;
• Increased skin temperature of the affected lower limb;
• Redness or pallor of the skin of the lower limb.

PE symptoms may include

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis;
• Acute chest pain;
• Nausea, vomiting, dizziness, fainting;
• Rapid or irregular heartbeat.

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

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

In cases of ocular vascular occlusion, symptoms can range from painless blurred vision, which may progress, to loss of vision. Sometimes vision loss can be acute.

Risk of arterial thromboembolism (ATE)

Epidemiological studies associate the use of COCs with an increased risk of ATE (myocardial infarction) or cerebrovascular diseases (e.g., transient ischemic attack (TIA), stroke). Arterial thromboembolic events can be fatal.

ATE risk factors

Table No. 2. ATE risk factors

Symptoms of ATE

If symptoms of ATE occur, the woman should immediately seek emergency medical help and inform the physician that she is taking COCs.

Symptoms of cerebrovascular diseases may include

• Sudden numbness or weakness of the muscles of the face, arm or leg, especially on one side of the body;
• Sudden difficulty walking, dizziness, loss of balance or coordination;
• Sudden confusion, problems with speech or understanding;
• Sudden, severe or prolonged headache without a specific cause;
• Sudden unilateral or bilateral loss of vision;
• Loss of consciousness or fainting with or without seizures.

If these symptoms are observed for no more than a day, this condition is regarded as an acute transient ischemic circulatory disorder – transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include

• Pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone, with radiation to the back, neck, jaw, upper limb, epigastric region;
• Feeling of stomach fullness, indigestion or suffocation;
• Sweating, nausea, vomiting and dizziness;
• Extreme weakness, anxiety or shortness of breath;
• Rapid or irregular heartbeat.

There is evidence of an increased incidence of venous and arterial thrombosis and thromboembolism when taking COCs.

However, the frequency of venous thromboembolism (VTE) developing while taking COCs is less than the frequency of VTE occurring during pregnancy (6 cases per 10,000 pregnant women per year).

Extremely rare cases of thrombosis of other blood vessels have been described in women taking COCs, for example, hepatic, mesenteric, renal arteries and veins, central retinal vein and its branches. A connection with COC use has not been proven.

Tumors

One of the significant risk factors for cervical cancer is persistent papillomavirus infection. There are reports of an increased risk of cervical cancer with long-term use of COCs. However, the connection with COC use has not been proven. This increase may be related to the detection of cervical pathology during mandatory examination before prescribing COCs or to sexual behavior characteristics (less frequent use of barrier contraception methods).

It has also been found that there is a slightly increased relative risk of breast cancer diagnosed in women who used COCs, but the connection with their use has not been proven. The observed increase in risk may be due not only to earlier diagnosis of breast cancer in women using COCs, but also to the biological effect of sex hormones or a combination of these two factors. Breast cancer in women taking or having taken COCs in the past is usually detected at clinically less advanced stages than in women who have never taken these preparations.

In rare cases, the development of liver tumors has been observed during the use of COCs. This should be taken into account when conducting a differential diagnosis in case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding.

Other conditions

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase during the use of the preparation Gestarella^®.

Although a slight increase in BP has been described in many women taking COCs, clinically significant increases in BP parameters have been rare. However, if a persistent, clinically significant increase in BP develops during the use of the preparation Gestarella^®, the preparation should be discontinued and treatment for arterial hypertension should be initiated. Use of the preparation Gestarella^® may be continued if normal BP values are achieved with antihypertensive therapy.

Conditions such as jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea, herpes during pregnancy, hearing loss associated with otosclerosis, may develop or worsen both during pregnancy and during COC use, but a causal relationship with their use has not been proven.

In women with hereditary forms of angioedema, COCs may cause or worsen symptoms of angioedema.

Cases of Crohn’s disease and ulcerative colitis have also been described during the use of COCs.

Acute diseases or exacerbation of chronic liver diseases may require discontinuation of the preparation Gestarella^® until liver function parameters return to normal. Recurrent cholestatic jaundice, which developed for the first time during a previous pregnancy or previous use of sex hormones, requires discontinuation of the preparation Gestarella^®.

Although COCs can affect insulin resistance and glucose tolerance, there is no need to change the dosing regimen of hypoglycemic drugs in patients with diabetes mellitus taking COCs with an ethinylestradiol content per tablet of <50 µg. Nevertheless, women with diabetes mellitus require careful medical supervision during the use of the preparation Gestarella^®.

During the use of the preparation Gestarella^®, worsening of endogenous depression and epilepsy may be noted.

Women prone to chloasma during the use of the preparation Gestarella^® should avoid prolonged sun exposure and UV radiation.

The preparation Gestarella^® contains lactose monohydrate and sucrose. Patients with rare congenital forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption, as well as with rare congenital forms of fructose intolerance or sucrase-isomaltase deficiency should not take this preparation.

Reduced contraceptive efficacy

The efficacy of COCs may decrease, for example, if a tablet is missed, in case of gastrointestinal disorders (vomiting or diarrhea) or when other medicinal products are used concomitantly. In this case, without discontinuing the preparation, additional non-hormonal (barrier) methods of contraception should be used simultaneously.

Laboratory tests

The use of the preparation Gestarella^® may affect the results of some laboratory tests, including liver, kidney, thyroid, adrenal function parameters, plasma transport protein concentrations, carbohydrate metabolism parameters, blood coagulation system parameters. The changes usually do not exceed the normal range.

Effect on the menstrual cycle

Irregular bleeding (“spotting” or “breakthrough” bleeding) may occur during the use of the preparation Gestarella^®, especially during the first month of use. For this reason, it is advisable to investigate the cause of irregular bleeding only after the body has adapted, i.e., approximately after three cycles of use.

If irregular bleeding continues or occurs after previous regular cycles, appropriate diagnostic procedures must be performed to rule out malignancy or pregnancy.

In some women, withdrawal bleeding does not occur during the tablet-free interval. If the preparation was taken as directed, pregnancy is unlikely. However, if the tablets were taken irregularly, or withdrawal bleeding did not occur 2 times in a row, then pregnancy must be ruled out before continuing the use of the preparation.

When using the preparation Gestarella^®, it should be taken into account that while taking hormonal contraceptives, the frequency and duration of menstrual-like bleeding, basal body temperature and properties of cervical mucus may change.

Medical examinations

Before starting or before resuming the use of the preparation Gestarella^®, a woman should undergo a thorough general medical and gynecological examination, including a detailed medical history (including family history), measurement of BP, heart rate, determination of BMI, ultrasound examination of the abdominal organs and pelvis, breast examination, cytological examination of the cervical epithelium. Pregnancy and disorders of the blood coagulation system must be ruled out. It is very important to draw the woman’s attention to information about venous and arterial thromboses, about symptoms of VTE and ATE, about known risk factors, as well as about what to do in case of suspected thrombosis.

The woman should also be instructed to carefully read the package leaflet and follow the recommendations contained therein.

The woman should be warned that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient, but not less than once every 6 months.

Effect on the Ability to Drive Vehicles and Machinery

Considering the profile of registered side effects (visual impairment, dizziness), caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during the period of Gestarella^® use.

Overdose

There are no available data on the development of serious adverse reactions in case of overdose.

The following symptoms may be observed: nausea, vomiting, mild vaginal bleeding in young girls.

Treatment: symptomatic therapy is administered. There is no specific antidote.

Drug Interactions

Effect of Other Medicinal Products on Gestarella^®

Interaction with medicinal products that induce microsomal enzymes of the cytochrome P450 system is possible, which may increase the clearance of sex hormones, which, in turn, can lead to acyclic “breakthrough” uterine bleeding and/or a decrease in the contraceptive effect.

If microsomal enzyme-inducing drugs are used in a short course

Women receiving treatment with microsomal enzyme-inducing drugs in addition to Gestarella^® are advised to temporarily use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method of contraception (intrauterine devices or condoms) should be used throughout the period of concomitant drug administration and for another 28 days after their discontinuation.

If microsomal enzyme-inducing drugs are used long-term

Women receiving long-term treatment with microsomal enzyme-inducing drugs are advised to consider using non-hormonal methods to ensure more reliable contraceptive efficacy.

• Substances that increase the clearance of Gestarella^® (reducing efficacy by enzyme induction): barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, HIV drugs – ritonavir, nevirapine, efavirenz and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and preparations containing St. John’s wort (Hypericum perforatum).
• Substances with variable effects on the clearance of Gestarella^®.

• When used concomitantly with Gestarella^®, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogens or progestins. In some cases, this effect may be clinically significant. Therefore, before using these medicinal products, the nature of their possible interaction with Gestarella^® should be preliminarily studied, and in case of any doubts, the woman should be advised to additionally use barrier contraceptives.
• When Gestarella^® is used concomitantly with perampanel, vemurafenib, dabrafenib, modafinil, or rufinamide, the possibility of reduced contraceptive efficacy due to accelerated metabolism of sex hormones should be considered. It is recommended to use additional methods of contraception (intrauterine devices or condoms) throughout the entire course of concomitant drug use and for 2-6 months after its discontinuation.

Substances that decrease the clearance of Gestarella^® (enzyme inhibitors)

Strong and moderate inhibitors of the CYP3A4 isoenzyme, such as azole derivative antifungal agents (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase plasma concentrations of estrogen or progestin, or both.

The use of etoricoxib at doses of 60 and 120 mg per day when taken concomitantly with combined oral contraceptives containing 35 mcg of ethinylestradiol increases the plasma concentration of ethinylestradiol by 1.4 and 1.6 times, respectively. This increase in ethinylestradiol concentration should be taken into account when selecting an appropriate combined oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increased frequency of thromboembolism due to increased exposure to ethinylestradiol.

A decrease in the effective plasma concentration of ethinylestradiol is observed with the simultaneous administration of some antibiotics (penicillins, tetracycline) due to changes in the intestinal microflora; therefore, during antibiotic therapy (except for rifampicin and griseofulvin) and for 7 days after their discontinuation, it is necessary to additionally use a barrier method of contraception.

NSAIDs reduce the efficacy of Gestarella^®.

Effect of Combined Oral Contraceptives on Other Medicinal Products

Combined oral contraceptives may affect the metabolism of other medicinal products; therefore, their plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Interaction with substrates of the CYP1A2 isoenzyme

Since Ethinylestradiol is an inhibitor of the CYP1A2 isoenzyme, when Gestarella^® is used concomitantly with medicinal products that are substrates of the CYP1A2 isoenzyme (e.g., clozapine, mirtazapine, olanzapine, theophylline, zolmitriptan), an increase in their plasma concentrations is possible, which, in turn, may increase the risk of adverse reactions. When Gestarella^® and HIV and hepatitis C protease inhibitors are used concomitantly, an increase in the frequency of hepatotoxicity manifestations (increased activity of liver transaminases) is possible.

Storage Conditions

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

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.