Egistina^® (Tablets) Instructions for Use

Marketing Authorization Holder

Egis Pharmaceuticals PLC (Hungary)

Manufactured By

Cyndea Pharma S.L. (Spain)

ATC Code

G03AA16 (Dienogest and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Egistina®

Film-coated tablets 2 mg+0.03 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

28 pcs. – blisters – cardboard packs (28 pcs.) /kit includes: placebo tablets – 7 pcs. and active tablets – 21 pcs./ – Prescription only
28 pcs. – blisters (3 pcs.) – cardboard packs (84 pcs.) /kit includes: placebo tablets – 7 pcs. and active tablets – 21 pcs./ – Prescription only

Film-coated tablets (placebo)

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; systemic hormonal contraceptives; progestogens and estrogens, fixed combinations

Pharmacological Action

A combined low-dose monophasic oral contraceptive.

The contraceptive effect is achieved through complementary mechanisms, the most important of which are suppression of ovulation and an increase in the viscosity of cervical mucus, making it impenetrable to sperm.

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

The antiandrogenic effect of the dienogest and ethinylestradiol combination is based on a reduction in the concentration of androgens in the blood plasma.

Administration of the ethinylestradiol and dienogest combination led to the resolution of symptoms of mild to moderate acne and had a positive result in patients with seborrhea, as confirmed by the results of a number of clinical studies.

Dienogest is a derivative of norethisterone, which has a lower affinity for progesterone receptors in vitro (10-30 times) compared to other synthetic progestogens. Dienogest has no significant androgenic, mineralocorticoid, or glucocorticoid effects in vivo.

When used alone, Dienogest inhibits ovulation at a dose of 1 mg/day.

In addition, Dienogest improves the blood lipid profile (increases HDL concentration).

In women taking combined oral contraceptives, the cycle becomes more regular, painful menstruation is less common, and the intensity and duration of bleeding are reduced, thereby lowering the risk of iron deficiency anemia. Furthermore, there is evidence of a reduced risk of endometrial and ovarian cancer with the use of combined oral contraceptives.

Pharmacokinetics

Dienogest is rapidly and completely absorbed in the intestine after oral administration. C_max in plasma (51 pg/ml) is reached after 2.5 h. The absolute bioavailability when taken simultaneously with ethinylestradiol is 96%. Dienogest binds to plasma albumin and does not bind to SHBG and corticosteroid-binding globulin. The fraction of free dienogest in plasma is 10%, while 90% is non-specifically bound to albumin. The apparent V_d is 37-45 L. The concentration of SHBG in plasma does not affect the pharmacokinetics of dienogest. As a result of daily administration, the plasma concentration of dienogest increases approximately 1.5-fold, reaching a steady state after approximately 4 days of administration. Dienogest is mainly metabolized by hydroxylation, with glucuronidation being an alternative pathway. The metabolites are inactive and rapidly eliminated from the plasma, so metabolites cannot be detected in plasma in significant amounts, but this does not apply to unchanged dienogest. The total clearance after a single dose is 3.6 L/h. T_1/2 of dienogest is about 9 h. An insignificant amount of dienogest is excreted unchanged by the kidneys. Dienogest metabolites are excreted by the kidneys and via the intestine in a ratio of 3:1, T_1/2 – 14.4 h.

Ethinylestradiol is rapidly and completely absorbed in the small intestine after oral administration. C_max in plasma (67 pg/ml) is reached after 1.5-4 h. During the first pass through the liver, a significant portion of ethinylestradiol is metabolized. The absolute bioavailability is approximately 44%. Ethinylestradiol is almost completely (about 98%), although non-specifically, bound to albumin. Ethinylestradiol increases the plasma concentration of sex hormone-binding globulin (SHBG). The apparent V_d is 2.8-8.6 L/kg. C_ss is reached during the second half of the cycle, when the serum concentration of ethinylestradiol increases approximately 2-fold. Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. The main pathway of ethinylestradiol metabolism is aromatic hydroxylation, but its metabolism also leads to the formation of a large number of hydroxylated and methylated metabolites, which are present as glucuronides, sulfates, and in free form. The clearance is approximately 2.3-7 ml/min/kg. The decrease in plasma concentration of ethinylestradiol is biphasic: the first phase is characterized by a T_1/2 of about 1 h, the second – 10-20 h. It is not excreted unchanged from the body. Ethinylestradiol metabolites are excreted by the kidneys and via the intestine in a ratio of 4:6 with a T_1/2 of about 24 h.

Indications

Oral contraception.

ICD codes

Dosage Regimen

Take one tablet orally at the same time each day.

Follow the blister pack order strictly, starting with the active tablets.

Begin the first pack on the first day of your menstrual cycle.

If switching from another combined hormonal contraceptive, start Egistina the day after the last active tablet of the previous product.

After a miscarriage or abortion in the first trimester, start immediately; after a second-trimester abortion or childbirth, start at week 4.

Take the 21 active tablets (containing Dienogest 2 mg and Ethinylestradiol 0.03 mg), then the 7 placebo tablets.

Withdrawal bleeding usually occurs during the placebo tablet days.

If a dose is more than 12 hours late, contraceptive reliability may be reduced.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet, consider it a missed dose.

For missed active tablets, take the most recent missed tablet immediately and continue the pack normally.

Use additional barrier contraception for 7 days if you miss a tablet in the first week and had intercourse in the previous 7 days.

If you miss two or more active tablets, contraceptive protection is no longer guaranteed.

Do not delay the start of the next pack by more than 7 days.

Consult a physician if you are unsure about the regimen.

Adverse Reactions

Infectious and parasitic diseases infrequently – vaginitis/vulvovaginitis, vaginal candidiasis or other fungal vulvovaginal infections; rarely – salpingo-oophoritis (adnexitis), urinary tract infections, cystitis, mastitis, cervicitis, fungal infections, candidiasis, oral herpes, influenza, bronchitis, sinusitis, upper respiratory tract infections, viral infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps) rarely – uterine fibroids, breast lipoma.

Blood and lymphatic system disorders rarely – anemia.

Immune system disorders rarely – allergic reactions.

Endocrine system disorders rarely – virilism.

Metabolism and nutrition disorders infrequently – increased appetite; rarely – anorexia.

Psychiatric disorders infrequently – depressed mood; rarely – depression, mental disorders, insomnia, sleep disorders, aggression; frequency unknown – mood changes, decreased libido, increased libido.

Nervous system disorders often – headache; infrequently – dizziness, migraine; rarely – ischemic stroke, cerebrovascular disorders, dystonia.

Eye disorders rarely – dry eye mucosa, eye mucosa irritation, oscillopsia, visual impairment; frequency unknown – contact lens intolerance (discomfort when wearing them).

Ear and labyrinth disorders rarely – sudden hearing loss, tinnitus, dizziness, hearing impairment.

Cardiac disorders infrequently – increased blood pressure, decreased blood pressure; rarely – cardiovascular disorders, tachycardia, venous and arterial thromboembolic complications*, thrombophlebitis, diastolic hypertension, orthostatic circulatory dystonia, “hot flashes”, varicose veins, venous pathology, venous pain.

Respiratory, thoracic and mediastinal disorders rarely – bronchial asthma, hyperventilation.

Gastrointestinal disorders infrequently – abdominal pain, including upper and lower abdominal pain, discomfort/bloating, nausea, vomiting, diarrhea; rarely – gastritis, enteritis, dyspepsia.

Skin and subcutaneous tissue disorders infrequently – acne, alopecia, rash (including maculopapular rash), pruritus (including generalized pruritus); rarely – allergic dermatitis, atopic dermatitis/neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorder/hyperpigmentation, seborrhea, dandruff, hirsutism, skin pathology, skin reactions, “orange peel skin”, spider veins; frequency unknown – urticaria, erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders rarely – back pain, musculoskeletal discomfort, myalgia, limb pain.

Reproductive system and breast disorders often – breast pain, discomfort sensation, breast engorgement; infrequently – changes in volume, duration and interval of withdrawal bleeding (including heavy withdrawal bleeding/bleeding, scanty or infrequent withdrawal bleeding, absence of withdrawal bleeding, acyclic bleeding/spotting), breast enlargement, breast swelling and fullness, breast edema, painful withdrawal bleeding/bleeding, genital tract discharge/vaginal discharge, ovarian cysts, pelvic pain; rarely – cervical dysplasia, uterine adnexal cysts, uterine adnexal pain, breast cysts, fibrocystic mastopathy, dyspareunia, galactorrhea, menstrual cycle disorder; frequency unknown – breast discharge.

General disorders and administration site conditions infrequently – fatigue, asthenia, malaise; rarely – chest pain, peripheral edema, flu-like symptoms, inflammation, increased body temperature, irritability; frequency unknown – fluid retention.

Investigations infrequently – changes in body weight (increase, decrease and fluctuations in body weight); rarely – increased blood triglycerides, hypercholesterolemia.

Congenital, familial and genetic disorders rarely – detection of accessory breast tissue/polymastia.

Contraindications

Thrombosis (arterial and venous) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders; conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history; identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); presence of a high risk of venous or arterial thrombosis.

Migraine with focal neurological symptoms currently or in history.

Planned surgery (at least 4 weeks before it) and the period of immobilization, for example, after trauma (including after application of plaster casts) and for at least 2 weeks after restoration of full mobility.

Diabetes mellitus with vascular complications.

Uncontrolled or severe arterial hypertension.

Severe dyslipoproteinemia.

Pancreatitis with severe hypertriglyceridemia currently or in history.

Hepatic insufficiency and severe liver diseases (until liver tests normalize); liver tumors (benign or malignant) currently or in history.

Identified hormone-dependent malignant diseases (including of the genital organs or mammary glands) or suspicion of them; vaginal bleeding of unknown origin.

Pregnancy or suspected pregnancy; breastfeeding period.

With caution

Presence of risk factors for thrombosis and thromboembolism (smoking; obesity; dyslipoproteinemia; controlled arterial hypertension; migraine without focal neurological symptoms; valvular heart disease; 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 circulatory disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis); hereditary angioedema; hypertriglyceridemia; liver diseases not classified as contraindications; diseases that first appeared or worsened during pregnancy or during previous use of sex hormones (for example, jaundice and/or pruritus associated with cholestasis, gallbladder disease, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea); postpartum period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated for use in hepatic insufficiency and severe liver diseases (until liver tests normalize); liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

The drug is approved for use in renal impairment

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

The drug is contraindicated for use in elderly patients

Special Precautions

If any of the conditions, diseases or risk factors listed below are currently present, the potential risk and expected benefit of using this contraceptive should be carefully weighed.

There is epidemiological data on an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) when taking combined oral contraceptives.

The risk of developing venous thromboembolism (VTE) is highest in the first year of taking such drugs. An increased risk is present after initial use of combined oral contraceptives (COCs) or resumption of use of the same or another combined oral contraceptive (after a break in taking the drug of 4 weeks or more). Data from a large prospective study involving 3 patient groups show that the increased risk is present mainly during the first 3 months. The overall risk of VTE in women taking low-dose COCs (<0.05 mg ethinylestradiol) is 2-3 times higher than in non-pregnant patients who do not take combined oral contraceptives, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth. VTE can be life-threatening or fatal (in 1-2% of cases). VTE, presenting as deep vein thrombosis or pulmonary embolism, can occur with the use of any combined oral contraceptives. Very rarely, thrombosis of other blood vessels, such as hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels, occurs with the use of COCs.

Arterial thromboembolism can lead to stroke, vascular occlusion or myocardial infarction. Arterial thromboembolism can be life-threatening or fatal.

In women with a combination of several risk factors or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than with simple summation of factors. In this case, drugs containing this combination are contraindicated.

The increased risk of thromboembolism in the postpartum period should be taken into account.

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

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

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of cervical cancer with long-term use of COCs. However, the connection with taking and COCs. Controversy remains regarding the extent to which these data are related to screening for cervical pathology or to sexual behavior characteristics (less frequent use of barrier contraceptive methods).

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase while taking COCs.

If a persistent clinically significant increase in blood pressure develops during COC use, COCs should be discontinued and treatment for arterial hypertension should be initiated. COC use may be continued if normal blood pressure values are achieved with antihypertensive therapy.

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

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

In diabetes mellitus, women taking COCs should be carefully monitored.

Women prone to chloasma during the use of this contraceptive should avoid prolonged exposure to the sun and UV radiation.

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

Conditions requiring medical consultation: any changes in health status, especially the occurrence of conditions listed in the “Contraindications” and “Precautions” sections; a localized lump in the breast; concurrent use of other medicinal products; if prolonged immobilization is expected (e.g., a cast on a lower limb), hospitalization or surgery is planned (at least 4 weeks before the planned surgery); unusually heavy vaginal bleeding; a missed pill in the first week of the pack and a sexual intercourse occurred 7 days or less before that; absence of two consecutive withdrawal bleedings or suspicion of pregnancy (the next pack should not be started until consultation with a doctor).

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

It should be remembered that sex hormones may promote the growth of some hormone-dependent tissues and tumors.

Drug Interactions

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

Agents that increase the clearance of the active substances of this combination (reducing effectiveness by enzyme induction): phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin, and agents for the treatment of HIV infection (ritonavir, nevirapine, and efavirenz) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

When used concomitantly with this combination, 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.

Dienogest is a substrate of the CYP3A4 isoenzyme.

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

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

In vitro, Ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, as well as an irreversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, the administration of a hormonal contraceptive containing Ethinylestradiol did not lead to any increase or led only to a weak increase in the plasma concentrations of CYP3A4 substrates (e.g., midazolam), while the plasma concentrations of CYP1A2 substrates may increase weakly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.