Trisiston (Dragee) Instructions for Use

Marketing Authorization Holder

Jenapharm, GmbH & Co. KG (Germany)

Manufactured By

Schering, GmbH & Co. Produktions KG (Germany)

ATC Code

G03AB03 (Levonorgestrel and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Levonorgestrel (Rec.INN registered by WHO)

Dosage Form

Trisiston

Dragees of three types: 21 or 63 pcs., incl.:; dragees of red-brown color 30 mcg+50 mcg: 6 pcs.,; dragees of white color 40 mcg+75 mcg: 6 pcs.,; dragees of ochre color 30 mcg+125 mcg: 9 pcs.

Dosage Form, Packaging, and Composition

Dragee of red-brown color (6 pcs. per pack).

Dragee of white color (6 pcs. per pack).

Dragee of ochre color (9 pcs. per pack).

21 pcs. – contour cell packs (1) – cardboard packs.
21 pcs. – contour cell packs (3) – cardboard packs.

Clinical-Pharmacological Group

Three-phase oral contraceptive

Pharmacotherapeutic Group

Contraceptive agent (estrogen + progestagen)

Pharmacological Action

Combined hormonal contraceptive for oral administration.

The contraceptive effect is due to two mechanisms. Under the influence of levonorgestrel, the release of hypothalamic releasing factors (LH and FSH) is blocked, and the secretion of gonadotropic hormones by the pituitary gland is suppressed, which leads to inhibition of the maturation and release of an egg ready for fertilization (ovulation). Ethinylestradiol helps maintain high viscosity of cervical mucus, which impedes the penetration of sperm into the uterine cavity.

In addition to the contraceptive effect, with regular use of drugs containing this combination, the menstrual cycle normalizes due to the replenishment of the level of endogenous hormones with hormonal components.

Pharmacokinetics

Levonorgestrel

After oral administration, Levonorgestrel is rapidly and completely absorbed; its C_max in blood plasma, equal to 3-4 ng/ml, is reached in about 1 hour. The bioavailability of levonorgestrel upon oral administration is almost complete. Levonorgestrel binds to blood plasma albumin and to sex hormone-binding globulin (SHBG). Only about 1.3% of the total substance concentration is found in free form in blood plasma; about 64% is specifically bound to SHBG and about 35% is non-specifically bound to albumin. The induction of SHBG synthesis by ethinylestradiol affects the binding of levonorgestrel to plasma proteins, causing an increase in the fraction bound to SHBG and a decrease in the fraction bound to albumin. The apparent volume of distribution of levonorgestrel is about 184 L after a single dose. Levonorgestrel undergoes extensive metabolism. The main metabolites in blood plasma are unconjugated and conjugated forms of 3α,5β-tetrahydrolevonorgestrel. The main enzyme involved in the metabolism of levonorgestrel is the CYP3A4 isoenzyme. Plasma clearance is approximately 1.3-1.6 ml/min/kg. The concentration of levonorgestrel in blood plasma decreases in two phases. The T_1/2 in the terminal phase is about 20-23 hours. Levonorgestrel is not excreted unchanged, but only as metabolites, which are excreted by the kidneys and through the intestine in a 1:1 ratio with a T_1/2 of about 24 hours. With daily administration, the substance concentration in blood plasma increases approximately 3-4 times, reaching C_ss in the second half of the intake cycle. The pharmacokinetics of levonorgestrel are influenced by the concentration of SHBG in blood plasma, which increases approximately 1.7 times when levonorgestrel is used together with ethinylestradiol. In the equilibrium state, clearance decreases to approximately 0.7 ml/min/kg.

Ethinylestradiol

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max in blood plasma, equal to approximately 95 pg/ml, is reached in 1-2 hours. During absorption and the “first pass” through the liver, Ethinylestradiol is metabolized, resulting in an average oral bioavailability of about 45% (individual variations within 20-65%). Ethinylestradiol is almost completely (approximately 98%), although non-specifically, bound to albumin. Ethinylestradiol induces the synthesis of SHBG. The apparent V_d of ethinylestradiol is 2.8-8.6 L/kg. Ethinylestradiol undergoes presystemic conjugation, both in the small intestinal mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation. The plasma clearance rate is 2.3-7 ml/min/kg. The decrease in ethinylestradiol concentration in blood plasma is biphasic; the first phase is characterized by a T_1/2 of about 1 hour, the second – 10-20 hours. It is not excreted unchanged from the body. Metabolites of ethinylestradiol are excreted by the kidneys and through the intestine in a 4:6 ratio with a T_1/2 of about 24 hours.
With daily oral administration of this combination, the concentration of ethinylestradiol in blood plasma increases slightly, reaching a maximum value of 114 pg/ml at the end of the cycle. Given the variable T_1/2 in the terminal phase and daily oral administration, C_ss is reached approximately after 1 week.

Indications

Oral contraception.

ICD codes

Dosage Regimen

Take one dragee daily at approximately the same time, with a small amount of water.

Follow the sequential order indicated on the blister pack: start with the red-brown dragees, then proceed to the white dragees, and finish with the ochre dragees.

Begin the first pack on the first day of your menstrual cycle. Continue for 21 consecutive days.

After the last ochre dragee, take a 7-day tablet-free interval. Withdrawal bleeding usually occurs during this break.

Start the next pack on the 8th day after the last dragee, even if bleeding has not finished.

For the first cycle, use an additional, non-hormonal barrier method of contraception for the first 7 days of dragee intake.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a dragee, treat it as a missed dragee and follow the relevant instructions.

If a dragee is missed and is less than 12 hours late, take it immediately and take the next dragee at the usual time.

If a dragee is missed and is more than 12 hours late, contraceptive protection may be reduced. Take the most recently missed dragee immediately, even if it means taking two dragees on the same day.

Discard any earlier missed dragees. Continue taking the remaining dragees at the usual time.

For the subsequent 7 days, use a barrier method of contraception. If there are fewer than 7 dragees left in the current pack after the missed one, omit the tablet-free interval and start the next pack immediately.

Adverse Reactions

From the reproductive system possible – breast engorgement, decreased libido, intermenstrual bleeding; rarely – increased vaginal discharge, vaginal candidiasis.

From the digestive system possible – nausea, vomiting; rarely – jaundice, hepatitis, liver adenoma, gallbladder diseases (e.g., cholelithiasis, cholecystitis), diarrhea.

From the nervous system possible – headache, depressed mood; with long-term use very rarely – increased frequency of epileptic seizures.

From the sensory organs in some cases – eyelid edema, conjunctivitis, visual impairment, discomfort when wearing contact lenses (these phenomena are temporary and disappear after discontinuation without any therapy); with long-term use very rarely – hearing loss.

From the metabolism possible – weight gain; rarely – increased concentration of triglycerides, blood glucose, decreased glucose tolerance.

From the skin and subcutaneous tissues possible – chloasma; rarely – skin rash, hair loss; very rarely with long-term use – generalized itching.

Other rarely – increased fatigue, increased blood pressure, thromboses and venous thromboembolisms; with long-term use very rarely – calf muscle cramps, voice coarsening.

Contraindications

Thromboses (venous and arterial) and thromboembolisms currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders); conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history; multiple or pronounced risk factors for venous or arterial thrombosis; hereditary or acquired predisposition to venous or arterial thrombosis: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); migraine with focal neurological symptoms currently or in history; uncontrolled arterial hypertension; diabetes mellitus with diabetic angiopathy; pancreatitis with severe hypertriglyceridemia currently or in history; hepatic insufficiency and severe liver diseases (until liver function tests normalize); liver tumors (benign or malignant) currently or in history; severe dyslipoproteinemia; identified hormone-dependent malignant diseases (including of the genital organs or mammary glands) or suspicion thereof; vaginal bleeding of unknown origin; pregnancy or suspicion thereof; period of lactation (breastfeeding); postmenopausal period; age under 18 years; simultaneous use with St. John’s wort preparations; hypersensitivity to the components of the combination.

With caution

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

• Risk factors for the development of thrombosis and thromboembolism: smoking, hereditary predisposition to thrombosis (thromboses, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives), excess body weight (BMI <30 kg/m²), dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve diseases;
• Other diseases in which peripheral circulation disorders may be noted: diabetes mellitus without diabetic angiopathy, SLE, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis;
• Hypertriglyceridemia;
• Mild and moderate liver diseases with normal liver function tests;
• Diseases that first appeared or worsened during a previous pregnancy or against the background of previous use of sex hormones (e.g., jaundice, cholestasis, gallbladder diseases, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea);
• Women with hereditary angioedema, chloasma, depression, epilepsy.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy or suspicion thereof; period of breastfeeding.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency, liver tumors (hemangioma, liver cancer).

With caution liver diseases

Use in Renal Impairment

With caution kidney diseases.

Pediatric Use

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

Geriatric Use

Contraindicated in postmenopause.

Special Precautions

Before starting hormonal contraception and subsequently every 6 months, a general medical and gynecological examination is recommended, including a cytological smear from the cervix, assessment of the condition of the mammary glands, determination of blood glucose, cholesterol and other liver function indicators, blood pressure control, urinalysis.

Oral contraception is allowed no earlier than 6 months after viral hepatitis, provided that liver functions have normalized.

If sharp pains in the upper abdomen, hepatomegaly and signs of intra-abdominal bleeding appear, suspicion of a liver tumor may arise.

If liver function is impaired while taking drugs containing this combination, consultation with a physician is necessary.

If acyclic (intermenstrual) bleeding appears, the use of this combination should be continued, since in most cases this bleeding stops spontaneously. If acyclic (intermenstrual) bleeding does not disappear or recurs, a medical examination should be performed to exclude organic pathology of the reproductive system.

In case of vomiting or diarrhea, the drug should be continued, using another, non-hormonal method of contraception.

Smoking women taking hormonal contraceptives have an increased risk of developing cardiovascular diseases with serious consequences (myocardial infarction, stroke). The risk increases with age and depending on the number of cigarettes smoked (especially in women over 35 years of age).

The use of drugs containing the Levonorgestrel/Ethinylestradiol combination should be discontinued in the following cases: when migraine-like headache appears for the first time or intensifies; when unusually severe headache appears; when early signs of phlebitis or phlebothrombosis appear (unusual pain or swelling of veins in the legs); when jaundice or hepatitis without jaundice occurs; in case of cerebrovascular disorders; when stabbing pains of unclear etiology appear when breathing or coughing, pain and feeling of tightness in the chest; with acute deterioration of visual acuity; if thrombosis or heart attack is suspected; with a sharp increase in blood pressure; when generalized itching occurs; with increased frequency of epileptic seizures; 3 months before planned pregnancy; approximately 6 weeks before planned surgical intervention; during prolonged immobilization; in case of pregnancy.

Drug Interactions

Barbiturates, some antiepileptic drugs (carbamazepine, phenytoin), sulfonamides, pyrazolone derivatives can enhance the metabolism of the steroid hormones included in the drug.

A decrease in contraceptive effectiveness can also be observed with simultaneous administration with some antimicrobial agents (including ampicillin, rifampicin, chloramphenicol, neomycin, polymyxin B, sulfonamides, tetracyclines), which is associated with a change in the intestinal microflora.

With simultaneous use with anticoagulants, coumarin or indandione derivatives, additional determination of the prothrombin index and a change in the dose of the anticoagulant may be required.

When using tricyclic antidepressants, maprotiline, beta-blockers, an increase in their bioavailability and toxicity is possible.

When using oral hypoglycemic drugs and insulin, the need to change their dose may arise.

When combined with bromocriptine, its effectiveness decreases.

When combined with drugs with potential hepatotoxic action, for example, with the drug dantrolene, an increase in hepatotoxicity is observed, especially in women over 35 years of age.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.