Tri-Regol^® 21+7 (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

ATC Code

G03AB03 (Levonorgestrel and Ethinylestradiol)

Active Substances

Ferrous fumarate (Ph.Eur.)

Ethinylestradiol (Rec.INN)

Levonorgestrel (Rec.INN)

Dosage Form

Tri-Regol® 21+7

Coated tablets: 28 pcs. in a blister, 1 or 3 blisters, incl.: tab.I pink color 0.05 mg+0.03 mg: 6 pcs.; tab.II white color 0.075 mg+0.04 mg: 5 pcs.; tab.III dark yellow color 0.125 mg+0.03 mg: 10 pcs.; tab.IV placebo reddish-brown color 76.05 mg:7 pcs.

Dosage Form, Packaging, and Composition

Coated tablets, four types.

Tablets I, coated, pink, round, biconvex, with a glossy surface; white on the break (6 pcs. in a blister).

Excipients: colloidal silicon dioxide – 0.275 mg, magnesium stearate – 0.55 mg, talc – 1.1 mg, corn starch – 19.995 mg, lactose monohydrate – 33 mg.

Coating composition sucrose – 22.013 mg, talc – 6.935 mg, calcium carbonate – 2.898 mg, titanium dioxide – 1.814 mg, copovidone – 0.828 mg, macrogol 6000 – 0.207 mg, colloidal silicon dioxide – 0.123 mg, povidone – 0.074 mg, carmellose sodium – 0.025 mg, red iron oxide – 0.083 mg.

Tablets II, coated, white, round, biconvex, with a glossy surface; white on the break (5 pcs. in a blister).

Excipients: colloidal silicon dioxide – 0.275 mg, magnesium stearate – 0.55 mg, talc – 1.1 mg, corn starch – 19.96 mg, lactose monohydrate – 33 mg.

Coating composition sucrose – 22.013 mg, talc – 6.935 mg, calcium carbonate – 2.898 mg, titanium dioxide – 1.897 mg, copovidone – 0.828 mg, macrogol 6000 – 0.207 mg, colloidal silicon dioxide – 0.123 mg, povidone – 0.074 mg, carmellose sodium – 0.025 mg.

Tablets III, coated, dark yellow, round, biconvex, with a glossy surface; white on the break (10 pcs. in a blister).

Excipients: colloidal silicon dioxide – 0.275 mg, magnesium stearate – 0.55 mg, talc – 1.1 mg, corn starch – 19.92 mg, lactose monohydrate – 33 mg.

Coating composition sucrose – 22.013 mg, talc – 6.935 mg, calcium carbonate – 2.898 mg, titanium dioxide – 1.317 mg, copovidone – 0.828 mg, macrogol 6000 – 0.207 mg, colloidal silicon dioxide – 0.123 mg, povidone – 0.074 mg, carmellose sodium – 0.025 mg, yellow iron oxide – 0.58 mg.

Tablets IV placebo, coated, reddish-brown, round, biconvex, glossy; light brown on the break (7 pcs. in a blister).

Excipients: colloidal silicon dioxide – 0.5 mg, croscarmellose sodium – 0.6 mg, magnesium stearate – 1.2 mg, povidone – 2.4 mg, talc – 2.4 mg, potato starch – 2.1 mg, corn starch – 10.2 mg, lactose monohydrate – 24.55 mg.

Coating composition sucrose – 38.295 mg, talc – 11.752 mg, calcium carbonate – 5.103 mg, titanium dioxide (col.ind. 77891/E171) – 2.226 mg, copovidone – 1.124 mg, colloidal silicon dioxide – 0.24 mg, red iron oxide (col.ind. 77491/E172) – 0.787 mg, povidone – 0.144 mg, macrogol 6000 – 0.281 mg, carmellose sodium – 0.048 mg.

28 pcs. (tablets I, II, III, IV) – blisters (1) – cardboard packs.
28 pcs. (tablets I, II, III, IV) – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Three-phase oral contraceptive

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

Combined (three-phase) oral contraceptive estrogen-gestagen drug.

It suppresses ovulation by blocking the release of FSH and LH in the pituitary gland, promotes secretory transformation of the endometrium, and increases the viscosity of cervical mucus.

Sequential intake of tablets containing different amounts of gestagen (Levonorgestrel) and estrogen (Ethinylestradiol) allows to replenish and provide blood concentrations of these hormones close to physiological, followed by normalization of the menstrual cycle.

Pharmacokinetics

Levonorgestrel

Absorption and Distribution

Rapidly (less than 4 hours) absorbed from the gastrointestinal tract. Most of levonorgestrel binds to albumin and sex hormone-binding globulin.

Metabolism and Excretion

It is not subject to the first-pass effect through the liver. T_1/2 is 8-30 hours (average – 16 hours).

Ethinylestradiol

Absorption

Rapidly and almost completely absorbed from the gastrointestinal tract. C_max is reached in 1-1.5 hours.

Metabolism and Excretion

When taken orally, Ethinylestradiol is eliminated from the blood plasma within 12 hours. Ethinylestradiol undergoes the “first-pass” effect through the liver. Metabolism occurs in the liver and intestine. Ethinylestradiol metabolites, which are water-soluble products of sulfate or glucuronide conjugation, enter the intestine with bile, where they are disintegrated by intestinal bacteria.

T_1/2 is about 26±6.8 hours.

Indications

• Oral contraception.

ICD codes

Dosage Regimen

The drug is taken orally, preferably at the same time of day. The tablets should be swallowed whole, without chewing, with a small amount of liquid.

Taking the drug starts on the 1st day of the menstrual cycle and continues for 28 days. Take 1 tablet/day daily.

During the intake of reddish-brown tablets, menstrual-like bleeding occurs. Starting the next pack should be done without a break, i.e., 4 weeks after starting the drug, on the same day of the week.

It is important to follow the sequence: first take pink tablets – 6 days, then take white tablets – 5 days, then dark yellow tablets – 10 days, and finally take reddish-brown tablets – 7 days. To ensure the required sequence, numbers and an arrow are indicated on the package.

If well tolerated, the drug is taken as long as there is a need for contraception.

When switching to Tri-Regol^® 21+7 after another hormonal contraceptive the drug is used according to the same scheme.

After an abortion it is recommended to start taking the drug on the day of the abortion or the day after the surgery.

After childbirth the drug is recommended only for women who are not breastfeeding. Taking should start no earlier than the 1st day of menstruation.

Use during lactation is contraindicated.

A missed tablet should be taken within the next 12 hours. If 36 hours have passed since the last tablet was taken, contraception cannot be considered reliable. In such cases, to prevent possible intermenstrual bleeding, it is necessary to continue taking the drug from the already started pack, minus the missed tablet(s).

In case of missed timely tablet intake, it is recommended to additionally use another, non-hormonal method of contraception (e.g., barrier). This rule does not apply to reddish-brown tablets, as they do not contain hormones.

Adverse Reactions

Side effects observed with the use of the drug are classified into categories depending on the frequency of their occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000, including isolated reports).

The drug is usually well tolerated.

Possible side effects, transient and not requiring treatment: nausea, vomiting, headache, breast engorgement, weight gain, decreased libido, depressed mood, intermenstrual bleeding; in some cases – eyelid edema, conjunctivitis, visual impairment, discomfort when wearing contact lenses (these phenomena are temporary and disappear after discontinuation without any therapy).

Uncommon: increased concentration of triglycerides, blood glucose, decreased glucose tolerance, increased blood pressure, hepatitis, liver adenoma, gallbladder diseases (e.g., cholelithiasis, cholecystitis), thromboses and venous thromboembolisms, jaundice, skin rash, hair loss, increased vaginal discharge, vaginal candidiasis, increased fatigue, diarrhea.

Very rare, with longer use: chloasma.

Ferrous fumarate, which is part of the reddish-brown tablets, can cause irritation of the gastrointestinal mucosa, nausea, vomiting, diarrhea, constipation, and color the stool black.

Contraindications

• Hypersensitivity to the components of the drug;
• Severe liver diseases;
• Liver tumors;
• Congenital hyperbilirubinemias (Gilbert’s syndrome, Dubin-Johnson syndrome, Rotor syndrome);
• Cholelithiasis;
• Cholecystitis;
• Chronic colitis;
• Severe cardiovascular diseases currently or in history (including decompensated heart defects);
• Cerebrovascular diseases currently or in history;
• Thromboembolisms and predisposition to them;
• Hormone-dependent malignant neoplasms of the genital organs and mammary glands (including suspected ones);
• Familial forms of hyperlipidemia;
• Arterial hypertension (BP ≥160/100 mm Hg);
• Major surgical interventions;
• Surgical operations on the lower extremities;
• Prolonged immobilization;
• Extensive trauma;
• Pancreatitis (including in history), accompanied by severe hyperlipidemia;
• Jaundice due to steroid use;
• Severe forms of diabetes mellitus;
• Sickle cell anemia;
• Chronic hemolytic anemia;
• Vaginal bleeding of unknown etiology;
• Migraine;
• Otosclerosis with worsening during previous pregnancy(ies);
• History of idiopathic jaundice during pregnancy;
• History of severe skin itching during pregnancy;
• History of herpes infection during pregnancy;
• Smoking over the age of 35;
• Age over 40 years;
• Lactase deficiency, galactose intolerance; glucose-galactose malabsorption (the drug form contains lactose);
• Pregnancy;
• Lactation period (breastfeeding).

With caution: diabetes mellitus, diseases of the endocrine glands, diseases of the cardiovascular system, arterial hypertension (BP up to 160/100 mm Hg), impaired renal function, varicose veins, multiple sclerosis, epilepsy, chorea minor, porphyria, tetany, bronchial asthma.

Use in Pregnancy and Lactation

Tri-Regol^® 21+7 is contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The use of the drug is contraindicated in severe liver diseases, liver tumors.

Use in Renal Impairment

The drug should be prescribed with caution in case of impaired renal function.

Geriatric Use

The use of the drug is contraindicated in patients over 40 years of age.

Special Precautions

Before prescribing the drug, it is necessary to exclude the presence of pregnancy, conduct a general medical examination (including blood pressure measurement, laboratory tests of liver function and blood glucose concentration) and a gynecological examination (condition of the mammary glands, cytological analysis of a vaginal smear).

During the use of the drug, such general medical and gynecological examinations should be carried out regularly, every 6 months.

The use of oral contraception is allowed no earlier than 6 months after viral hepatitis, provided that liver functions are completely normalized.

If there are sharp pains in the upper abdomen, hepatomegaly and signs of intra-abdominal hemorrhage, suspicion of a liver tumor may arise. In this case, the drug should be discontinued.

If liver function disorders are detected during the use of the drug, the advisability of continuing the use of Tri-Regol^® 21+7 should be decided.

If acyclic bloody discharge appears, it is possible to continue taking Tri-Regol^® 21+7 after excluding organic pathology by the attending physician.

In case of vomiting or diarrhea, the drug should be continued, while simultaneously using an additional, non-hormonal method of contraception.

It is necessary to stop taking the drug at least 3 months before the planned pregnancy.

Under the influence of oral contraceptives (due to the estrogenic component), functional indicators of the liver, kidneys, adrenal glands, thyroid gland, blood coagulation and fibrinolytic factors, levels of lipoproteins and transport proteins may change.

The drug should be discontinued in the following cases:

• If migraine-like pains occur for the first time or existing ones intensify, or unusually severe headaches occur;
• In case of acute deterioration of visual acuity;
• If thrombosis or heart attack is suspected;
• In case of a sharp increase in blood pressure;
• If jaundice or hepatitis without jaundice, generalized itching appears;
• If epileptic seizures become more frequent;
• Before a planned operation (6 weeks before surgery);
• In case of prolonged immobilization;
• If pregnancy occurs.

Effect on the ability to drive vehicles and mechanisms

No studies have been conducted to study the effect of the drug on the ability to drive a car and other mechanisms associated with an increased risk of injury.

Overdose

Accidental ingestion of large doses of the drug may lead to overdose, including in children.

Symptoms: nausea, uterine bleeding.

Treatment: if signs of overdose appear within the first 2-3 hours, gastric lavage and symptomatic treatment are recommended. There is no specific antidote.

Drug Interactions

When used simultaneously with Tri-Regol^® 21+7, ampicillin, rifampicin, chloramphenicol, neomycin, polymyxin B, sulfonamides, tetracyclines, dihydroergotamine, tranquilizers, phenylbutazone can weaken the contraceptive effect. These combinations should be used with caution; it is recommended to additionally use another, non-hormonal method of contraception.

When Tri-Regol^® 21+7 is used simultaneously with anticoagulants, coumarin or indandione derivatives, an extraordinary determination of the prothrombin index and a change in the dose of the anticoagulant may be required.

When Tri-Regol^® 21+7 is used simultaneously with tricyclic antidepressants, maprotiline, beta-blockers, an increase in bioavailability and, in connection with this, an increase in toxicity is possible.

When Tri-Regol^® 21+7 is used simultaneously with oral hypoglycemic drugs, insulin, it may be necessary to change their doses.

When Tri-Regol^® 21+7 is used simultaneously with bromocriptine, the effectiveness of the latter decreases.

When Tri-Regol^® 21+7 is used simultaneously with drugs with possible hepatotoxic effects, primarily dantrolene, the risk of increased hepatotoxicity increases, especially in women over 35 years of age.

Storage Conditions

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

Shelf Life

Shelf life – 2 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.