Euthyrox^® (Tablets) Instructions for Use

Marketing Authorization Holder

Merck LLC (Russia)

Manufactured By

Merck Healthcare, KGaA (Germany)

ATC Code

H03AA01 (Levothyroxine sodium)

Active Substance

Levothyroxine sodium

Dosage Forms

	Euthyrox®	Tablets 25 mcg: 50 or 100 pcs.
		Tablets 50 mcg: 50 or 100 pcs.
		Tablets 75 mcg: 50 or 100 pcs.
		Tablets 88 mcg: 50 or 100 pcs.
		Tablets 100 mcg: 50 or 100 pcs.
		Tablets 112 mcg: 50 or 100 pcs.
		Tablets 125 mcg: 50 or 100 pcs.
		Tablets 137 mcg: 50 or 100 pcs.
		Tablets 150 mcg: 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 25”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.625 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 50”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.6 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 75”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.575 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, round, flat on both sides, with beveled edges, with a score line on both sides and an inscription on one side “EM 88”.

Excipients: mannitol – 69.562 mg, corn starch – 20.0 mg, gelatin – 5.0 mg, croscarmellose sodium – 3.5 mg, anhydrous citric acid – 0.85 mg, magnesium stearate – 1.0 mg.

25 pcs. – blisters (2) – cardboard boxes.
25 pcs. – blisters (4) – cardboard boxes.

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 100”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.55 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, round, flat on both sides, with beveled edges, with a score line on both sides and an inscription on one side “EM 112”.

Excipients: mannitol – 69.538 mg, corn starch – 20.0 mg, gelatin – 5.0 mg, croscarmellose sodium – 3.5 mg, anhydrous citric acid – 0.85 mg, magnesium stearate – 1.0 mg.

25 pcs. – blisters (2) – cardboard boxes.
25 pcs. – blisters (4) – cardboard boxes.

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 125”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.525 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, round, flat on both sides, with beveled edges, with a score line on both sides and an inscription on one side “EM 137”.

Excipients: mannitol – 69.513 mg, corn starch – 20.0 mg, gelatin – 5.0 mg, croscarmellose sodium – 3.5 mg, anhydrous citric acid – 0.85 mg, magnesium stearate – 1.0 mg.

25 pcs. – blisters (2) – cardboard boxes.
25 pcs. – blisters (4) – cardboard boxes.

Tablets white or almost white, round, flat on both sides, with a bevel; there is a score line on both sides of the tablet, on one side of the tablet there is an engraving “EM 150”.

Excipients: corn starch – 20 mg, gelatin – 5 mg, croscarmellose sodium – 3.5 mg, magnesium stearate – 1 mg, anhydrous citric acid – 0.85 mg, mannitol – 69.5 mg.

25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Thyroid drug

Pharmacotherapeutic Group

Drugs for the treatment of thyroid gland diseases; thyroid preparations; thyroid hormones

Pharmacological Action

Levothyroxine sodium is a synthetic levorotatory isomer of thyroxine, identical in its action to thyroxine, which is synthesized by the human thyroid gland. After partial conversion to triiodothyronine (in the liver and kidneys) and transfer into the body’s cells, it affects tissue development and growth, and metabolism. In small doses, it has an anabolic effect on protein and fat metabolism. In medium doses, it stimulates growth and development, increases tissue oxygen demand, stimulates the metabolism of proteins, fats, and carbohydrates, and increases the functional activity of the cardiovascular system and central nervous system. In large doses, it inhibits the production of thyrotropin-releasing hormone by the hypothalamus and thyroid-stimulating hormone (TSH) by the pituitary gland.

The therapeutic effect is observed after 7-12 days, and the effect persists for the same period after drug withdrawal. The clinical effect in hypothyroidism appears after 3-5 days. Diffuse goiter decreases or disappears within 3-6 months.

Pharmacokinetics

Absorption

When taken orally, Levothyroxine sodium is absorbed mainly in the upper part of the small intestine. Up to 80% of the administered dose of the drug is absorbed. Food intake reduces the absorption of levothyroxine sodium.

C_max in blood serum is reached approximately 5-6 hours after oral administration.

Distribution

After absorption, more than 99% of the drug binds to serum proteins (thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin). In various tissues, monodeiodination of approximately 80% of levothyroxine occurs with the formation of triiodothyronine (T₃) and inactive products.

Metabolism

Thyroid hormones are metabolized mainly in the liver, kidneys, brain, and muscles. A small amount of the drug undergoes deamination and decarboxylation, as well as conjugation with sulfuric and glucuronic acids (in the liver). The estimated V_d is 10-12 L. The metabolic clearance is about 1.2 L of plasma per day.

Elimination

The T_1/2 of the drug is 6-7 days. In thyrotoxicosis, T_1/2 is shortened to 3-4 days, and in hypothyroidism, it is prolonged to 9-10 days. Metabolites are excreted by the kidneys and through the intestines.

Indications

• Hypothyroidism;
• Euthyroid goiter;
• As replacement therapy and for the prevention of goiter recurrence after surgical interventions on the thyroid gland;
• As suppressive and replacement therapy for malignant neoplasms of the thyroid gland, mainly after surgical treatment;
• Diffuse toxic goiter: after achieving a euthyroid state with antithyroid agents (as combined or monotherapy);
• As a diagnostic tool when performing a thyroid suppression test.

ICD codes

Dosage Regimen

The daily dose is determined individually depending on the indications, the clinical condition of the patient, and laboratory data.

The daily dose of levothyroxine sodium is taken orally in the morning on an empty stomach, at least 30 minutes before a meal, swallowing the tablet with a small amount of liquid (half a glass of water) and without chewing.

When conducting replacement therapy for hypothyroidism in patients younger than 55 years without cardiovascular diseases, Levothyroxine sodium is prescribed at a daily dose of 1.6-1.8 mcg/kg of body weight; in patients older than 55 years or with cardiovascular diseases – 0.9 mcg/kg of body weight.

Infants and children under 3 years should be given the daily dose of levothyroxine sodium in a single dose 30 minutes before the first feeding. The tablet is dissolved in water to a thin suspension immediately before taking the drug.

In patients with severe long-standing hypothyroidism, treatment should be started with particular caution, with small doses – 12.5 mcg/day. The dose is increased to a maintenance dose at longer intervals – by 12.5 mcg/day every 2 weeks and the blood TSH level is determined more frequently.

In hypothyroidism, Levothyroxine sodium is usually taken for life. In thyrotoxicosis, Levothyroxine sodium is used in complex therapy with antithyroid drugs after achieving a euthyroid state. In all cases, the duration of treatment with the drug is determined by the doctor.

For accurate dosing, the most appropriate dosage of levothyroxine sodium should be used.

Adverse Reactions

With the correct use of levothyroxine sodium under medical supervision, no side effects are observed.

Cases of allergic reactions in the form of angioedema have been reported.

Contraindications

• Hypersensitivity to levothyroxine sodium and/or any of the excipients;
• Untreated thyrotoxicosis;
• Untreated pituitary insufficiency;
• Untreated adrenal insufficiency;
• Use during pregnancy in combination with antithyroid agents.

Treatment should not be started in the presence of acute myocardial infarction, acute myocarditis, acute pancarditis.

The dosage form of the drug contains lactose, therefore its use is not recommended for patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

With caution, Levothyroxine sodium should be used in cardiovascular diseases: coronary artery disease (atherosclerosis, angina pectoris, history of myocardial infarction), arterial hypertension, arrhythmia; in diabetes mellitus, severe long-standing hypothyroidism, malabsorption syndrome (dose adjustment may be required), in patients predisposed to psychotic reactions.

Use in Pregnancy and Lactation

During pregnancy and especially during breastfeeding, treatment with thyroid hormones should be carried out consistently. During pregnancy, an increase in the dose of the drug may be required. Since an increase in plasma TSH concentration can be observed as early as the 4th week of pregnancy, pregnant women receiving levothyroxine sodium therapy should have their plasma TSH concentration determined during each trimester to ensure that it is within the range recommended for that trimester of pregnancy. An increase in plasma TSH concentration should be corrected by increasing the dose of levothyroxine sodium. Since the plasma TSH concentration in the postpartum period is similar to its pre-pregnancy values, immediately after delivery the woman should be switched to the dose of levothyroxine sodium she was receiving before pregnancy. Plasma TSH concentration should be determined 6-8 weeks after delivery.

Pregnancy

During pregnancy, it is necessary to refrain from performing diagnostic tests for suppression of thyroid function, since the use of radioactive substances in pregnant women is contraindicated.

There are no data on the presence of teratogenic and fetotoxic effects in humans when taking levothyroxine sodium in recommended therapeutic doses. Taking the drug during pregnancy in excessively high doses may adversely affect the fetus and postnatal development.

The use of the drug during pregnancy in combination with antithyroid agents is contraindicated, since taking levothyroxine sodium may require an increase in the doses of antithyroid agents. Since antithyroid agents, unlike levothyroxine sodium, can cross the placenta, hypothyroidism may develop in the fetus.

Breastfeeding period

Levothyroxine sodium passes into breast milk during breastfeeding. However, when using levothyroxine sodium in recommended therapeutic doses, the concentration of thyroid hormones in breast milk does not reach a level capable of causing hyperthyroidism and suppression of TSH secretion in the child.

Geriatric Use

When conducting replacement therapy for hypothyroidism in patients under 55 years of age without cardiovascular diseases, Euthyrox^® is prescribed at a daily dose of 1.6-1.8 mcg/kg of body weight; in patients over 55 years of age or with concomitant cardiovascular diseases – 0.9 mcg/kg of body weight.

For replacement therapy for hypothyroidism, the initial dose for patients under 55 years of age (without cardiovascular diseases) is for women 75-100 mcg/day, for men 100-150 mcg/day. For patients over 55 years of age or with concomitant cardiovascular diseases, the initial dose is 25 mcg/day; the dose should be increased by 25 mcg at intervals of 2 months until the blood TSH level normalizes; if symptoms from the cardiovascular system appear or worsen, adjust the appropriate therapy.

Special Precautions

Thyroid hormones should not be prescribed for weight loss. In euthyroid patients, treatment with levothyroxine does not lead to weight loss. High doses of levothyroxine sodium can cause the development of serious and life-threatening adverse reactions, particularly in combination with some weight loss substances, especially sympathomimetic amines.

Before starting replacement therapy with thyroid hormones or before performing a thyroid suppression test, the following diseases or pathological conditions must be excluded or treated: acute coronary insufficiency, angina pectoris, atherosclerosis, arterial hypertension, pituitary insufficiency or adrenal insufficiency. Also, before starting therapy with thyroid hormones, functional autonomy of the thyroid gland should be excluded or treated.

In patients at risk of developing psychotic disorders, it is recommended to start therapy with a low dose of levothyroxine sodium with a subsequent slow increase at the beginning of therapy. Patient monitoring is recommended. If signs of psychotic disorders are detected, the dose of levothyroxine sodium taken should be adjusted.

The possibility of even minor drug-induced hyperthyroidism must be excluded in patients with coronary insufficiency, heart failure, or tachyarrhythmias. Therefore, in these cases, regular monitoring of thyroid hormone concentrations is necessary.

Before initiating thyroid hormone replacement therapy, the etiology of secondary hypothyroidism must be determined. If necessary, replacement therapy should be initiated to compensate for adrenal insufficiency.

If the development of functional autonomy of the thyroid gland is suspected, it is recommended to perform a thyrotropin-releasing hormone stimulation test (TRH test) or a suppressive scintigraphy before starting therapy.

In premature newborns with very low birth weight, hemodynamic parameters should be monitored at the beginning of levothyroxine sodium therapy, as immaturity of adrenal function can lead to vascular insufficiency.

In postmenopausal women with hypothyroidism and an increased risk of osteoporosis, plasma concentrations of levothyroxine sodium exceeding physiological values should be avoided, which requires careful monitoring of thyroid function.

The use of levothyroxine sodium is not recommended in the presence of metabolic disorders accompanied by hyperthyroidism. An exception is concomitant use during drug therapy of hyperthyroidism with antithyroid drugs.

If a patient needs to be switched to another levothyroxine sodium preparation, due to the potential risk of thyroid hormone imbalance during the transition period, a thorough clinical examination, which may include laboratory tests, is necessary. Some patients may require dose adjustment.

Concomitant use of orlistat and levothyroxine sodium may lead to the development of hypothyroidism and/or reduced control of thyroid hypofunction. Patients taking Levothyroxine sodium should consult a physician before starting orlistat, as it may be necessary to take orlistat and Levothyroxine sodium at different times of the day and adjust the dose of levothyroxine sodium. Further monitoring of thyroid function is recommended.

Influence on the ability to drive vehicles and mechanisms

Studies of the effect of the drug on the ability to drive vehicles and mechanisms have not been conducted. Nevertheless, since Levothyroxine sodium is identical to the natural thyroid hormone, no effect on the ability to drive vehicles and mechanisms is expected.

Drug Interactions

The use of tricyclic antidepressants with levothyroxine sodium may lead to an enhancement of the antidepressant effect.

Levothyroxine sodium reduces the effect of cardiac glycosides.

Concomitant use of cholestyramine and colestipol (ion-exchange resins), as well as aluminum hydroxide, reduces the plasma concentration of levothyroxine sodium by inhibiting its absorption in the intestine. Therefore, Levothyroxine sodium must be taken 4-5 hours before taking these drugs.

Concomitant use with anabolic steroids, asparaginase, and tamoxifen may result in a pharmacokinetic interaction at the level of plasma protein binding.

Protease inhibitors (e.g., ritonavir, indinavir, lopinavir) may affect the efficacy of levothyroxine sodium. Careful monitoring of thyroid hormone concentrations is recommended. The dose of levothyroxine sodium should be adjusted if necessary.

Phenytoin may affect the efficacy of levothyroxine sodium due to the displacement of levothyroxine sodium from plasma protein binding, which may lead to an increase in the concentration of free _{^{T4 and T3.}} On the other hand, phenytoin increases the intensity of levothyroxine sodium metabolism in the liver. Careful monitoring of thyroid hormone concentrations is recommended.

Levothyroxine sodium may contribute to a decrease in the efficacy of hypoglycemic drugs. Therefore, frequent monitoring of blood glucose concentration is necessary from the start of thyroid hormone replacement therapy. The dose of the hypoglycemic drug should be adjusted if necessary.

Levothyroxine sodium may enhance the effect of anticoagulants (coumarin derivatives) by displacing them from plasma protein binding, which may increase the risk of bleeding, such as central nervous system hemorrhage or gastrointestinal bleeding, especially in elderly patients. Therefore, regular monitoring of coagulation parameters is necessary both at the beginning and during the course of concomitant therapy with these drugs. The dose of the anticoagulant should be adjusted if necessary.

Salicylates, dicumarol, furosemide in high doses (250 mg), clofibrate, and other drugs may displace Levothyroxine sodium from plasma protein binding, leading to an increase in the concentration of the free T4 fraction.

Orlistat: Concomitant intake of orlistat and levothyroxine sodium may lead to the development of hypothyroidism and/or reduced control of hypothyroidism. The reason for this may be reduced absorption of iodine salts and/or levothyroxine sodium.

Sevelamer may reduce the absorption of levothyroxine sodium. Tyrosine kinase inhibitors (e.g., imatinib, sunitinib) may reduce the efficacy of levothyroxine sodium. Therefore, at the beginning or end of a course of concomitant therapy with these drugs, monitoring for changes in thyroid function in patients is recommended. The dose of levothyroxine sodium is adjusted if necessary.

Medicinal products containing aluminum, iron, and calcium salts: Aluminum-containing medicinal products (antacids, sucralfate) are described in the literature as potentially reducing the efficacy of levothyroxine sodium. Therefore, it is recommended to take levothyroxine sodium at least 2 hours before taking aluminum-containing medicinal products. This recommendation also applies to the use of medicinal products containing iron and calcium salts.

Somatropin, when used concomitantly with levothyroxine sodium, may accelerate the closure of epiphyseal growth plates.

Propylthiouracil, corticosteroids, beta-sympatholytics, iodine-containing contrast agents, and amiodarone inhibit the peripheral conversion of T4 to T3. Due to the high iodine content, the use of amiodarone may be accompanied by the development of both hyperthyroidism and hypothyroidism. Particular attention should be paid to nodular goiter with the possible development of unrecognized functional autonomy.

Sertraline, chloroquine/proguanil reduce the efficacy of levothyroxine sodium and increase the serum TSH level.

Drugs that induce hepatic enzymes (e.g., barbiturates, carbamazepine) may contribute to the hepatic clearance of levothyroxine sodium.

In women using estrogen-containing contraceptives or in postmenopausal women receiving hormone replacement therapy, the requirement for levothyroxine sodium may increase.

Consumption of soy-containing products may contribute to reduced intestinal absorption of levothyroxine sodium. Therefore, dose adjustment may be required, especially at the start or after discontinuation of soy-containing products.

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.