Euthyrox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUTHYROX® (EUTHYROX®)

Composition:

Active substance: levothyroxine sodium;

1 tablet contains 25 mcg, or 50 mcg, or 75 mcg, or 100 mcg, or 125 mcg, or 150 mcg of levothyroxine sodium;

Excipients: mannitol (E 421); corn starch; gelatin; sodium croscarmellose; anhydrous citric acid; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: almost white, round, flat on both sides, bevelled edge tablets, with a breakline on both sides, engraved on one side with the symbols "EM + dosage strength".

Pharmacotherapeutic group. Hormone preparations for systemic use (except sex hormones and insulin). Preparations for treatment of thyroid disorders. Thyroid preparations. Levothyroxine sodium. ATC code H03AA01.

Pharmacological properties.

Pharmacodynamics. The synthetic levothyroxine contained in the drug Euthyrox produces effects identical to those of the hormone secreted by the thyroid gland. It is converted to T3 (triiodothyronine) in peripheral organs and, like the endogenous hormone, acts on T3 receptors. There is no difference between the functions of endogenous hormone and exogenous levothyroxine.

Pharmacokinetics. After oral administration, levothyroxine is almost completely absorbed in the upper part of the small intestine. Depending on the pharmaceutical formulation, up to 80% of the administered dose is absorbed. Maximum concentration (Tmax) is reached approximately 5–6 hours after administration.

The clinical effect of the drug appears 3–5 days after oral administration. Levothyroxine rapidly binds to specific plasma proteins (up to 99.97%). The binding to proteins is non-covalent, thus the bound hormone in plasma can continuously and rapidly exchange with free hormone fractions.

Due to the high degree of protein binding, levothyroxine is not removed by either hemodialysis or hemoperfusion.

The elimination half-life of the drug is 7 days. In hyperthyroidism, this period is reduced to 3–4 days, while in hypothyroidism it is prolonged to 9–10 days. The volume of distribution is 10–12 L. Approximately one-third of the total administered levothyroxine accumulates in the liver, rapidly equilibrating with levothyroxine present in blood serum. Thyroid hormones are mainly metabolized in the liver, kidneys, brain, and muscles. Metabolites are excreted in urine and feces. Total metabolic clearance of levothyroxine is approximately 1.2 L plasma/day.

Clinical characteristics.

Indications.

Euthyrox 25–200 mcg

• Treatment of benign euthyroid goiter.
• Prevention of recurrences after surgical treatment of euthyroid goiter, depending on hormone levels in the postoperative period.
• Replacement therapy in hypothyroidism.
• Suppressive therapy in thyroid cancer.

Euthyrox 25–100 mcg

• As an adjunctive agent during antithyroid therapy in hyperthyroidism.

Euthyrox 100/150/200 mcg

• As a diagnostic agent in performing the thyroid suppression test.

Contraindications.

• Hypersensitivity to any component of the drug.
• Adrenal insufficiency, pituitary insufficiency, untreated thyrotoxicosis.
• Acute myocardial infarction, acute myocarditis, acute pancarditis.
• Combined therapy with levothyroxine and antithyroid agents during pregnancy is not recommended (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Antidiabetic agents. Levothyroxine may reduce the effect of antidiabetic drugs. Frequent monitoring of blood glucose levels is recommended at the beginning of thyroid hormone therapy, and dosage adjustment of antidiabetic agents may be necessary.

Coumarin derivatives. Levothyroxine enhances the effect of anticoagulant drugs by displacing them from plasma protein binding, increasing the risk of hemorrhage, e.g., hemorrhage into the spinal cord and brain or gastrointestinal bleeding, especially in elderly patients. Therefore, regular laboratory monitoring of coagulation parameters is required at the beginning and during concomitant therapy, and the daily dose of anticoagulant drugs should be adjusted if necessary.

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

Phenytoin may affect the action of levothyroxine by displacing it from plasma protein binding, resulting in increased levels of free thyroxine (fT4) and free triiodothyronine (fT3) fractions. On the other hand, phenytoin increases hepatic metabolism of levothyroxine. Careful monitoring of thyroid hormone levels is recommended.

Cholestyramine, colestipol. Administration of such ion-exchange resins as cholestyramine and colestipol inhibits the absorption of sodium levothyroxine. Therefore, sodium levothyroxine should be taken 4–5 hours before taking these drugs.

Drugs containing aluminium, iron, and calcium salts. According to data from relevant literature sources, drugs containing aluminium (antacids, sucralfate) may potentially reduce the effect of levothyroxine. Therefore, levothyroxine should be taken at least 2 hours before administration of drugs containing aluminium. This also applies to medicinal products containing iron and calcium salts.

Salicylates, dicumarol, furosemide in high doses (250 mg), clofibrate, and other substances may displace sodium levothyroxine from plasma protein binding, leading to an increase in the fT4 fraction.

Proton pump inhibitors (PPIs). Concomitant use with PPIs may lead to reduced absorption of thyroid hormones due to increased intragastric pH caused by PPIs. During concomitant therapy, regular monitoring of thyroid function and clinical monitoring are recommended, with possible dose increase of thyroid hormones.

Caution should also be exercised when PPI treatment is discontinued.

Orlistat. Concomitant use of orlistat and levothyroxine may lead to the development of hypothyroidism and/or worsening of hypothyroidism control. This may be due to reduced absorption of iodine salts and/or levothyroxine.

Sevelamer may reduce levothyroxine absorption. Therefore, monitoring of changes in thyroid function parameters at the beginning and end of concomitant therapy is recommended. The dose of levothyroxine should be adjusted if necessary.

Tyrosine kinase inhibitors (e.g., imatinib, sunitinib) may reduce the efficacy of levothyroxine. Therefore, monitoring of changes in thyroid function parameters at the beginning and end of concomitant therapy is recommended. The dose of levothyroxine should be adjusted if necessary.

Propylthiouracil, glucocorticoids, beta-sympatholytics, amiodarone, and iodine-containing contrast agents inhibit peripheral conversion of T4 to T3. Due to its high iodine content, amiodarone may promote the development of both hyperthyroidism and hypothyroidism. The drug should be prescribed with particular caution to patients with nodular goiter of undefined etiology.

Sertraline, chloroquine/proguanil reduce the efficacy of levothyroxine and increase serum TSH laboratory values.

Enzyme-inducing drugs, such as barbiturates, carbamazepine, or products containing St. John's wort (Hypericum perforatum L.), may increase hepatic clearance of levothyroxine, leading to decreased serum concentrations of thyroid hormones.

Thus, patients receiving thyroid replacement therapy may require an increased dose of thyroid hormone if these drugs are taken concomitantly.

Estrogens. Women taking estrogen-containing contraceptives, as well as postmenopausal women taking hormone replacement therapy, may require higher doses of levothyroxine.

Products containing soy may inhibit intestinal absorption of levothyroxine. Therefore, the dose of Euthyrox should be adjusted, especially at the beginning and after completion of intake of supplements containing soy.

Effect on laboratory tests. Biotin may interfere with immunoassays of thyroid function based on biotin/streptavidin interaction, leading to falsely decreased or falsely increased test results (see section "Special precautions for use").

Special precautions for use

Before initiating therapy with thyroid hormones or performing thyroid suppression tests, it is essential to exclude or first treat conditions such as coronary insufficiency, angina pectoris, atherosclerosis, arterial hypertension, and pituitary insufficiency. Functional autonomy of the thyroid gland should also be excluded or appropriately treated prior to starting thyroid hormone therapy.

In cases of adrenocortical dysfunction, appropriate replacement therapy should be initiated before starting levothyroxine to prevent acute adrenal insufficiency (see section "Contraindications").

Therapy with levothyroxine in patients at risk of developing psychotic disorders should be initiated at low doses, with gradual dose escalation at the beginning of treatment. Close monitoring of the patient is recommended. If psychotic disorders develop, dose adjustment of levothyroxine should be considered.

Even minor manifestations of hyperthyroidism induced by the drug should be avoided in patients with coronary insufficiency, heart failure, or tachyarrhythmia. In treating such patients, regular monitoring of thyroid hormone levels is necessary.

In cases of suspected secondary hypothyroidism, the underlying cause should be identified before initiating replacement therapy. If necessary, corticosteroid replacement therapy should be administered to compensate for adrenal insufficiency.

In suspected cases of functional autonomy of the thyroid gland, TSH levels should be measured or thyroid scintigraphy performed before initiating treatment with the drug.

When initiating levothyroxine therapy in preterm neonates with very low birth weight, hemodynamic parameters should be monitored, as circulatory disturbances may occur due to immature adrenal function.

Postmenopausal women with hypothyroidism and at increased risk of osteoporosis should avoid excessively high serum levels of levothyroxine exceeding the physiological range. Therefore, laboratory parameters of thyroid function should be carefully monitored.

Levothyroxine should not be prescribed to patients with hyperthyroidism who are already receiving antithyroid drugs for treatment of hyperthyroidism.

Thyroid hormones must not be used for weight reduction. Administration of levothyroxine does not lead to weight loss in euthyroid patients. Higher doses may cause serious or even life-threatening adverse reactions. High-dose levothyroxine should not be combined with certain weight-loss agents (e.g., sympathomimetics) (see section "Overdose").

When switching from one levothyroxine-containing product to another, careful monitoring—including clinical and biological monitoring—should be performed throughout the transition period due to the potential risk of thyroid dysfunction. Some patients may require dose adjustments.

Concomitant use of orlistat and levothyroxine may lead to the development of hypothyroidism and/or worsening of hypothyroidism control (see section "Interaction with other medicinal products and other forms of interaction"). Patients taking levothyroxine should consult their physician before starting, stopping, or changing orlistat therapy, as orlistat and levothyroxine must be taken at different times and levothyroxine dosage may need adjustment. Monitoring of serum hormone levels is recommended thereafter.

The drug should be used with caution in patients with diabetes mellitus and in those taking anticoagulant medications (see section "Interaction with other medicinal products and other forms of interaction").

Effect on laboratory tests

Biotin may interfere with immunoassays of thyroid function based on the biotin-streptavidin principle, leading to falsely low or falsely high test results. The risk of interference increases with higher doses of biotin.

When interpreting laboratory test results, potential interference by biotin should be considered, especially if there is a lack of concordance with the clinical picture.

Patients taking biotin-containing products should inform laboratory personnel when thyroid function tests are required. Alternative assays insensitive to biotin interference should be used, if available (see section "Interaction with other medicinal products and other forms of interaction").

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., is essentially "sodium-free."

Use during pregnancy or breastfeeding

During pregnancy or breastfeeding, treatment with levothyroxine for hypothyroidism should be continued. During pregnancy, an increased dose of the drug may be required. Since serum TSH levels may rise as early as week 4 of pregnancy, pregnant women taking levothyroxine should have their TSH levels monitored during each trimester. Serum TSH levels in pregnant women should remain within trimester-specific reference ranges. Dose increases of levothyroxine are recommended to correct elevated serum TSH levels. As postnatal TSH levels return to pre-pregnancy values, the levothyroxine dose should be adjusted back to the pre-pregnancy dose immediately after delivery. Normal serum TSH levels should be re-established within 6–8 weeks postpartum.

Pregnancy

There are no data on teratogenicity or fetotoxicity associated with the use of the drug at recommended therapeutic doses. However, administration of very high doses of levothyroxine during pregnancy may adversely affect fetal and postnatal development.

Combination therapy with levothyroxine and antithyroid drugs during pregnancy is not recommended for the treatment of hyperthyroidism, as this combination requires higher doses of antithyroid drugs, which can cross the placenta and may cause hypothyroidism in the newborn. Thyroid suppression testing is not performed during pregnancy, as the use of radioactive substances is contraindicated in pregnancy.

Breastfeeding

Levothyroxine passes into breast milk; however, when administered at recommended therapeutic doses, the concentration in breast milk is insufficient to cause hyperthyroidism or suppress TSH secretion in the infant.

Ability to affect the speed of reaction while driving or operating machinery

There are no data on the potential effect on the ability to drive or operate machinery. However, since levothyroxine is biologically identical to the natural thyroid hormone, no effect of Euthyrox on reaction speed during driving or operating machinery is expected.

Method of Administration and Dosage.

Dosage.

For the treatment of each individual patient according to their specific needs, the drug Euthyrox is available in tablets containing from 25 mcg to 150 mcg of sodium levothyroxine. Therefore, patients are usually prescribed only one tablet per day.

Dosage information is provided for guidance only.

The daily dose must be individualized, based on laboratory parameters and the clinical picture of the disease.

Since in some patients an increase in T4 and fT4 concentrations has been observed during levothyroxine therapy, the basal concentration of thyroid-stimulating hormone (TSH) in serum is a more reliable indicator for subsequent dose adjustment.

Therapy with thyroid hormones should be initiated at a low dose and gradually increased (every 2–4 weeks) to the required therapeutic dose.

In elderly patients, patients with coronary heart disease, and those with severe or long-standing hypothyroidism, treatment should be initiated with particular caution, starting with low doses (12.5 mcg per day). The dose should be increased to the maintenance level at longer intervals (gradually by 12.5 mcg every 2 weeks), with regular monitoring of thyroid hormone levels. It should be noted that prescribing doses lower than the optimal dose required for full replacement therapy does not lead to complete normalization of TSH levels.

Clinical experience shows that lower doses may be sufficient for patients with low body weight and for patients with large nodular goiter.