L-thyroxine-pharmak®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT L-THYROXIN-FARMAKÒ (L-ThyroxinE-FarmakÒ)

Composition:

Active substance: levothyroxine sodium;

One tablet contains levothyroxine sodium, calculated as 100% dry substance: 25 μg, 50 μg, 100 μg;

Excipients: potato starch, lactose monohydrate, sucrose, heavy magnesium carbonate, magnesium stearate, povidone.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white tablets with a yellowish tint, flat cylindrical in shape, with a score line and chamfer.

Pharmacotherapeutic group.

Hormone preparations for systemic use (excluding sex hormones and insulin). Preparations for treatment of thyroid disorders. Thyroid preparations. Levothyroxine sodium. ATC code H03A A01.

Pharmacological Properties

Pharmacodynamics

The synthetic levothyroxine contained in the drug L-Thyroxine-Pharmak® exhibits effects identical to those of the hormone secreted by the thyroid gland. It is converted into 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 segment of the small intestine. Depending on the galenical form of the drug, 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 becomes apparent 3–5 days after oral intake. 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 the free hormone fractions.

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

The elimination half-life of the drug is 7 days. In hyperthyroidism, this period is shortened to 3–4 days, whereas 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, where it rapidly equilibrates with levothyroxine present in blood serum. Thyroid hormones are metabolized primarily in the liver, kidneys, brain, and muscles. Metabolites are excreted in urine and feces. Total metabolic clearance of levothyroxine is approximately 1.2 L of plasma per day.

Clinical characteristics.

Indications.

• 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.
• As an adjunctive agent during antithyroid therapy in hyperthyroidism.
• 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 during 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 drugs may be necessary.

Coumarin derivatives. Levothyroxine enhances the effect of anticoagulant drugs by displacing them from plasma protein binding, increasing the risk of hemorrhage, for example, hemorrhage into the spinal cord and brain or gastrointestinal bleeding, especially in elderly patients. Therefore, laboratory monitoring of coagulation parameters should be performed regularly at the beginning and during concomitant therapy, and the daily dose of anticoagulants should be adjusted as needed.

Protease inhibitors (e.g., ritonavir, indinavir, lopinavir) may affect the action of levothyroxine. Close monitoring of thyroid hormone levels is required. The dose of levothyroxine may need to be adjusted.

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. Close monitoring of thyroid hormone levels is recommended.

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

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

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

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 the absorption of levothyroxine. Therefore, monitoring of thyroid function parameters at the beginning and end of concomitant treatment is recommended. The dose of levothyroxine should be adjusted as needed.
Tyrosine kinase inhibitors (e.g., imatinib, sunitinib) may reduce the effectiveness of levothyroxine. Therefore, monitoring of thyroid function parameters at the beginning and end of concomitant treatment is recommended. The dose of levothyroxine should be adjusted as needed.

Propylthiouracil, glucocorticoids, beta-sympathomimetics, amiodarone, and iodine-containing contrast agents inhibit peripheral conversion of T4 to T3. Due to its high iodine content, amiodarone may cause 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 effectiveness of levothyroxine and increase serum levels of thyroid-stimulating hormone (TSH) laboratory parameters.

Drugs inducing cytochrome P-450. Medicinal products that induce enzymes, such as barbiturates, carbamazepine, and preparations containing St. John's wort (Hypericum perforatum L.), may increase hepatic clearance of levothyroxine, leading to decreased serum thyroid hormone concentrations.

Thus, patients receiving thyroid replacement therapy may require an increased dose of thyroid hormones if these drugs are administered simultaneously.

Estrogens. Women taking estrogen-containing contraceptives and 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 L-Thyroxine-Pharmak® should be adjusted, especially at the beginning and after discontinuation of soy-containing supplements.

Proton pump inhibitors (PPIs). Concomitant use with PPIs may lead to reduced absorption of thyroid hormones due to increased gastric pH caused by PPIs.

During concomitant treatment, regular monitoring of thyroid function and clinical observation are recommended. An increase in thyroid hormone dosage may be required.

Caution should also be exercised when PPI treatment is discontinued.

Effect on laboratory test results. 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, the presence of conditions such as coronary insufficiency, angina pectoris, atherosclerosis, arterial hypertension, pituitary insufficiency, or adrenal insufficiency should be excluded or appropriately treated prior to starting thyroid hormone therapy.

Functional autonomy of the thyroid gland should also be excluded or treated before initiating thyroid hormone therapy.

In patients at risk of developing psychotic disorders, levothyroxine therapy 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 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, glucocorticoid 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.

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

Levothyroxine should not be prescribed to patients with hyperthyroidism who are undergoing antithyroid drug therapy 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-reducing agents (e.g., sympathomimetics) (see section "Overdose").

When switching from L-Thyroxine-Pharmak® to another medicinal product containing the same active substance, dosage adjustment should be based on the patient's response and laboratory test results.

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 should be administered at different times and levothyroxine dosage may require adjustment. Subsequently, monitoring of thyroid hormone levels in serum is recommended.

During initiation of levothyroxine therapy, hemodynamic parameters should be monitored in preterm infants with very low birth weight, due to the risk of circulatory disturbances associated with adrenal immaturity.

Effect on laboratory test results

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

When interpreting laboratory test results, potential biotin interference should be considered, especially if test results are inconsistent with the clinical picture.

Patients taking biotin-containing supplements should inform laboratory personnel about the optimal timing for thyroid function testing. Alternative testing methods not susceptible to biotin interference should be used if available (see section "Interaction with other medicinal products and other forms of interaction").

The product should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption, as it contains lactose. The product 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").

Use during pregnancy or breastfeeding

During pregnancy or breastfeeding, treatment with thyroid hormone replacement 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 TSH levels monitored during each trimester. Serum TSH levels in pregnant women should remain within trimester-specific reference ranges. Levothyroxine dosage should be increased to correct elevated serum TSH levels. As postpartum TSH levels return to pre-pregnancy values, levothyroxine dosage should be adjusted to the pre-pregnancy dose immediately after delivery. Target serum TSH levels should be achieved within 6–8 weeks postpartum.

Pregnancy

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

Combined 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 contraindicated during pregnancy due to the prohibition of radioactive substances in pregnancy.

Breastfeeding

Levothyroxine is excreted in breast milk during lactation; however, when administered at recommended therapeutic doses, the concentration in breast milk is insufficient to cause hyperthyroidism or suppression of TSH secretion in the infant.

Ability to influence reaction speed when driving or operating machinery

There are no data on the potential effect of levothyroxine on the ability to drive or operate machinery. However, since levothyroxine has an action identical to that of the natural thyroid hormone, no effect of L-Thyroxine-Pharmak® on reaction speed during driving or operating machinery is expected.

Dosage and Administration

For the treatment of each individual patient according to their specific needs, the drug L-Thyroxine-Pharmak® is available in tablets containing 25 mcg, 50 mcg, and 100 mcg of sodium levothyroxine.

Dosage information provided is for guidance only.

The daily dose should be individually determined based on laboratory parameters and the clinical presentation of the disease.

Since in some patients undergoing levothyroxine therapy increased concentrations of T4 and fT4 have been observed, the basal serum concentration of thyroid-stimulating hormone (TSH) is a more reliable parameter for further dose adjustment.

Thyroid hormone therapy should be initiated at a low dose and gradually increased (every 2–4 weeks) until the required therapeutic dose is reached.

Children. For newborns and infants with congenital hypothyroidism, where achieving a rapid therapeutic effect is critical, the recommended initial dose is 10 to 15 mcg/kg body weight per day during the first 3 months of life. After this period, the dose should be individually adjusted based on clinical parameters and TSH levels.

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 daily). The dose should be increased gradually toward the maintenance dose (by increments of 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 result in complete normalization of TSH levels.

Clinical experience indicates that lower doses are sufficient for patients with low body weight and for patients with large nodular goiter.

* - apply in the appropriate dosage.

The daily dose may be administered as a single dose.

The daily dose of the medication should be taken in the morning on an empty stomach, 30 minutes before eating, with a small amount of water (half a glass of water).

For infants, administer the daily dose as a single dose 30 minutes before the first feeding. Dissolve the tablet in water to obtain a suspension, which should be prepared immediately before administration, and use after adding a small amount of additional liquid.

L-Thyroxin-Pharmak® should be used lifelong as replacement therapy in hypothyroidism, following surgical interventions (strumectomy or thyroidectomy), and also for prevention of recurrences after removal of euthyroid goiter. Combination therapy with antithyroid agents should be initiated after achieving a euthyroid state.

In benign forms of euthyroid goiter, treatment duration ranges from 6 months to 2 years. If there is no improvement after treatment, surgical intervention or radioactive iodine therapy should be considered.

Children.

The medication can be used in children from birth (see section "Method of administration and dosage").

Overdose.

Elevated T3 (triiodothyronine) levels are a reliable indicator of drug overdose, more so than increased T4 and fT4 (free) levels in blood serum.

As a result of overdose, symptoms characteristic of increased metabolic rate may occur (see section "Adverse reactions").

In case of overdose, discontinue the medication and perform laboratory tests.

If symptoms manifest as pronounced beta-sympathomimetic effects, such as tachycardia, restlessness, nervous excitability, or hyperkinesia, beta-blockers should be prescribed. In cases of significant overdose, plasmapheresis is recommended.

In individual cases, in patients predisposed to seizures, convulsions may develop when the individual tolerable dose has been exceeded.

Levothyroxine overdose may cause symptoms of hyperthyroidism and lead to acute psychosis, especially in patients at risk of developing psychotic disorders.

There have been several reports of sudden coronary death in patients who chronically abused (exceeded the recommended dosage) levothyroxine over many years.

Side effects.

Clinical symptoms of hyperthyroidism may occur in cases of overdose, exceeding the individual tolerance dose of levothyroxine, or when the dose is rapidly increased at the beginning of treatment.

Symptoms:

Cardiovascular system: cardiac arrhythmia (atrial fibrillation, extrasystoles), tachycardia, angina pectoris, palpitations, hot flushes;

Nervous system: headache, insomnia, anxiety, pseudotumor cerebri, tremor;

Gastrointestinal tract: vomiting, diarrhea, weight loss;

Skin and musculoskeletal system: increased sweating, muscle weakness and cramps;
General disorders: increased body temperature, menstrual cycle disturbances.

In such cases, the daily dose of the drug should be reduced or treatment should be interrupted for several days. After the side effects disappear, treatment may be continued.

Allergic reactions on the skin and respiratory tract may occur in patients with hypersensitivity to the drug components, including skin rashes, pruritus, urticaria, angioedema, dyspnea. Cases of Quincke's edema development have been reported.

Reporting suspected side effects

Reporting of suspected side effects after medicinal product registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life.

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 5 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.