L-thyroxine 50 berlin-chemi

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT L-THYROXIN 50 BERLIN-CHEMIE / L-THYROXIN 100 BERLIN-CHEMIE (L-THYROXIN 50 BERLIN-CHEMIE / L-THYROXIN 100 BERLIN-CHEMIE)

Composition:

Active substance: levothyroxine sodium;

1 tablet contains 50 mcg or 100 mcg of sodium levothyroxine;

Excipients: cysteine hydrochloride monohydrate (partially present in tablets as cystine); microcrystalline cellulose; pregelatinized starch; corn starch; light magnesium oxide; talc.

Pharmaceutical form. Tablets.

Main physicochemical properties:

L-Thyroxin 50 Berlin-Chemie: round, slightly convex tablets, white to beige in colour, with a score line on one side.

L-Thyroxin 100 Berlin-Chemie: round, slightly convex tablets, white to beige in colour, with a score line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group. Thyroid therapy, thyroid hormones. ATC code H03A A01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The synthetic levothyroxine contained in L-Thyroxine 50 Berlin-Chemie and L-Thyroxine 100 Berlin-Chemie is identical in action to the natural thyroid hormone primarily produced by the thyroid gland. There are no differences between endogenously produced and exogenous levothyroxine for the organism.

Pharmacodynamic effects.

Following partial conversion to liothyronine (T3), primarily in the liver and kidneys, and entry into body cells, the characteristic effects of thyroid hormones on development, growth, and metabolism are observed via activation of T3 receptors.

Clinical efficacy and safety.

Thyroid hormone replacement leads to normalization of metabolic processes. For example, levothyroxine administration results in a significant reduction of elevated cholesterol levels caused by hypothyroidism.

Pharmacokinetics.

Absorption.

Orally administered levothyroxine is absorbed primarily in the upper segment of the small intestine. The extent of absorption depends mainly on the galenical form of the preparation and may reach up to 80% when administered on an empty stomach. Absorption is significantly reduced when the drug is taken with food.

Maximum plasma concentration is reached approximately 2–3 hours after administration.

Therapeutic effects are observed 3–5 days after initiation of oral therapy.

Distribution.

The volume of distribution is approximately 10–12 L. Levothyroxine is bound to specific plasma transport proteins by approximately 99.97%. The binding of hormones to proteins is non-covalent, thus allowing continuous and very rapid exchange between free and protein-bound hormone.

Elimination.

Metabolic clearance of levothyroxine is approximately 1.2 L of plasma per day. Metabolism occurs primarily in the liver, kidneys, brain, and muscles. Metabolites are excreted in urine and feces. The elimination half-life is approximately 7 days; in hyperthyroidism, this period is shortened (to 3–4 days), whereas in hypothyroidism it is prolonged (approximately 9–10 days).

Pregnancy and breastfeeding.

Levothyroxine crosses the placenta only in negligible amounts. When administered in usual doses, levothyroxine is excreted into breast milk only in negligible amounts.

Renal impairment.

Due to its high degree of protein binding, neither hemodialysis nor hemoperfusion affects levothyroxine levels.

Clinical characteristics.

Indications.

L-THYROXINE 50 BERLIN-CHEMIE, L-THYROXINE 100 BERLIN-CHEMIE:

• Benign goitre with euthyroid function of the thyroid gland;
• Prevention of goitre recurrence after resection of goitre with euthyroid function of the thyroid gland;
• Replacement therapy for hypothyroidism of various etiologies;
• Adjunctive agent in antithyroid therapy of hyperthyroidism after achieving euthyroid functional status;
• Suppressive and replacement therapy in thyroid cancer, primarily after thyroidectomy.

For L-THYROXINE 100 BERLIN-CHEMIE:

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Untreated hyperthyroidism of any origin. Untreated adrenal insufficiency. Untreated pituitary insufficiency (this leads to adrenal insufficiency requiring treatment). Acute myocardial infarction. Acute myocarditis. Acute pancarditis.

During pregnancy, concomitant use of levothyroxine and any antithyroid agent is contraindicated (more detailed information on use during pregnancy or breastfeeding is provided in the section «Use during pregnancy or breastfeeding» ).

Interaction with other medicinal products and other forms of interaction.

Antidiabetic agents

Levothyroxine may reduce the blood glucose-lowering effect of antidiabetic drugs (e.g., metformin, glimepiride, glyburide, and insulin). More frequent monitoring of blood glucose levels is recommended in patients with diabetes, especially at the beginning and end of thyroid hormone therapy. Dose adjustment of the antidiabetic medicinal product may be necessary.

Coumarin derivatives

Levothyroxine may potentiate the effect of coumarin derivatives by displacing them from plasma protein binding sites. Therefore, regular monitoring of coagulation parameters is required when used concomitantly, and the dose of anticoagulant agents may need to be adjusted (reduced) if necessary.

Ion-exchange resins

Ion-exchange resins such as cholestyramine, colestipol, or calcium and sodium salts of polystyrene sulfonate inhibit levothyroxine absorption by binding thyroid hormones in the gastrointestinal tract; therefore, they should be administered 4–5 hours after taking L-Thyroxine Berlin-Chemie.

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.

Drugs binding bile acids

Colesevelam binds levothyroxine and thereby reduces its gastrointestinal absorption. No interaction was observed when levothyroxine was administered at least 4 hours before colesevelam. Therefore, L-Thyroxine Berlin-Chemie should be administered at least 4 hours before colesevelam.

Aluminium-containing antacids, as well as iron- and calcium-containing drugs

Absorption of levothyroxine may be reduced when aluminium-containing antacids (antacids, sucralfate), iron- or calcium-containing medicinal products are taken concomitantly. L-Thyroxine Berlin-Chemie should be administered at least 2 hours before these products.

Sevelamer and lanthanum carbonate

Sevelamer and lanthanum carbonate may reduce the bioavailability of levothyroxine (see also section «Special precautions for use» ).

Propylthiouracil, glucocorticoids, and beta-blockers (especially propranolol)

These substances inhibit the conversion of thyroxine (T4) to T3 and may lead to decreased plasma T3 concentration.

Amiodarone and iodinated contrast agents

Due to their high iodine content, amiodarone and iodinated contrast agents may cause both hyperthyroidism and hypothyroidism. Particular caution is required in nodular goitre with possible latent autonomy. Amiodarone inhibits the conversion of T4 to T3, resulting in decreased T3 concentration and increased levels of thyroid-stimulating hormone (TSH) in plasma. Due to the effect of amiodarone on thyroid function, dose adjustment of L-Thyroxine Berlin-Chemie may be necessary.

Salicylates, dicoumarol, furosemide, clofibrate

Salicylates (especially at doses above 2 g daily), dicoumarol, high-dose furosemide (250 mg), clofibrate, and other substances may displace levothyroxine from plasma protein binding sites. This may lead to an initial transient increase in free thyroid hormone levels, resulting in decreased total thyroid hormone levels.

Estrogen-containing contraceptives, postmenopausal hormone replacement therapy

The requirement for levothyroxine may increase during use of estrogen-containing contraceptives or postmenopausal hormone replacement therapy. Increased binding of levothyroxine may occur, potentially leading to diagnostic and therapeutic errors.

Sertraline, chloroquine/proguanil

These substances reduce the effectiveness of levothyroxine and increase serum TSH levels.

Cytochrome P450 inducers

Medicinal products that induce enzymes, such as rifampicin, carbamazepine, phenytoin, barbiturates, and products containing St. John’s wort (Hypericum perforatum L.), may increase hepatic clearance of levothyroxine, leading to decreased serum thyroid hormone concentration. Thus, patients receiving thyroid hormone replacement therapy may require an increased dose of thyroid hormones when these drugs are used concomitantly.

Protease inhibitors

There have been reports of loss of therapeutic effect of levothyroxine when co-administered with lopinavir/ritonavir. Therefore, patients taking levothyroxine concomitantly with protease inhibitors require careful monitoring of clinical symptoms and thyroid function. In patients receiving levothyroxine, TSH levels should be monitored at least during the first month after initiation and/or discontinuation of ritonavir therapy.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (e.g., imatinib, sunitinib, sorafenib, motesanib) may reduce the effectiveness of levothyroxine. Therefore, patients receiving levothyroxine and tyrosine kinase inhibitors concomitantly require careful monitoring of clinical symptoms and thyroid function parameters. Dose adjustment of levothyroxine may be necessary.

Products containing soy

Products containing soy may inhibit intestinal absorption of levothyroxine. Reports have described increased serum TSH levels in children on soy-based diets who were treated with levothyroxine for congenital hypothyroidism. High doses of levothyroxine are recommended to achieve normal serum T4 and TSH levels. Careful monitoring of serum T4 and TSH levels is required during and after discontinuation of soy-based diets; dose adjustment of levothyroxine may be necessary.

Orlistat

Hypothyroidism and/or reduced control of hypothyroidism may occur when levothyroxine and orlistat are used concomitantly. This may be due to reduced absorption of levothyroxine.

Coffee

Concomitant intake of levothyroxine with coffee should be avoided, as it may reduce absorption of levothyroxine from the gastrointestinal tract. Therefore, an interval of half an hour to one hour between administration of levothyroxine and coffee consumption is recommended to minimize the risk of interaction. Patients already receiving levothyroxine therapy are advised not to change their coffee consumption habits without medical evaluation and monitoring of levothyroxine levels.

Semaglutide

Concomitant use of semaglutide may affect levothyroxine exposure. The area under the concentration-time curve (AUC) of levothyroxine (corrected for endogenous levels) increased by 33% after a single oral dose of semaglutide, while the maximum concentration (Cmax) remained unchanged. When treating patients with levothyroxine concomitantly with semaglutide, monitoring of thyroid parameters and dose adjustment should be considered.

Effect on laboratory test results

Biotin may interfere with immunoassays of thyroid function based on biotin-streptavidin interaction, leading to falsely low or falsely high test results (see section «Special precautions for use»).

Special precautions for use

Prior to initiating thyroid hormone therapy or performing thyroid suppression tests, the presence of the following diseases or conditions should be excluded or adequately treated:

• Ischemic heart disease
• Angina pectoris
• Hypertension
• Pituitary insufficiency and/or adrenal cortex insufficiency.

Autonomous thyroid function should also be excluded or treated prior to starting thyroid hormone therapy.

In patients with ischemic heart disease, heart failure, tachyarrhythmia, myocarditis (outside the acute phase), chronic hypothyroidism, or those who have suffered a myocardial infarction, pharmacologically induced hyperthyroidism—even in its mildest form—must be strictly avoided. When treating such patients with thyroid hormones, more frequent monitoring of thyroid hormone levels is required (see section "Dosage and administration").

In cases of secondary hypothyroidism, concomitant adrenocortical insufficiency must be ruled out. If present, replacement therapy (e.g., with hydrocortisone) should be initiated first. Without adequate corticosteroid replacement, thyroid hormone therapy in patients with adrenocortical or pituitary insufficiency may precipitate an Addisonian crisis.

Hemodynamic parameters should be closely monitored when initiating levothyroxine therapy in preterm neonates with very low birth weight, as circulatory disturbances may occur due to immaturity of adrenal function.

In suspected autonomous thyroid dysfunction, TSH levels should be measured or thyroid scintigraphy performed prior to initiating treatment.

Postmenopausal women are at increased risk of developing osteoporosis; therefore, the dose of sodium levothyroxine should be carefully titrated to achieve the lowest effective dose. To avoid exceeding physiological levothyroxine concentrations in blood, thyroid function should be monitored more frequently in these patients (see section "Undesirable effects").

Thyroid hormones must not be used for weight reduction. Administration of physiological doses does not lead to weight loss in euthyroid patients. Higher doses may cause serious or even life-threatening adverse reactions, particularly when combined with certain weight-loss agents.

Serious hypersensitivity reactions (including angioedema) have been reported during levothyroxine treatment. If signs or symptoms of allergic reactions occur, levothyroxine therapy should be discontinued and appropriate symptomatic treatment initiated (see sections "Contraindications" and "Undesirable effects").

Once a levothyroxine treatment regimen has been established, switching to another thyroid hormone-containing medicinal product should only be done under laboratory and clinical monitoring.

Patients receiving levothyroxine concomitantly with other medicinal products that may affect thyroid function (e.g., amiodarone, tyrosine kinase inhibitors, salicylates, and high-dose furosemide) require regular monitoring of thyroid function (see also section "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised when prescribing levothyroxine to patients with a history of epilepsy, as these patients may be at increased risk of seizures.

For patients with diabetes mellitus or those receiving anticoagulant therapy, see section "Interaction with other medicinal products and other forms of interaction".

Cases of hypothyroidism have been reported in patients receiving concomitant sevelamer and levothyroxine. Therefore, TSH levels should be closely monitored in patients receiving both agents (see also section "Interaction with other medicinal products and other forms of interaction").

Effect on laboratory test results:

Biotin may interfere with thyroid function assays based on the biotin-streptavidin principle, 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 results are inconsistent with the clinical picture. Laboratory personnel should be informed about biotin use in patients, and optimal timing for thyroid function testing should be determined. Alternative assays insensitive to biotin 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 (23 mg)/tablet of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Thyroid hormone therapy should be continued throughout pregnancy and breastfeeding.

Thyroid suppression testing should not be performed during pregnancy or breastfeeding.

Pregnancy

Maintaining thyroid hormone levels within the normal range is critically important during pregnancy to ensure optimal maternal and fetal health. To date, despite widespread use during pregnancy, no negative effects of levothyroxine on pregnancy or fetal/neonatal health have been observed.

Thyroid hormone requirements may increase during pregnancy due to estrogen effects. Therefore, thyroid function should be monitored both during and after pregnancy, and thyroid hormone dosage adjusted as necessary.

Since serum TSH levels may rise as early as week 4 of pregnancy, pregnant women receiving levothyroxine should have their TSH levels measured each trimester to ensure values remain within the trimester-specific reference range. Elevated TSH levels should be corrected by increasing the levothyroxine dose. As postpartum TSH levels typically return to pre-pregnancy values, levothyroxine dosage should be adjusted back to the pre-pregnancy dose immediately after delivery. Serum TSH levels should be reassessed 6–8 weeks postpartum.

The use of sodium levothyroxine as an adjunctive treatment in hyperthyroidism managed with antithyroid drugs is contraindicated during pregnancy. Additional levothyroxine may necessitate higher doses of antithyroid drugs. Unlike levothyroxine, antithyroid agents cross the placental barrier in significant amounts and may cause fetal hypothyroidism. Therefore, antithyroid drugs should always be used as monotherapy and at the lowest effective dose in pregnant women with hyperthyroidism.

Breastfeeding

Levothyroxine is excreted into human breast milk; however, concentrations achieved with recommended therapeutic doses are not sufficient to cause hyperthyroidism or suppress TSH secretion in the nursing infant.

Fertility

Hypothyroidism or hyperthyroidism may impair fertility. During levothyroxine treatment of hypothyroidism, dosage should be adjusted based on laboratory monitoring, as underdosing will not produce a beneficial effect, while overdosing may lead to hyperthyroidism.

Ability to influence the ability to drive and use machines

No specific studies have been conducted to assess the effect of levothyroxine on the ability to drive or operate machinery.

Dosage and Administration.

The dosage information provided should be considered as recommendations. The individual daily dose of the drug should be determined based on laboratory test results and clinical evaluation. Thyroid hormone therapy should be initiated at a low dose and gradually increased (every 2–4 weeks) to the required therapeutic dose.

Since serum T4 or free thyroxine (fT4) levels may be elevated in some patients, monitoring of treatment regimens is best achieved by measuring serum TSH concentration.

Adults.

Treatment of benign goiter: 75–200 mcg/day.

Prevention of goiter recurrence: 75–200 mcg/day.

Replacement therapy in hypothyroidism: initial dose is 25–50 mcg/day, maintenance dose is 100–200 mcg/day.

Concomitant therapy during antithyroid treatment of hyperthyroidism: 50–100 mcg/day.

Suppressive and replacement therapy in thyroid cancer: 150–300 mcg/day.

Thyroid suppression test (only for L-Thyroxin 100 Berlin-Chemie): 200 mcg (equivalent to 2 tablets)/day for 14 days (starting 14 days before the test).

Children with congenital and acquired hypothyroidism.

The maintenance dose is usually 100–150 mcg of levothyroxine per 1 m² body surface area per day.

For infants and children with congenital hypothyroidism requiring immediate levothyroxine replacement therapy, the recommended initial dose during the first 3 months is 10–15 mcg of levothyroxine per kilogram of body weight per day. Subsequent dose adjustments should be made individually according to clinical findings, thyroid hormone levels, and TSH values.

For children with acquired hypothyroidism, the recommended initial dose is 12.5–50 mcg of levothyroxine per day, using the appropriate dosage strength of the medication. Based on clinical data, thyroid hormone levels, and TSH values, the dose should be gradually increased at intervals of 2–4 weeks until the full replacement dose is achieved. Infants and children under 3 years of age should receive the full daily dose at least 30 minutes before the first feeding of the day. Tablets may also be administered as a suspension. Tablets should first be dissolved in a small amount of water (10–15 mL), and the freshly prepared suspension should be administered to the child with an additional small amount of water (5–10 mL).

Elderly patients.

In certain cases, particularly in elderly patients with cardiac disease, a gradual reduction in the dose of sodium levothyroxine is recommended, with continuous monitoring of TSH levels.

Clinical experience suggests that using the lowest effective dose is optimal in patients with low body weight or large nodular goiter.

The entire daily dose should be swallowed whole, without chewing the tablets, with a small amount of liquid, e.g., ½ glass of water. The drug should be taken on an empty stomach, at least 30 minutes before breakfast.

Due to the special design of the tablet, it can be divided as follows: place the tablet on a hard surface with the dividing notch facing upwards and press down perpendicularly with a finger (see Figure 1).

Figure 1

Treatment duration.

The drug is generally administered for life in cases of hypothyroidism, following surgical procedures such as strumectomy or thyroidectomy, and for prevention of recurrence after removal of euthyroid goiter. The duration of use as an adjunctive treatment in hyperthyroidism after achieving euthyroid status corresponds to the duration of antithyroid therapy. In mild forms of euthyroid goiter, treatment duration ranges from 6 months to 2 years. If the patient's condition does not improve after treatment, surgical intervention or radioactive iodine therapy should be considered.

Thyroid suppression test.

For the thyroid suppression test, take 150–200 mcg of sodium levothyroxine daily for 14 days.

Children.

The drug may be used in pediatric practice. Detailed information on recommended doses and administration methods is provided in the section «Dosage and Administration».

Overdose.

Symptoms of overdose include tachycardia, palpitations, anxiety, heat sensation, elevated body temperature, increased sweating, arrhythmia, insomnia, tremor, increased frequency of angina attacks, restlessness, weight loss, vomiting, diarrhea, headache, weakness, muscle cramps, menstrual cycle disturbances, and pseudotumor cerebri. There have been isolated reports of epileptic seizures in patients when the individual tolerance threshold was exceeded.

It is recommended to discontinue the drug and perform follow-up examinations.

Elevated T3 levels are a more reliable indicator of drug overdose than elevated T4 or fT4 levels.

In cases of overdose and intoxication, symptoms typical of moderate or marked metabolic acceleration occur (see section «Adverse Reactions»). Depending on the severity of the overdose, discontinuation of the drug and follow-up evaluation are recommended.

Human intoxication (suicide attempts) with levothyroxine doses up to 10 mg has been tolerated without complications. Development of severe complications such as life-threatening dysfunction (respiration and circulation) is unlikely if there is no history of ischemic heart disease. Nevertheless, there have been reports of thyrotoxic crisis, seizures, cardiac failure, and coma. Isolated cases of sudden fatal outcome related to cardiac arrhythmias have been reported in patients who have used high doses of levothyroxine for prolonged periods.

In cases of acute overdose, absorption of the drug from the gastrointestinal tract can be reduced by administering activated charcoal. Treatment is generally symptomatic and supportive. In cases of severe beta-sympathomimetic symptoms such as tachycardia, restlessness, agitation, or hyperkinesis, beta-adrenergic blockers may be used to alleviate symptoms. Antithyroid drugs should not be used, as thyroid function is already fully suppressed.

In cases of extreme overdose (suicide attempts), plasmapheresis may be beneficial.

Prolonged observation is required after levothyroxine overdose. Due to the gradual conversion of levothyroxine to liothyronine, symptom onset may be delayed up to 6 days.

Adverse reactions.

If the patient does not tolerate the dose, which is very rare, or in case of overdose, especially with too rapid dose escalation at the beginning of treatment, typical symptoms of hyperthyroidism may occur.

In such cases, the daily dose should be reduced or administration of the drug should be discontinued for several days. Once adverse effects have subsided, treatment may be resumed, carefully adjusting the dose of the medication.

Allergic reactions may occur in patients hypersensitive to levothyroxine or to any of the excipients, affecting the skin (e.g., angioneurotic edema, skin rash, urticaria) or respiratory tract. There have been isolated reports of anaphylactic shock. In such cases, the drug must be discontinued.

Adverse reactions are classified by frequency of occurrence as follows:

Very common (≥ 1/10) Common (≥ 1/100 — < 1/10) Occasional (≥ 1/1000 — < 1/100) Rare (≥ 1/10000 — < 1/1000) Very rare (< 1/10000) Not known (cannot be estimated from available data)

Immune system side effects

Unknown: hypersensitivity

Endocrine system side effects:

Frequent: hyperthyroidism

Cardiac side effects

Very common: palpitations

Frequent: tachycardia

Unknown: arrhythmia, angina pectoris

Skin and subcutaneous tissue side effects

Unknown: angioedema, rash, urticaria, hyperhidrosis

Psychiatric disorders

Very common: insomnia

Frequent: nervousness

Unknown: inner restlessness

Musculoskeletal and connective tissue side effects

Unknown: muscle weakness, muscle cramps, osteoporosis due to suppressive doses of levothyroxine, especially in postmenopausal women, mainly during long-term treatment

Vascular side effects

Unknown: hot flushes, collapse (acute circulatory failure) in premature infants with very low birth weight (see section «Special precautions for use»)

Reproductive system and breast side effects

Unknown: menstrual disorders

Gastrointestinal side effects

Unknown: diarrhoea, vomiting, nausea

Additional investigation findings

Unknown: weight loss

Nervous system side effects

Very common: headache

Rare: pseudotumor cerebri (mainly in children)

Unknown: tremor

General disorders and administration site reactions

Unknown: heat intolerance, fever

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: 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 at temperatures not exceeding 30 °C. Keep in the original blister packaging to protect from light. The medicinal product should be stored out of reach of children.

Packaging.

Blister pack of 25 tablets; 1, 2, or 4 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's name and address.

Glienicker Weg 125, 12489 Berlin, Germany.