L-thyroxine 75 berlin-chemi

INSTRUCTION for medical use of the medicinal product L-THYROXIN 75 BERLIN-CHEMIE (L-THYROXIN 75 BERLIN-CHEMIE)

Composition:

Active substance: levothyroxine sodium;

1 tablet contains 75 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 physico-chemical properties: round, slightly convex tablets of white to beige color, with a score line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group. Thyroid therapy, thyroid hormones. ATC code H03AA01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The synthetic levothyroxine contained in the L-Thyroxine 75 Berlin-Chemie preparation 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, characteristic effects of thyroid hormones on development, growth, and metabolism are observed through activation of T3 receptors.

Clinical efficacy and safety.

Replacement therapy with thyroid hormones 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 drug and may reach up to 80% when taken on an empty stomach. Absorption is significantly reduced if 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 a continuous and very rapid exchange between free and bound hormone.

Elimination.

Metabolic clearance for 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), and 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 in breast milk only in insignificant quantities.

Renal impairment.

Due to the high degree of protein binding, neither hemodialysis nor hemoperfusion significantly affect levothyroxine levels.

Clinical characteristics.

Indications.

• Replacement therapy in hypothyroidism of various etiologies;
• Prevention of goiter recurrence after thyroid resection in patients with euthyroid thyroid function;
• Benign goiter with euthyroid thyroid function;
• Adjunctive therapy in antithyroid treatment of hyperthyroidism after achieving euthyroid functional status;
• Suppressive and replacement therapy in malignant thyroid tumors, primarily after thyroidectomy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Untreated hyperthyroidism of any origin. Untreated adrenal cortex insufficiency. Untreated pituitary insufficiency (this leads to adrenal cortex 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 diabetic patients, 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, when used concomitantly, regular monitoring of coagulation parameters is required, and the dose of anticoagulant agents may need to be adjusted (reduced).

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 the medicinal product L-Thyroxine 75 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 therapy, 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 that bind bile acids

Colesevelam binds levothyroxine and thereby reduces its absorption in the gastrointestinal tract. No interaction was observed when levothyroxine was administered at least 4 hours before colesevelam. Therefore, L-Thyroxine 75 Berlin-Chemie should be administered at least 4 hours before colesevelam.

Aluminum-containing antacids, as well as iron- and calcium-containing preparations

Absorption of levothyroxine may be reduced when co-administered with aluminum-containing antacids (antacids, sucralfate), iron- or calcium-containing medicinal products. L-Thyroxine 75 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 iodine-containing contrast agents

Due to their high iodine content, amiodarone and iodine-containing contrast agents may cause both hyperthyroidism and hypothyroidism. Particular caution is required in nodular goiter with possible undefined 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 impact of amiodarone on thyroid function, dose adjustment of L-Thyroxine 75 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 a decrease in total thyroid hormone levels.

Estrogen-containing contraceptives, medicinal products for hormone replacement therapy in postmenopausal women

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

Sertraline, chloroquine/proguanil

These substances reduce the efficacy 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 replacement therapy may require an increased dose of thyroid hormones when these drugs are administered 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 taking 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 efficacy of levothyroxine. Therefore, careful monitoring of clinical symptoms and thyroid function parameters is required in patients taking levothyroxine and tyrosine kinase inhibitors concomitantly. Levothyroxine dosage may need to be adjusted if necessary.

Preparations containing soy

Preparations containing soy may inhibit intestinal absorption of levothyroxine. Reports have been published on increased serum TSH levels in children on soy-based diets who were treated with levothyroxine for congenital hypothyroidism. To achieve normal serum T4 and TSH levels, high doses of levothyroxine are recommended. Careful monitoring of serum T4 and TSH levels is required during and after completion of a soy-based diet; 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.

Kava

Concomitant intake of levothyroxine with kava 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 levothyroxine intake and kava consumption is recommended to minimize the risk of interaction. Patients already receiving levothyroxine therapy are advised not to change their kava 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, consideration should be given to monitoring thyroid function parameters and dose adjustment.

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 thyroid hormone therapy, the presence of the following diseases or conditions should be excluded or appropriately treated:

• Ischaemic heart disease
• Angina pectoris
• Hypertension
• Pituitary insufficiency and/or adrenal cortical insufficiency
• Thyroid autonomy.

In patients with ischaemic heart disease, heart failure, tachyarrhythmia, myocarditis (outside the acute phase), chronic hypothyroidism, or those who have had a myocardial infarction, pharmacologically induced hyperthyroidism—even in its mild 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, adrenal cortical insufficiency should be ruled out. If present, replacement therapy (e.g., with hydrocortisone) should be initiated first. Thyroid hormone therapy in patients with adrenal or pituitary insufficiency, without adequate corticosteroid replacement, may precipitate an Addisonian crisis.

During initiation of levothyroxine therapy, hemodynamic parameters should be monitored in preterm infants 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 starting 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 "Adverse reactions").

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 with levothyroxine use. If signs or symptoms of allergic reactions occur, levothyroxine therapy should be discontinued and appropriate symptomatic treatment initiated (see sections "Contraindications" and "Adverse reactions").

Once a stable levothyroxine regimen has been established, switching to another thyroid hormone-containing medicinal product should only be done under close 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 anticoagulants, 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, careful monitoring of TSH levels is required 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 the optimal timing for thyroid function testing should be determined. Alternative assays not susceptible 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 (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Thyroid hormone therapy should be continued consistently during pregnancy and breastfeeding.

The thyroid suppression test should not be performed during pregnancy or breastfeeding.

Pregnancy

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

During pregnancy, levothyroxine requirements may increase under the influence of oestrogen. Therefore, thyroid function should be monitored both during and after pregnancy, and thyroid hormone dosage adjusted as necessary.

Since elevated serum TSH levels may occur as early as week 4 of pregnancy, pregnant women taking levothyroxine should have their TSH levels measured during each trimester to ensure values remain within the trimester-specific reference range. Elevated serum 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 adjunct in the treatment of hyperthyroidism with antithyroid drugs is contraindicated during pregnancy. Additional levothyroxine may necessitate higher doses of antithyroid drugs. Unlike levothyroxine, antithyroid drugs cross the placental barrier in significant amounts and may cause fetal hypothyroidism. Therefore, antithyroid drugs should always be used as monotherapy at the lowest effective dose in pregnant women with hyperthyroidism.

Breastfeeding

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

Fertility

Hypothyroidism or hyperthyroidism may affect fertility. During levothyroxine treatment of hypothyroidism, the dose should be adjusted based on laboratory monitoring, as an insufficient dose will not produce a beneficial effect, while overdosing may lead to hyperthyroidism.

Ability to affect reaction speed when driving or operating machinery

No specific studies have been conducted to assess the effect of this medicinal product 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. In cases of residual thyroid function, the lowest replacement dose should be used.

Treatment with thyroid hormones should be initiated with particular caution in elderly patients, patients with ischemic heart disease, and those with severe or chronic hypothyroidism. It is recommended to start therapy with a low dose, gradually increasing it at significant intervals, with frequent monitoring of thyroid hormone levels. According to clinical experience, lower doses of the drug are sufficient both in patients with low body weight and in those with large nodular goiter.

Since serum T4 or free thyroxine (fT4) levels may be elevated in some patients, monitoring of serum TSH concentration is more appropriate for assessing the treatment regimen.

Adult Patients

Hypothyroidism. Initial dose: 25–50 mcg/day; maintenance dose: 00–200 mcg/day (increase dose by 25–50 mcg at intervals of 2–4 weeks).

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

Benign goiter with euthyroid function. 75–200 mcg/day.

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

After thyroidectomy due to malignant tumor. 150–300 mcg/day.

If dose adjustment of this drug is not possible, alternative dosage strengths are available. Consult a physician for advice.

Children with congenital and acquired hypothyroidism

The maintenance dose in congenital and acquired hypothyroidism 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 of life is 10–15 mcg of levothyroxine per kilogram of body weight per day. Subsequent dose adjustments should be made individually based on clinical findings, thyroid hormone levels, and TSH levels.

For children with acquired hypothyroidism, the recommended initial dose is 12.5–50 mcg/day, using a preparation of appropriate strength. The dose should be increased gradually every 2–4 weeks, based on clinical evaluation and monitoring of thyroid hormone and TSH levels, until the full replacement dose is achieved.

The full daily dose should be administered to children at least 30 minutes before the first feeding of the day. Tablets may also be given as a suspension. The 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, adding a small additional amount of water (5–10 mL).

Elderly Patients

In individual cases, particularly in elderly patients with heart disease, gradual reduction of levothyroxine sodium dose with continuous monitoring of TSH levels is recommended.

The entire daily dose should be swallowed whole, without chewing the tablets, with a small amount of liquid. 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 score line facing upwards, and press down vertically with a finger (see Figure 1).

Fig. 1

Treatment Duration

The drug is usually administered for life in cases of hypothyroidism and after thyroidectomy due to malignant thyroid tumors. For euthyroid goiter and prevention of goiter recurrence, treatment may last from several months to years, or may be lifelong. As an adjunct in the treatment of hyperthyroidism, duration depends on the length of antithyroid therapy.

The treatment duration for euthyroid goiter should be from 6 months to 2 years. If the patient's condition does not improve after treatment with L-Thyroxine 75 Berlin-Chemie, alternative therapeutic approaches should be considered.

Children

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

Overdose

Symptoms of overdose include rapid pulse, tachycardia, anxiety, sensation of heat, 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. Discontinuation of the drug and follow-up examinations are recommended.

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

In cases of overdose and intoxication, symptoms typical of moderate or marked acceleration of metabolism may occur (see section «Side Effects»). Depending on the degree of overdose, discontinuation of the drug and follow-up evaluation are recommended.

In human cases of intoxication (suicide attempts), levothyroxine doses up to 10 mg have been tolerated without complications. The development of severe complications such as life-threatening respiratory or circulatory disturbances is unlikely, provided there is no history of ischemic heart disease. Nevertheless, cases of thyrotoxic crisis, seizures, heart failure, and coma have been reported. There have been isolated reports of sudden fatal outcomes related to cardiac dysfunction 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, these can be alleviated with beta-adrenergic blockers. Antithyroid drugs should not be used, as thyroid function is already fully suppressed.

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

Prolonged monitoring is required after levothyroxine overdose. Due to the gradual conversion of levothyroxine to triiodothyronine (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. After the adverse effects have subsided, treatment should be resumed, carefully adjusting the dose of the drug.

Allergic reactions from the skin (e.g., angioedema, skin rash, urticaria) and respiratory tract may occur in patients hypersensitive to levothyroxine or to any of the excipients of the medicinal product L-Thyroxine 75 Berlin-Chemie. There have been isolated reports of anaphylactic shock. In such cases, the drug must be discontinued.

Adverse reactions are classified according to frequency of occurrence as follows:

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

From the immune system

Unknown: hypersensitivity

From the endocrine system

Frequent: hyperthyroidism

From the cardiac system

Very common: tachycardia

Frequent: tachycardia

Unknown: arrhythmia, angina pectoris

From the skin and subcutaneous tissue

Unknown: angioneurotic edema, rash, urticaria, hyperhidrosis

Psychiatric disorders

Very common: insomnia

Frequent: nervousness

Unknown: inner restlessness

From the musculoskeletal and connective tissue

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

From the vascular system

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

From the reproductive system and breast

Unknown: menstrual disorders

From the gastrointestinal tract

Unknown: diarrhea, vomiting, nausea

Results of additional diagnostic tests

Unknown: weight loss

From the nervous system

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 drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy 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 a temperature not exceeding 30 °C. Keep in the original blister packaging to protect from light. Keep the medicinal product out of the reach of children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG

Manufacturer's location and address of place of business.

Glienicker Weg 125, 12489 Berlin, Germany.