Thyrozol^® (Tablets) Instructions for Use

Marketing Authorization Holder

Merck LLC (Russia)

Manufactured By

Merck, KGaA (Germany)

ATC Code

H03BB02 (Thiamazole)

Active Substance

Thiamazole (Rec.INN registered by WHO)

Dosage Forms

	Thyrozol®	Film-coated tablets, 5 mg: 20, 40, 50, 100, 125 or 250 pcs.
		Film-coated tablets, 10 mg: 20, 40, 50, 100, 125 or 250 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex, with score lines on both sides; the core on the cross-section is white or almost white.

Excipients: colloidal silicon dioxide – 2 mg, sodium carboxymethyl starch – 2 mg, magnesium stearate – 2 mg, hypromellose 2910/15 – 3 mg, talc – 6 mg, cellulose powder – 10 mg, corn starch – 20 mg, lactose monohydrate – 200 mg.

Film coating composition iron oxide yellow dye – 0.04 mg, dimethicone 100 – 0.16 mg, macrogol 400 – 0.79 mg, titanium dioxide – 1.43 mg, hypromellose 2910/15 – 3.21 mg.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.
25 pcs. – blisters (5) – cardboard packs.
25 pcs. – blisters (10) – cardboard packs.

Film-coated tablets grey-orange in color, round, biconvex, with score lines on both sides; the core on the cross-section is white or almost white.

Excipients: colloidal silicon dioxide – 2 mg, sodium carboxymethyl starch – 2 mg, magnesium stearate – 2 mg, hypromellose 2910/15 – 3 mg, talc – 6 mg, cellulose powder – 10 mg, corn starch – 20 mg, lactose monohydrate – 195 mg.

Film coating composition iron oxide yellow dye – 0.54 mg, iron oxide red dye – 0.004 mg, dimethicone 100 – 0.16 mg, macrogol 400 – 0.79 mg, titanium dioxide – 0.89 mg, hypromellose 2910/15 – 3.21 mg.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
25 pcs. – blisters (2) – cardboard packs.
25 pcs. – blisters (4) – cardboard packs.
25 pcs. – blisters (5) – cardboard packs.
25 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antithyroid drug

Pharmacotherapeutic Group

Antithyroid agent

Pharmacological Action

Antithyroid agent. It disrupts the synthesis of thyroid hormones by blocking the peroxidase enzyme involved in the iodination of thyronine in the thyroid gland with the formation of triiodothyronine and thyroxine. This property allows for symptomatic therapy of thyrotoxicosis, except in cases of thyrotoxicosis due to hormone release after destruction of thyroid cells (after treatment with radioactive iodine or in thyroiditis).

Thiamazole does not affect the process of release of synthesized thyronines from the thyroid follicles. This explains the latent period of varying duration that may precede the normalization of T₃ and T₄ levels in the blood plasma, i.e., the improvement of the clinical picture.

It reduces the basal metabolic rate, accelerates the excretion of iodides from the thyroid gland, increases the reciprocal activation of the synthesis and secretion of TSH by the pituitary gland, which may be accompanied by some hyperplasia of the thyroid gland.

The duration of action of the drug after a single dose is almost 24 hours.

Pharmacokinetics

Thiamazole is rapidly and almost completely absorbed after oral administration. C_max in plasma is reached within 0.4-1.2 hours. It practically does not bind to plasma proteins. Thiamazole accumulates in the thyroid gland, where it is slowly metabolized. Small amounts of thiamazole are found in breast milk. T_1/2 is about 3-6 hours, it increases in hepatic insufficiency. No dependence of kinetics on the functional state of the thyroid gland was found.

Metabolism of thiamazole occurs in the kidneys and liver, excretion of the drug is carried out by the kidneys and with bile. 70% of thiamazole is excreted by the kidneys within 24 hours, with 7-12% unchanged.

Indications

• Thyrotoxicosis;
• Preparation for surgical treatment of thyrotoxicosis;
• Preparation for treatment of thyrotoxicosis with radioactive iodine;
• Therapy during the latent period of radioactive iodine action – carried out until the onset of radioactive iodine action (for 4-6 months);
• In exceptional cases – long-term maintenance therapy of thyrotoxicosis, when radical treatment is impossible due to the general condition or for individual reasons;
• Prevention of thyrotoxicosis when prescribing iodine preparations (including cases of using iodine-containing X-ray contrast agents) in the presence of latent thyrotoxicosis, autonomous adenomas or a history of thyrotoxicosis.

ICD codes

Dosage Regimen

The tablets should be taken orally after meals, without chewing, with a sufficient amount of liquid.

The daily dose is prescribed in one dose or divided into 2-3 single doses. At the beginning of treatment, single doses are taken during the day at a strictly defined time. The maintenance dose should be taken in one dose after breakfast.

Thyrotoxicosis

Depending on the severity of the disease, the drug is prescribed at a dose of 20-40 mg/day for 3-6 weeks. After normalization of thyroid function (usually after 3-8 weeks), they switch to taking a maintenance dose of 5-20 mg/day. From this time, additional administration of levothyroxine sodium is recommended.

When preparing for surgical treatment of thyrotoxicosis, 20-40 mg/day is prescribed until a euthyroid state is achieved. From this time, additional administration of levothyroxine sodium is recommended. To reduce the time required for preparation for surgery, beta-blockers and iodine preparations are additionally prescribed.

When preparing for treatment with radioactive iodine, Thiamazole is prescribed at a dose of 20-40 mg/day until a euthyroid state is achieved.

Therapy during the latent period of radioactive iodine action: depending on the severity of the disease, Thiamazole is prescribed at a dose of 5-20 mg/day until the onset of radioactive iodine action (4-6 months).

Long-term thyrostatic maintenance therapy

Thiamazole is prescribed at a dose of 1.25-2.5-10 mg/day with additional administration of levothyroxine sodium in small doses. In the treatment of thyrotoxicosis, the duration of therapy is from 1.5 to 2 years.

Prevention of thyrotoxicosis when prescribing iodine preparations (including cases of using iodine-containing X-ray contrast agents) in the presence of latent thyrotoxicosis, autonomous adenomas or a history of thyrotoxicosis: Thiamazole is prescribed 10-20 mg/day and 1 g of potassium perchlorate per day for 8-10 days before taking iodine-containing agents.

Children

Not recommended for use in children from 0 to 3 years.

For children from 3 to 17 years, Thiamazole is prescribed at an initial dose of 0.3-0.5 mg/kg, which is divided into two or three equal doses daily. The maximum recommended dose for children weighing more than 80 kg is 40 mg/day. Maintenance dose is 0.2-0.3 mg/kg/day. If necessary, levothyroxine sodium is additionally prescribed.

Dosage in pregnant women

Pregnant women are prescribed at the lowest possible doses: single – 2.5 mg, daily – 10 mg.

In hepatic insufficiency, the drug is prescribed at the minimum effective dose under careful medical supervision.

When preparing for surgery in patients with thyrotoxicosis, treatment with the drug is carried out until a euthyroid state is achieved for 3-4 weeks before the planned day of surgery (in some cases – longer) and ends the day before it.

Adverse Reactions

Possible adverse reactions when using thiamazole are distributed by system-organ classes with an indication of the frequency of their occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be calculated from the available data).

Blood and lymphatic system disorders uncommon – agranulocytosis (symptoms /see section “Special Precautions”/ may appear even weeks and months after the start of treatment and lead to the need to discontinue the drug); very rare – generalized lymphadenopathy, thrombocytopenia, pancytopenia.

Endocrine system disorders very rare – insulin autoimmune syndrome with hypoglycemia.

Nervous system disorders rare – reversible change in taste sensations, dizziness; very rare – neuritis, polyneuropathy.

Vascular disorders frequency unknown – vasculitis.

Gastrointestinal disorders very rare – acute salivary gland edema, vomiting; frequency unknown – acute pancreatitis.

Hepatobiliary disorders very rare – cholestatic jaundice and toxic hepatitis.*

*These symptoms usually subside after discontinuation of the drug. Subtle clinical signs of cholestasis during treatment must be differentiated from disorders caused by hyperthyroidism, such as increased levels of GGT and ALP or its bone-specific isoenzyme.

Skin and subcutaneous tissue disorders very common – allergic skin reactions of varying severity (itching, rash, urticaria)**; very rare – severe forms of allergic reactions, including generalized dermatitis; alopecia; drug-induced lupus erythematosus.

** In most cases, they are mild and often resolve with continued therapy.

Musculoskeletal and connective tissue disorders common – slowly progressive arthralgia without clinical signs of arthritis, which may develop gradually and occur even after several months of therapy.

General disorders and administration site conditions rare – drug fever, weakness, weight gain.

Children

The frequency, type and severity of adverse reactions in children are similar to those in adult patients. Reports of severe skin hypersensitivity adverse reactions in adults and children have been registered, including Stevens-Johnson syndrome (in very rare cases – severe forms, including generalized dermatitis).

Contraindications

Not recommended for use in children under 3 years of age.

• Hypersensitivity to thiamazole, to thiourea derivatives and/or any excipient in the drug;
• Agranulocytosis during previous therapy with carbimazole or thiamazole;
• Granulocytopenia (including history);
• Cholestasis before starting treatment;
• Therapy with thiamazole in combination with levothyroxine during pregnancy;
• Previously noted bone marrow damage after treatment with thiamazole or carbimazole;
• History of acute pancreatitis as a result of using thiamazole or carbimazole;
• In patients with a history of mild hypersensitivity reactions (e.g., allergic rash, itching).

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

With caution, the drug should be used in patients with very large goiter with tracheal narrowing (only short-term treatment during preparation for surgery), with hepatic insufficiency.

Use in Pregnancy and Lactation

To prevent serious complications in the mother and fetus, pregnant women with hyperthyroidism should be prescribed adequate treatment. Thiamazole is able to cross the placenta.

Based on epidemiological studies and spontaneous reports: Thiamazole may cause congenital malformations in the fetus, especially when used in the first trimester of pregnancy and in high doses.

The following developmental defects are known: congenital aplasia cutis, congenital malformations of the craniofacial region (choanal atresia, facial dysmorphism), omphalocele, esophageal atresia, vitelline duct anomaly and ventricular septal defect.

Therapy with thiamazole during pregnancy is allowed only after a thorough individual assessment of the “benefit-risk” ratio and only at the minimum effective dose without additional prescription of thyroid hormones. When using thiamazole during pregnancy, careful monitoring of the health of the mother, fetus or newborn is recommended.

Therapy with thiamazole during breastfeeding can be continued if necessary. Since Thiamazole passes into breast milk and can reach concentrations corresponding to its level in the mother’s blood, the development of hypothyroidism in the newborn is possible. Therapy with thiamazole during breastfeeding is possible at a dose not exceeding 10 mg/day (without additional use of thyroid hormones).

Thyroid function in newborns should be regularly monitored.

Use in Hepatic Impairment

In hepatic insufficiency, the drug is prescribed at the minimum effective dose under careful medical supervision.

Pediatric Use

Use in children aged 0 to 3 years is not recommended.

Special Precautions

In patients with a significant enlargement of the thyroid gland that narrows the tracheal lumen, short-term therapy with thiamazole is carried out under careful observation, because with long-term use, an increase in goiter and further compression of the trachea is possible.

Myelotoxicity

Agranulocytosis develops in 0.3-0.6% of cases. Before starting treatment, the patient should be informed about the symptoms of agranulocytosis (stomatitis, pharyngitis, fever).

Agranulocytosis usually occurs within the first weeks of treatment, but may also appear several months after the start of treatment and after its resumption. Careful monitoring of the leukocyte count is recommended before and after the start of treatment, especially in cases where there is already a mild degree of granulocytopenia. If any of these symptoms are detected, especially during the first weeks of treatment, patients are recommended to immediately contact their doctor for a blood test to determine the leukocyte count. If agranulocytosis is confirmed, discontinuation of the drug is necessary.

When using the drug in recommended doses, other adverse reactions associated with myelotoxicity occur rarely. The occurrence of these adverse reactions has been noted in connection with the use of very high doses of thiamazole (about 120 mg/day). Such doses can only be used for the treatment of severe forms of the disease and in thyrotoxic crisis. If toxic effects on the bone marrow occur during the use of thiamazole, the drug should be discontinued and, if necessary, an antithyroid drug containing an active substance from another group should be prescribed.

Acute pancreatitis

Post-registration data reported acute pancreatitis in patients taking Thiamazole or carbimazole. In acute pancreatitis, therapy with thiamazole must be discontinued immediately. The use of thiamazole is contraindicated in patients with a history of acute pancreatitis after using thiamazole or carbimazole. Repeated use of the drug may lead to a relapse of acute pancreatitis with a reduced time to disease development.

Control of thyroid function

Exceeding the dose of the drug can lead to subclinical or clinical hypothyroidism and goiter growth due to an increase in TSH levels. Thus, the dose of thiamazole must be reduced as soon as a euthyroid metabolic state is achieved, and levothyroxine should be additionally prescribed if necessary. Simultaneous discontinuation of thiamazole and continuation of treatment only with levothyroxine is not used. Despite TSH suppression, goiter growth during treatment with thiamazole is a result of the underlying disease and cannot be prevented by additional treatment with levothyroxine.

Achieving normal TSH levels is key to minimizing the risk of worsening endocrine orbitopathy. The manifestations or disorders of endocrine orbitopathy are largely independent of the course of the thyroid disease. Such a complication in itself is not a reason to change the treatment regimen and should not be considered as an adverse reaction to properly conducted treatment.

In a low percentage of cases after antithyroid therapy without any additional ablation measures, such as surgery or radioactive iodine therapy, late hypothyroidism may occur. It is probably not an adverse reaction to the drug itself and should be considered as an inflammatory and destructive process in the thyroid parenchyma caused by the underlying disease.

A decrease in the pathologically increased energy consumption in hyperthyroidism can lead to weight gain (usually desirable) during treatment with thiamazole. Patients should be informed that an improvement in the clinical picture indicates normalization of their energy consumption.

During therapy with thiamazole, women with preserved reproductive potential should use effective methods of contraception.

Effect on ability to drive vehicles and mechanisms

Thiamazole does not affect the ability to drive vehicles and mechanisms.

Drug Interactions

When prescribing the drug after the use of high-dose iodine-containing X-ray contrast agents, a weakening of the effect of thiamazole is possible.

Iodine deficiency enhances the effect of thiamazole.

In patients taking Thiamazole for the treatment of thyrotoxicosis, after achieving a euthyroid state, i.e., normalization of thyroid hormone levels in the blood serum, it may be necessary to reduce the doses of cardiac glycosides (digoxin and digitoxin), aminophylline, as well as to increase the doses of warfarin and other anticoagulants – coumarin and indandione derivatives (pharmacodynamic interaction).

Lithium preparations, beta-blockers, reserpine, amiodarone enhance the effect of thiamazole (dose adjustment is required).

When used concomitantly with sulfonamides, sodium metamizole, and myelotoxic drugs, the risk of leukopenia increases.

Leukogen and folic acid, when used concomitantly with thiamazole, reduce the risk of leukopenia.

Gentamicin enhances the antithyroid effect of thiamazole.

There are no data on the influence of other drugs on the pharmacokinetics and pharmacodynamics of the drug. However, it should be borne in mind that in thyrotoxicosis, the metabolism and elimination of substances are accelerated. Therefore, in some cases, it is necessary to adjust the dose of other drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.