Tyrozol
Ukraine
INSTRUCTION |
THYROZOL® |
Composition:active substance: thiamazole; 1 tablet contains thiamazole 5 mg or 10 mg; excipients: lactose monohydrate; corn starch; powdered cellulose; talc; hypromellose 2910/15; magnesium stearate VS; sodium starch glycolate (type C); colloidal anhydrous silicon dioxide; film coating for 5 mg tablets: dimethicone 100, polyethylene glycol 400, titanium dioxide E 171, iron oxide yellow E 172, hypromellose 2910/15; film coating for 10 mg tablets: dimethicone 100, polyethylene glycol 400, titanium dioxide E 171, iron oxide yellow E 172, hypromellose 2910/15; iron oxide red E 172. |
| Pharmaceutical form. Film-coated tablets. |
| Basic physico-chemical properties: 5 mg tablets: light yellow, round, biconvex film-coated tablets with a dividing line on both sides; 10 mg tablets: grey-orange, round, biconvex film-coated tablets with a dividing line on both sides. Pharmacotherapeutic group. Antithyroid agents. Sulfur-containing imidazole derivatives. ATC code H03B B02. |
Pharmacological properties.Pharmacodynamics. Depending on its dosage, thiamazole inhibits the incorporation of iodine into tyrosine, thereby suppressing the de novo synthesis of thyroid hormones. This property allows symptomatic treatment of hyperthyroidism regardless of its etiology. Whether thiamazole, apart from this, affects the natural course of the disease in immunologically mediated hyperthyroidism (Graves' disease), i.e., whether it suppresses the immunopathogenetic process underlying the disease, remains undetermined to date. Thiamazole does not affect the secretion of previously synthesized thyroid hormones, which explains the variable latency period of the drug's action in individual cases until normalization of serum thyroxine and triiodothyronine concentrations, and consequently, until clinical improvement. The drug also does not affect hyperthyroidism that develops due to hormone release following destruction of thyroid cells (after radioactive iodine therapy or in thyroiditis). Pharmacokinetics. Thiamazole is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration is reached within 0.4–1.2 hours. It binds to plasma proteins to a very small extent. Thiamazole accumulates in the thyroid gland and is slowly metabolized there. Despite fluctuations in serum levels, accumulation of thiamazole in the thyroid gland still leads to a plateau concentration, resulting in a duration of action lasting approximately 24 hours after a single dose. According to recent data, the kinetics of thiamazole metabolism do not depend on thyroid function. The elimination half-life is about 3–6 hours. It is prolonged in patients with hepatic insufficiency. Thiamazole is excreted in urine and bile, and to a minor extent in feces, indicating enterohepatic circulation. It is excreted in urine (70% within 24 hours). Only a small amount of thiamazole is excreted unchanged. There is no current experience regarding the pharmacological activity of metabolites. Limited data are available on the pharmacokinetics of thiamazole in patients with impaired renal or hepatic function (see section "Dosage and administration"). Data on repeated dosing are lacking (see section "Dosage and administration"). |
Clinical characteristics.Indications. Treatment of hyperthyroidism, including:
|
| Contraindications.
Concomitant therapy with thiamazole and thyroid hormones during pregnancy is contraindicated (see section "Use in pregnancy or lactation"). Interaction with other medicinal products and other forms of interaction. Iodine deficiency increases the thyroid gland's sensitivity to thiamazole, whereas iodine excess reduces it. Direct interactions with other medicinal products are unknown. However, it should be considered that metabolism and elimination of other drugs may be increased in hyperthyroidism. These parameters normalize upon restoration of thyroid function. Dosage adjustments may be necessary. Additionally, correction of hyperthyroidism may normalize the increased activity of anticoagulants in patients with hyperthyroidism. |
Drug interaction studies involving pediatric patients have not been conducted.
Special precautions for use.Thyrozol® should not be administered to patients with a history of moderate hypersensitivity reactions (e.g., allergic rash, pruritus). Patients with very large goiters and tracheal compression should receive Thyrozol® for as short a duration as possible and under close medical supervision due to the risk of goiter growth. Myelotoxicity. Agranulocytosis has been observed in approximately 0.3–0.6% of cases. Before initiating treatment, patients should be informed about symptoms of agranulocytosis (e.g., stomatitis, pharyngitis, fever). Symptoms typically occur within the first weeks of treatment, but may appear after several months or during subsequent treatment courses. Close monitoring of blood parameters before and during therapy is recommended, especially in patients with moderate granulocytopenia. If any of the above symptoms develop, particularly during the first weeks of treatment, patients should seek immediate medical evaluation including blood testing. If agranulocytosis is confirmed, treatment with the drug must be discontinued. Adverse reactions due to bone marrow toxicity are rare when the drug is used at recommended doses. Such reactions have been more frequently reported with very high doses of thiamazole (approximately 120 mg daily). These high doses are prescribed only under special indications (severe disease forms, thyrotoxic crisis). If signs of bone marrow toxicity occur during thiamazole therapy, treatment should be discontinued immediately and, if necessary, switched to an antithyroid agent from another class. Acute pancreatitis. During the post-marketing period, cases of acute pancreatitis have been reported in patients receiving medicinal products containing thiamazole or prodrugs of carbimazole. Thiamazole should be discontinued immediately in patients who develop acute pancreatitis. Thiamazole should not be administered to patients who previously experienced acute pancreatitis during thiamazole or carbimazole prodrug therapy. Re-administration may lead to recurrent acute pancreatitis, with a shorter time to recurrence. Women of reproductive age and pregnant women. Women of reproductive age should use effective contraceptive methods during thiamazole therapy. Thiamazole should be administered during pregnancy only after careful benefit-risk assessment and at the lowest effective dose without additional thyroid hormone supplementation. If used during pregnancy, careful monitoring of the mother, fetus, and newborn is required (see section "Use during pregnancy or breastfeeding"). Control of hyperthyroidism. Excess drug in the body after administration of very high doses may lead to subclinical or clinical hypothyroidism or goiter growth due to increased secretion of thyroid-stimulating hormone (TSH). Therefore, the dose of thiamazole should be reduced immediately after restoration of normal thyroid function, and levothyroxine may be added if necessary. Complete discontinuation of thiamazole therapy and use of levothyroxine alone is not advisable. Goiter enlargement during therapy with Thyrozol®, despite suppression of TSH secretion, occurs due to the underlying disease and cannot be prevented by additional levothyroxine administration. Maintaining normal TSH secretion levels is important to minimize the risk of development or worsening of endocrine ophthalmopathy. However, this condition often occurs independently of the course of thyroid disease. Such complications are not a reason to change an otherwise adequate treatment regimen and are not considered adverse reactions when treatment is properly administered. Rarely, late-onset hypothyroidism has been observed after completion of antithyroid therapy without additional surgical intervention. This is likely not a drug-related adverse reaction but rather a result of inflammatory and destructive processes in the thyroid parenchyma caused by the underlying disease. Due to reduced pathologically elevated energy expenditure in hyperthyroidism, body weight may increase during thiamazole therapy. Patients should be informed that clinical improvement reflects normalization of energy expenditure. Excipients. Thyrozol® contains lactose; therefore, this medication should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, Lapp lactase deficiency, or glucose-galactose malabsorption. Thyrozol® contains less than 1 mmol sodium (23 mg) per tablet, which is considered clinically insignificant. Use during pregnancy or breastfeeding. Women of reproductive age. Women of reproductive age should use effective contraception during thiamazole therapy. Pregnancy. Adequate treatment of hyperthyroidism in pregnant women is necessary to prevent serious complications in both mother and fetus. Thiamazole crosses the placental barrier. Analysis of data from studies and spontaneous reports has revealed a pattern of congenital anomalies associated with high-dose thiamazole, particularly during the first trimester of pregnancy. The most common congenital malformations include scalp aplasia in newborns whose mothers received thiamazole during pregnancy, craniofacial developmental abnormalities (choanal atresia, facial dysmorphism), exomphalos, esophageal atresia, omphalomesenteric duct anomalies, and ventricular septal defects. Thiamazole should be administered during pregnancy only after careful benefit-risk assessment at the lowest effective dose without additional thyroid hormone supplementation. If thiamazole is used during pregnancy, careful monitoring of the pregnant woman, fetus, and newborn is recommended. Breastfeeding. Thiamazole is excreted into breast milk, where its concentration reaches levels comparable to maternal serum concentrations, thereby posing a risk of hypothyroidism in the infant. During breastfeeding, thiamazole should be administered at the lowest effective dose not exceeding 10 mg daily, without additional thyroid hormone supplementation. Thyroid function in newborns should be monitored regularly. Ability to affect reaction speed when driving or operating machinery. Thiamazole does not affect reaction speed when driving or operating machinery. Method of administration and dosage.Thiamazole is the active metabolite of carbimazole; however, 1 mg of thiamazole is not equivalent to 1 mg of carbimazole. This should be considered when initiating thiamazole therapy or switching from carbimazole to thiamazole. The following dosage recommendations should be followed. The daily dose may be taken once or divided into several doses throughout the day. At the beginning of treatment, doses should be taken at regular intervals throughout the day. The maintenance dose should be taken as a single dose during or after breakfast. Tablets should be swallowed whole with sufficient liquid. If a dose is missed, do not double the next dose. General dosage recommendations. Adults. Depending on disease severity and iodine intake, the recommended adult dose is 10–40 mg daily. In many cases, suppression of thyroid hormone production is achieved with a daily dose of 20–30 mg of Thyrozol®. For mild disease, lower doses are recommended; for severe disease, an initial dose of 40 mg daily of Thyrozol® is required. Dose adjustments should be individualized based on metabolic activity related to thyroid hormone production levels. The following dosing is recommended for maintenance therapy:
In iodine-induced thyrotoxicosis, higher doses of the drug may be used. Conservative treatment of thyrotoxicosis. The goal of therapy is to achieve euthyroidism and sustained remission after a limited treatment duration. Depending on patient selection, remission may be achieved in up to 50% of patients within one year after therapy. Time to remission varies significantly depending on initial parameters. Probable influencing factors include the type of hyperthyroidism (immunogenic or non-immunogenic), treatment duration, thiamazole dosage, and source of iodine: dietary or iatrogenic. Duration of Thyrozol® therapy in conservative treatment of hyperthyroidism ranges from 6 months to 2 years (on average, 1 year). The possibility of prolonged remission depends on treatment duration. If remission cannot be achieved and other therapeutic interventions are not feasible, Thyrozol® may be used for long-term therapy at the lowest effective doses, either alone or in combination with a low dose of levothyroxine. Patients with tracheal compression and very large goiters should receive Thyrozol® for a short duration only. Prolonged therapy may lead to goiter growth. Preparation for surgical treatment in all forms of hyperthyroidism. Short-term preparatory therapy (lasting 3–4 weeks; in some cases, the drug may be used longer) helps restore euthyroidism, thereby reducing risks associated with surgery. Surgery should be performed immediately after achieving euthyroidism. If surgery is not performed, levothyroxine should be administered. Drug therapy may be discontinued one day before surgery. Increased tissue friability and bleeding tendency of the thyroid gland caused by thiamazole can be counteracted by additional preoperative administration of high-dose iodine 10 days before surgery (Plummer's iodine therapy). Preparation for radioactive iodine therapy. The drug should be used to achieve euthyroidism before starting radioactive iodine therapy. Prior therapy with Thyrozol® is particularly important for patients with severe thyrotoxicosis, as isolated cases of thyrotoxic crisis have been reported after radioactive iodine treatment without prior therapy with Thyrozol®. Note. It should be noted that thionamide derivatives may reduce the sensitivity of thyroid tissue to radiation therapy. In planned radioactive iodine therapy for autonomous adenomas, prior treatment with Thyrozol® is necessary to prevent activation of perinodular tissue. Therapy during the latent period of radioactive iodine action. The duration and dose of Thyrozol® therapy should be individualized depending on disease severity and the time until onset of radioactive iodine action (approximately 4–6 months). Prophylactic treatment of patients at risk of developing hyperthyroidism following administration of iodine-containing agents for diagnostic purposes. The usual recommended dose is 10–20 mg Thyrozol® daily and/or 1 g of perchlorate daily for 10 days (e.g., when administration of a renal-excreted radiographic contrast agent is required). The duration of prophylactic treatment should be determined based on the period during which iodine-containing agents remain in the body. Special patient groups. Patients with hepatic impairment. In patients with impaired liver function, the elimination of thiamazole is reduced. Therefore, the drug should be used at the lowest effective doses, and patients should be monitored during therapy. Patients with renal impairment. Patients with renal impairment require individual dose adjustment and ongoing monitoring due to limited pharmacokinetic data in this patient group. Elderly patients. Elderly patients should receive individualized dose adjustments and ongoing monitoring, as data on drug accumulation are lacking. The drug should be used at the lowest effective doses. Children. Children and adolescents (3–17 years) The initial dose for treatment of children and adolescents (3–17 years) is calculated according to body weight. Treatment usually starts at 0.5 mg/kg daily, divided into two or three equal doses. The maintenance dose may be reduced depending on individual response to therapy and administered once daily. To prevent hypothyroidism, additional levothyroxine may be required. The total daily dose should not exceed 40 mg of thiamazole. Children under 2 years of age The safety and efficacy of thiamazole in children under 2 years of age have not been established. Thiamazole is not recommended for use in children under 2 years of age. Overdose. Overdose leads to hypothyroidism with corresponding symptoms of slowed metabolism and, via feedback mechanism, to activation of the anterior pituitary gland with subsequent goiter growth. This can be avoided by reducing the drug dose once euthyroidism is achieved and, if necessary, adding levothyroxine. The adverse effects of accidental ingestion of high doses of thiamazole are unknown. |
Adverse reactions.Adverse effects are classified by frequency of occurrence as follows: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data). Blood and lymphatic system disorders. Uncommon: agranulocytosis (occurs in approximately 0.3–0.6% of cases). May also manifest weeks or months after treatment initiation, requiring discontinuation of the drug. In most cases, agranulocytosis resolves spontaneously. Very rare: thrombocytopenia, pancytopenia, generalized lymphadenopathy. Endocrine system disorders. Very rare: insulin autoimmune syndrome (with marked hypoglycemia). Nervous system disorders. Rare: taste disturbances (dysgeusia, ageusia) rarely occur and resolve spontaneously after discontinuation of the drug. However, taste sensation may take several weeks to recover. Very rare: neuritis, polyneuropathy. Vascular disorders. Not known: vasculitis. Gastrointestinal disorders. Very rare: acute inflammation of salivary glands. Not known: acute pancreatitis. Hepatobiliary disorders. Very rare: isolated cases of cholestatic jaundice or toxic hepatitis have been reported. Symptoms usually resolve after discontinuation of the drug. Clinically subtle signs of cholestasis during therapy should be differentiated from dysfunctions caused by hyperthyroidism, such as elevated γ-glutamyl transferase and alkaline phosphatase levels or increased levels of the specific bone isoenzyme of alkaline phosphatase. Skin and subcutaneous tissue disorders. Very common: allergic skin reactions of varying severity (pruritus, rash, urticaria). Allergic skin reactions of moderate severity are common and often resolve during continued therapy. Very rare: severe forms of allergic skin reactions, including generalized dermatitis; alopecia; drug-induced lupus erythematosus. Musculoskeletal and connective tissue disorders. Common: arthralgia, which may develop gradually and occur even several months after therapy initiation. General disorders. Rare: drug fever. Children. The frequency, type, and severity of adverse reactions in children are expected to be similar to those observed in adult patients. Very rare cases of serious hypersensitivity skin reactions, such as generalized dermatitis including Stevens-Johnson syndrome, have been reported in adult patients and children. |
| Shelf life. 4 years. Do not use after the expiry date. |
| Storage conditions. Store below 25°C in a dry place protected from moisture. Keep out of reach of children! |
| Packaging. 10 tablets per blister. 5 blisters per cardboard box. 25 tablets per blister; 2 blisters per cardboard box. |
| Prescription status. Prescription only. |
| Manufacturer. Merck Healthcare KGaA, Germany. |
| Manufacturer's address. Frankfurter Strasse 250, 64293 Darmstadt, Germany. |