Thyrozol

Thiamazole.

Pharmacology: Mode of Action: Thiamazole inhibits dose-dependently the incorporation of iodine into tyrosine and thereby the neosynthesis of thyroid hormones. This property permits symptomatic therapy of hyperthyroidism regardless of its cause. Whether thiamazole furthermore affects the "natural course" taken by the immunologically-induced type of hyperthyroidism (Graves' disease) ie, whether it suppresses the underlying immunopathogenetic process, can presently not be decided with certainty. The release of previously synthesised thyroid hormones from the thyroid is not affected. This explains why the length of the latency period until normalisation of the serum concentrations of thyroxine and triiodothyronine, and thus to clinical improvement, differs in individual cases. Hyperthyroidism is also unaffected by the release of hormones after destruction of the thyroid cells eg, after radioiodine therapy or in thyroiditis.
Nonclinical Safety Data: Preclinical safety studies are available to a limited extent only. Single-dose toxicity data show that the acute toxicity of thiamazole is low. In repeated-dose studies, bone marrow depression was seen at dose levels, which were considerably higher than the therapeutic dose levels.
Mutagenicity studies did not reveal any evidence of mutagenic or clastogenic effects. In a 2-year chronic toxicity study in rats, no relevant findings other than pharmacologically mediated effects on the thyroid were observed. In a 2-year chronic toxicity study in mice, a higher incidence of hepatomas, which did not reach the level of statistical significance, was seen when thiamazole was administered at a concentration of 500 mg/L in drinking water. The relevance of the latter finding is questionable and thiamazole is not classified as a carcinogenic substance according to the International Agency for Research of Cancer (IARC) or National Toxicology Program (NTP) criteria.

Drug treatment of hyperthyroidism, especially in slight or absent thyroid enlargement (goiter) as well as in younger patients. Preparation for surgery in all forms of hyperthyroidism and patients with hyperthyroidism for planned radioiodine treatment to prevent the risk of a thyrotoxic crisis after therapy.

Conservative Treatment of Hyperthyroidism: 2 different dosage regimens are recommended: Complete blocking of thyroid hormone production is achieved with daily doses of thiamazole 25-40 mg.
Initial therapy: To Achieve Normal Metabolic Activity of the Thyroid Gland: Maximum Daily Dose: 40 mg in single doses of maximally thiamazole 20 mg, depending on the severity of the disease. Mild Cases: 2 times 1 tab Thyrozol 10 mg (20 mg). Severe Cases: 2 times 1 tab Thyrozol 20 mg (40 mg).
Initial Therapy of Hyperthyroidism: The previously specified single doses should be taken at regular intervals throughout the day. Maintenance Dose: Can be taken all at once in the morning after breakfast.
After normalization of the thyroid function (generally between weeks 3 and 8), the dose is stepwise reduced in long-term treatment to a maintenance dose of 5-20 mg daily. This dosage usually requires the additional administration of thyroid hormones.
In therapy with Thyrozol alone, the dose depends on metabolic activity which must be checked individually in each patient, paying particular attention to the thyroid-stimulating hormone (TSH) values. The dose is in this case between 2.5 mg and 10 mg daily. Iodine-induced hyperthyroidism may possibly require higher doses.
Preparation for Surgery in All Forms of Hyperthyroidism: Normal metabolic activity of the thyroid gland is attained, as previously described. Surgery should be performed as soon as normal function is achieved. Otherwise, supplementary thyroid hormones must be administered. In the last 10 days before surgery, the surgeon may prefer to administer iodine to consolidate the thyroid tissue.
Treatment Before Radioiodine Therapy: Normal metabolic activity of the thyroid gland is attained, as previously described. Thyrozol reduces the biological half-life of iodine in the thyroid tissue. Therefore, higher radioiodine doses may be necessary.
Children: Initial Dose Depending on the Severity of the Disease: 0.3-0.5 mg/kg body weight daily. Maintenance Dose: 0.2-0.3 mg/kg body weight daily. Additional treatment with thyroid hormone may be required.
Pregnant Women: Dose should be kept as low as possible, 2.5-10 mg daily should be selected and treatment be carried out without the additional administration of thyroid hormone.
In patient with liver damage, the dose should be kept as low as possible.
When preparing patients with hyperthyroidism for surgery, treatment with Thyrozol can be commenced about 3-4 weeks prior to the scheduled time of operation (or earlier in individual cases) and discontinued on the day before surgery.
When used in preparing patients with autonomous adenoma or latent hyperthyroidism for a required exposure to iodine, the duration of treatment with Thyrozol depends on the time the iodine-containing substance is retained in the body.
Patients with considerably enlarged thyroid glands and constriction of the trachea should only undergo short-term treatment with Thyrozol, since long-term administration can result in further thyroid growth, which is associated with the risk of further constriction of the airways. Where necessary, treatment must be monitored particularly carefully.
The treatment is preferably combined with thyroid hormones.
Administration: Take Thyrozol tablets whole with some liquid (eg, ½ glass of water) after meals.
In conservative treatment of hyperthyroidism, therapy with Thyrozol is usually continued over a period of 6 months to 2 years (1 year on average). Statistically, the probability of remission increases with the duration of therapy.

Overdosage leads to hypothyroidism with corresponding symptoms of a reduced metabolism and through the feedback effect, to activation of the anterior pituitary lobe with subsequent goiter growth. This can be avoided by dose reduction as soon as a euthyroid metabolic condition is achieved and, if necessary, by additional administration of levothyroxine (see Dosage & Administration).
Negative consequences of accidental ingestion of high doses of thiamazole are not known.

Hypersensitivity to thiamazole, other thiourea derivatives or to any of the excipients of Thyrozol. Moderate to severe blood count disturbances (granulocytopenia). Preexisting cholestasis not caused by hyperthyroidism. Previous damage to bone marrow after treatment with thiamazole or carbimazole.
Combination therapy with thiamazole and thyroid hormones is contraindicated during pregnancy (see Use in pregnancy & lactation under Precautions).

Thyrozol should not be used in patients with history of mild hypersensitivity reactions (eg, allergic rashes, pruritus). Thiamazole should only be used in short-term treatment and with careful monitoring in patients with large goiters with constriction of the trachea because of the risk of goiter growth.
Agranulocytosis has been reported to occur in about 0.3-0.6% of cases. Therefore, patient must be informed prior to the start of therapy of the related symptoms (stomatitis, pharyngitis, fever). It usually occurs during the 1st weeks of treatment, but may still become apparent some months after the start of therapy and upon its reintroduction. A close monitoring of blood count is recommended before and after initiation of therapy especially in cases with preexisting mild granulocytopenia.
In the case that any of these symptoms occured, especially during the 1st weeks of treatment, patients should be advised to contact their physician immediately for a blood count. If agranulocytosis is confirmed, Thyrozol must be discontinued.
Other myelotoxic adverse reactions rarely occur in the recommended dose range. They have frequently been reported in connection with very high doses of thiamazole (about 120 mg daily). These dosages should be reserved for special indications (severe courses of disease, thyrotoxic crisis). Occurrence of damage to the bone marrow during treatment with thiamazole requires discontinuation of the medication and if necessary, switching to an antithyroid drug of another substance group.
Excess dosage can lead to subclinical or clinical hypothyroidism and goiter growth due to thyroid-stimulating hormone (TSH) increase. Therefore, the dose of thiamazole should be reduced as soon as a euthyroid metabolic condition is achieved and if necessary, levothyroxine should be given additionally. It is not useful to discontinue thiamazole altogether and to continue with levothyroxine only.
Goiter growth under therapy with thiamazole in spite of suppressed TSH is a result of the underlying disease and cannot be prevented by additional treatment with levothyroxine.
Achievement of normal TSH levels is crucial to minimize the risk of occurrence or deterioration of endocrine orbitopathy. However, this condition is frequently independent of the course taken by the thyroid disease. Such a complication itself does not constitute a reason to change the adequate treatment regimen and is not to be regarded as an adverse reaction of appropriately performed therapy.
At a low percentage, late hypothyroidism can occur after antithyroid therapy without any additional ablative measures. This is probably not an adverse drug reaction, but to be regarded as inflammatory and destructive processes in the thyroid parenchyma due to the underlying disease.
The reduction in the pathologically increased energy consumption in hyperthyroidism can lead to a (generally desired) gain in body weight during treatment with thiamazole. Patients are to be informed that their energy consumption normalizes along with the improving clinical picture.
Thyrozol contains lactose; therefore, patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Thyrozol.
Effects on the Ability to Drive or Operate Machinery: Thiamazole does not affect the capability to drive a vehicle or to operate machinery.
Use in pregnancy & lactation: In general, pregnancy has a positive effect on hyperthyroidism. Nevertheless, treatment of hyperthyroidism is often required especially in the 1st months of pregnancy. Untreated hyperthyroidism during pregnancy may lead to serious complications eg, premature birth and malformation. However, hypothyroidism caused by treatment with inappropriate thiamazole doses is also associated with a tendency to abortion.
Thiamazole passes the placental barrier, and in fetal blood, reaches concentrations equal to those found in maternal serum. At an inappropriate dosage, this may lead to goiter formation and hypothyroidism in the fetus as well as to reduced birth weight. There have been repeated reports of partial aplasia cutis on the head of neonates born to women treated with thiamazole. This defect healed spontaneously within a few weeks.
In addition, a certain pattern of diverse malformations has been associated with high-dose thiamazole therapy during the 1st weeks of pregnancy eg, choanalatresia, oesophageal atresia, hypoplastic nipples, delayed mental as well as motor development. In contrast, several case studies on prenatal thiamazole exposure have neither revealed any morphological development disorders nor impact on thyroid development or the physical and intellectual development of the children.
Since embryotoxic effects cannot be completely excluded, Thyrozol may only be administered during pregnancy after carefully weighing the benefit-risk ratio and only at the lowest still effective dose level without additional administration of thyroid hormones.
Thiamazole passes into breast milk where it can reach concentrations corresponding to maternal serum levels, so that there is a risk of hypothyroidism developing in the infant.
Breastfeeding is possible during thiamazole treatment; however, only low doses up to 10 mg daily may be used without additional administration of thyroid hormones. The infant's thyroid function is to be monitored regularly.

Combination therapy with thiamazole and thyroid hormones is contraindicated during pregnancy.
In general, pregnancy has a positive effect on hyperthyroidism. Nevertheless, treatment of hyperthyroidism is often required especially in the 1st months of pregnancy. Untreated hyperthyroidism during pregnancy may lead to serious complications eg, premature birth and malformation. However, hypothyroidism caused by treatment with inappropriate thiamazole doses is also associated with a tendency to abortion.
Thiamazole passes the placental barrier, and in fetal blood, reaches concentrations equal to those found in maternal serum. At an inappropriate dosage, this may lead to goiter formation and hypothyroidism in the fetus as well as to reduced birth weight. There have been repeated reports of partial aplasia cutis on the head of neonates born to women treated with thiamazole. This defect healed spontaneously within a few weeks.
In addition, a certain pattern of diverse malformations has been associated with high-dose thiamazole therapy during the 1st weeks of pregnancy eg, choanalatresia, oesophageal atresia, hypoplastic nipples, delayed mental as well as motor development. In contrast, several case studies on prenatal thiamazole exposure have neither revealed any morphological development disorders nor impact on thyroid development or the physical and intellectual development of the children.
Since embryotoxic effects cannot be completely excluded, Thyrozol may only be administered during pregnancy after carefully weighing the benefit-risk ratio and only at the lowest still effective dose level without additional administration of thyroid hormones.
Thiamazole passes into breast milk where it can reach concentrations corresponding to maternal serum levels, so that there is a risk of hypothyroidism developing in the infant.
Breastfeeding is possible during thiamazole treatment; however, only low doses up to 10 mg daily may be used without additional administration of thyroid hormones. The infant's thyroid function is to be monitored regularly.

Minor adverse reactions eg, allergic skin reactions (itching, redness, rash) of varying degree occur frequently. They mostly take a mild course and frequently recede during continued therapy. Serious courses to the point of generalized dermatitis have been described only in isolated cases. Nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy and lymphadenopathy.
Dru fever occurs rarely.
Disturbances in the sense of taste occur rarely; they can recede after discontinuation of Thyrozol; however, normalisation may take several weeks.
Changes in the blood count, granulocytopenia, thrombocytopenia, aplastic anemia, hypoprothrombinemia and nephritis can occur; agranulocytosis occur in about 0.3-0.6% of cases. They become apparent as inflammation of oral mucosa and pharynx, fever, formation of furuncles. In the case that any of these symptoms occur, especially during the 1st weeks of treatment, patients should discontinue Thyrozol immediately and have the physician perform a blood count check. The symptoms can still occur weeks or months after the start of therapy. In most cases, they recede spontaneously.
Isolated cases of pain in the joints have been reported, which generally develop gradually and also after several months of therapy. There are no signs of arthritis.
Isolated cases of jaundice due to impaired flow of bile or toxic inflammation of the liver have been described. The symptoms generally recede after discontinuation of Thyrozol.
The following have been described in isolated cases: Inflammation of lymph nodes (lymphadenitis), acute salivary gland swelling, decrease in the number of blood platelets and other blood constituents, inflammation of vessels and nerves, generally impaired sensitivity, loss of hair, Thyrozol-induced lupus erythematosus (autoimmune disease, the symptoms of which disappear after discontinuation of Thyrozol), as well as insulin autoimmune syndrome (with pronounced drop in blood glucose values).
Thiamazole reduces the energy requirement which was pathologically increased due to hyperthyroidism. This means that, with an unaltered diet, a gain in body weight can occur during treatment with Thyrozol. This is generally desired from a medical point of view.
Excessive dosage can cause hypothyroidism as well as diffuse thyroid growth. Consequently, the Thyrozol dose should be reduced after the metabolic activity of the thyroid gland has been normalized and/or a thyroid hormone should be given additionally. It is not appropriate to discontinue Thyrozol completely and continue treatment with thyroid hormones.
Further growth of the already enlarged thyroid under thiamazole therapy in spite of suppressed thyroid-stimulating hormone (TSH) levels is a result of the underlying disease and cannot be prevented by additional treatment with thyroid hormones.
The occurrence or deterioration of an eye disease which is typical in patients with hyperthyroidism (endocrine orbital disease) is largely independent of the course taken by the thyroid disease. Such a complication, by itself, is no reason to change the treatment regimen and is not to be regarded as a side effect of thiamazole therapy correctly carried out.
At low percentage, late hypothyroidism can occur after therapy with Thyrozol without any additional surgical measures. This is probably not a side effect of Thyrozol, but to be regarded as inflammatory process in the thyroid tissue occurring alongside the underlying disease.
If the patient have symptoms of agranulocytosis, granulocytopenia and thrombocytopenia drug fever or disturbances in the sense of taste, discontinue treatment with Thyrozol tablets and prescribe a different medication. Consult the doctor immediately if any side effects are experienced. Take any appropriate counter measures when necessary.
It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white blood cell count <4000/mm³) often with relative granulopenia.

Iodine deficiency increases, excess iodine reduces the response of the thyroid gland to Thyrozol. No further direct interactions with other medication are known. It should, however, be noted that in the presence of hyperthyroidism the breakdown and excretion of other medication can be accelerated. With increasing normalization of the thyroid function, these also return to normal. If necessary, the doctor will have to correct the dosage. The activity of anticoagulants may be potentiated by anti-vitamin K activity attributed to methimazole.

Store in a dry place, below 25°C.

Antithyroid Agents

H03BB02 - thiamazole ; Belongs to the class of sulfur-containing imidazole derivative agents. Used in the management of thyroid diseases.

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