SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Thiamazole Uni-Pharma 5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each Thiamazole Uni-Pharma 5 mg tablet contains 5 mg thiamazole.

Excipient(s) with known effect Contains 179 mg lactose monohydrate, see section 4.4.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Tablet. Thiamazole Uni-Pharma 5 mg tablets are white, flat-faced bevel-edged, bisect on one side tablets, with a diameter of 8.06 mm. The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Treatment of hyperthyroidism (thyrotoxicosis) in adults and children and adolescence from the age of 3 years.

4.2 Posology and method of administration The dosage should be individually adjusted depending on the severity of the disease.

Posology

Severe cases:

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Initial dose: 30-40 mg daily in divided doses.

Mild cases: Initial dose: 10-20 mg daily. The dose can be divided in two daily doses.

Maintenance dose: 5-10 mg daily.

In some cases higher initial doses may be required – especially in cases with large goitres and with prior iodine therapy. For maintenance treatment, the dose can be reduced based on the patient’s response to treatment. Additional treatment with levothyroxine may be required to avoid hypothyroidism.

Paediatric population Use in children and adolescents (3-17 years) The initial dose for treatment of children and adolescents over three years old should be adjusted according to the patient’s body weight. As a general rule, the initial dosage is 0.5 mg / kg body weight per day, divided into two or three equal doses. For maintenance treatment, the dose can be reduced based on the patient’s response to treatment. Additional treatment with levothyroxine may be required to avoid hypothyroidism. The total daily dose should not exceed 40 mg thiamazole.

Use in children (2 years and below) The safety and efficacy of thiamazole in children aged 2 years and below, has not been systematically studied. Thiamazole is therefore not recommended in children who are 2 years and below.

Special populations In patients with hepatic impairment, the plasma clearance of thiamazole is reduced. Therefore, the dose should be kept as low as possible and patients should be closely monitored – please refer to sections 4.4 and 5.2. The plasma half-life also increases in the event of impaired renal function; careful individual dose adjustment under close monitoring is recommended. The dose should be kept as low as possible. Please also refer to sections 4.4 and 5.2.

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Method of administration The tablets should be swallowed with sufficient liquid and not chewed because of bad taste. During high-dose initial therapy of hyperthyroidism the above stated daily doses can be subdivided and taken at regular intervals over the day. The maintenance dose can be taken at once in the morning during or after breakfast.

4.3 Contraindications Thiamazole Uni-Pharma must not be used in patients with - Hypersensitivity to thiamazole or to any of the excipients listed in section 6.1. - Severe hypersensitivity to other thionamide derivatives, e.g. carbimazole and propylthiouracil (for mild hypersensitivity reactions to thionamide derivatives, see section 4.4). - Moderate to severe blood count disturbances (granulocytopenia), - Pre-existing cholestasis not caused by hyperthyroidism, - Previous damage to bone marrow after treatment with thiamazole or carbimazole. - Patients with a history of acute pancreatitis after administration of thiamazole or its prodrug carbimazole. Combination therapy with thiamazole and thyroid hormones is contraindicated during pregnancy (see section 4.6).

4.4 Special warnings and precautions for use Thiamazole should be used with caution in patients with history of mild hypersensitivity reactions (e.g. allergic rashes, pruritus). Thiamazole should only be used in short-term treatment and under careful monitoring in patients with large goitres with constriction of the trachea because of the risk of goitre growth. Agranulocytosis has been reported to occur in about 0.3 to 0.6% of cases and the patient´s attention should be drawn to its symptoms (stomatitis, pharyngitis, fever) prior to the start of therapy. In the case that any of these symptoms are observed, patients should be advised to contact their physician immediately for a blood count. It usually occurs during the first weeks of treatment, but may still become manifest 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 pre-existing mild granulocytopenia. If an agranulocytosis is confirmed, a discontinuation of the medicinal product is necessary. Other myelotoxic adverse reactions are rare with the recommended doses. They have frequently been reported in connection with very high doses of thiamazole (about 120 mg per day). These dosages should be reserved for special indications (severe forms of disease,

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thyrotoxic crisis). Occurrence of bone marrow toxicity during treatment with thiamazole requires discontinuation of the medicinal product and, if necessary, switch to an anti-thyroid medicinal product of another substance group. Thiamazole should be used with caution in patients with hepatic disorder. Thiamazole can cause hepatic disorder. Treatment should be discontinued in the event of abnormal liver function. Half-life may be prolonged in the presence of hepatic impairment. There is a risk of cross-sensitivity among carbimazole, thiamazole and propylthiouracil. Excess dosage can lead to sub-clinical or clinical hypothyroidism and goitre growth due to 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. Goitre 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 minimise 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 is no reason to change the adequate treatment regimen and is not to be regarded as an adverse reaction to the correctly carried out therapy. At a low percentage late hypothyroidism may occur after anti-thyroid therapy without any additional ablative measures. This is probably not an adverse reaction to the medicinal product, but to be regarded as inflammatory and destructive processes in the parenchyma of the thyroid 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 should be informed that improvement of the clinical picture indicates normalisation of their energy consumption. Monitoring of serum thyroxine is necessary. Caution is necessary in cases of intrathoracic goitre, which can grow during the treatment. Intrathoracic goitre can cause tracheal obstruction. Thiamazole Uni-Pharma contains lactose; patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Women of childbearing potential have to use effective contraceptive measures during treatment. The use of thiamazole in pregnant women must be based on the individual benefit/risk assessment. If thiamazole is used during pregnancy, the lowest effective dose without additional administration of thyroid hormones should be administered. Close maternal, foetal, and neonatal monitoring is warranted (see section 4.6). There have been post-marketing reports of acute pancreatitis in patients receiving thiamazole or its prodrug carbimazole. In case of acute pancreatitis, thiamazole should be discontinued

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immediately. Thiamazole must not be given to patients with a history of acute pancreatitis after administration of thiamazole or its prodrug carbimazole. Re-exposure may result in recurrence of acute pancreatitis, with decreased time to onset.

4.5 Interaction with other medicinal products and other forms of interaction Iodine deficiency increases the response of the thyroid to thiamazole, whereas iodine excess lowers the response. Further direct interactions with other medicinal products are not known. However, it should be taken into account that the metabolism and elimination of other medicinal products can be accelerated in hyperthyroidism. They normalise in correlation with increasing normalisation of thyroid function. The dosage must be adjusted where necessary. Furthermore, there is evidence that correction of hyperthyroidism may normalise the enhanced activity of anticoagulants in hyperthyroid patients. No drug interaction studies have been performed in paediatric patients.

4.6 Pregnancy and lactation Women of childbearing potential Women of childbearing potential have to use effective contraceptive measures during treatment (see section 4.4).

Pregnancy Hyperthyroidism in pregnant women should be adequately treated to prevent serious maternal and foetal complications. However, hypothyroidism caused by treatment with inappropriate thiamazole doses is also associated with a tendency to abortion. Thiamazole is able to cross the human placenta. Based on human experience from epidemiological studies and spontaneous reporting, thiamazole is suspected to cause congenital malformations when administered during pregnancy, particularly in the first trimester of pregnancy and at high doses. Reported malformations include aplasia cutis congenita, craniofacial malformations (choanal atresia; facial dysmorphism), exomphalos, oesophageal atresia, omphalo-mesenteric duct anomaly, and ventricular septal defect. Thiamazole must only be administered during pregnancy after a strict individual benefit/risk assessment and only at the lowest effective dose without additional administration of thyroid hormones. If thiamazole is used during pregnancy, close maternal, foetal and neonatal monitoring is recommended (see section 4.4). Breastfeeding

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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. Breast-feeding is possible during thiamazole treatment; however, only low doses up to 10 mg daily may be used without additional administration of thyroid hormones. The function of the thyroid gland of the neonate has to be monitored regularly.

4.7 Effects on ability to drive and use machines Thiamazole has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects Undesirable effects listed below are classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). The undesirable effects are dose-dependent. Blood and lymphatic system disorders

Very common (≥ 1/10) Granulocytopenia.

Common (≥1/100, to <1/10) Leukopenia.

Uncommon (≥ 1/1,000 to Agranulocytosis; please refer to <1/100) section 4.4. Thrombocytopaenia.

Rare (≥ 1/10,000 to <1/1,000) Aplastic anaemia, lymphadenopathy.

Very rare (<1/10,000) Pancytopenia.

Endocrine disorders

Not known Insulin autoimmune syndrome (with pronounced decline in blood glucose level).

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Nervous system disorders Rare (≥ 1/10,000 to <1/1,000) Disturbances in the sense of taste (dysgeusia, ageusia). Dizziness.

Very rare (<1/10,000) Neuritis, polyneuropathy.

Vascular disorders Very rare (<1/10,000) Vasculitis.

Gastrointestinal disorders Uncommon (≥ 1/1000 to <1/100) Nausea or vomiting, abdominal pain.

Rare (≥ 1/10,000 to <1/1,000) Sialoadenitis.

Not known Acute pancreatitis. Hepatobiliary disorders Uncommon (≥ 1/1,000 to Liver function abnormalities, <1/100) jaundice.

Rare (≥ 1/10,000 to <1/1,000) Hepatic necrosis.

Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10) Allergic skin reactions of varying degrees (pruritus, rash, urticaria).

Rare (≥1/10,000 to <1/1,000) Mucocutaneous syndrome

Musculoskeletal and connective tissue disorders

Common (≥1/100, to <1/10) Arthritis, arthralgia (particularly in the thumb)

Very rare (<1/10,000) Myalgia.

Renal and urinary disorders Rare (≥ 1/10,000 to <1/1,000) Nephritis.

General disorders and

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administration site conditions Common (≥1/100, to <1/10) Fever.

Rare (≥1/10,000 to <1/1,000) Drug fever.

Description of selected adverse reactions Disturbances in the sense of taste (dysgeusia, ageusia) can recede after discontinuation of therapy. A return to normal can take several weeks, however. Individual cases of cholestatic jaundice or toxic hepatitis have been described. The symptoms generally recede after discontinuation of the medicinal product. Clinically inconspicuous signs of cholestasis during treatment have to be differentiated from disturbances caused by hyperthyroidism, such as an increase in GGT (Gamma Glutamyl Transferase) and alkaline phosphatase or its bone specific isoenzyme. Allergic skin reactions of varying degrees (pruritus, rash, urticaria) mostly take a mild course and frequently recede during continued therapy. Arthritis and arthralgia (particularly in the thumb) may develop gradually and occur even after several months of therapy.

Reporting of suspected adverse reactions Reporting suspected adverse reaction after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reaction via the national reporting system list in Appendix V.

4.9 Overdose Symptoms: Myxoedema, agranulocytosis, potentially hypoglycaemia, hepatic effects can occur as a result of overdose. Overdose may also lead to hypothyroidism with corresponding symptoms of a reduced metabolism and, through the feedback effect, to activation of the adenohypophysis with subsequent goitre 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 section 4.2).

Management: Symptomatic treatment. Gastric emptying, charcoal and monitoring. Control of bone marrow and hepatic function.

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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anti-thyroid preparation, sulfur-containing imidazole derivative. ATC-Code: H03BB02 Thiamazole inhibits dose-dependently the incorporation of iodine into tyrosine and thereby the neo-synthesis 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), i.e. whether it suppresses the underlying immunopathogenitic 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 due to the release of hormones after destruction of thyroid cells, e.g. after radioiodine therapy or in thyroiditis, is also not affected.

5.2 Pharmacokinetic properties Absorption/distribution: Thiamazole is almost completely absorbed from the gastrointestinal tract. The bioavailability is 93%. The maximum plasma concentration is reached after 30 to 60 minutes. Initial effect occurs after approx. 8 hours. It is not bound to plasma proteins.

Biotransformation and elimination: The plasma half-life is 3 to 5 hours. The plasma half-life increases in the event of impaired hepatic and renal function. It is metabolised in the liver and eliminated through urine. Less than 12% of the ingested dose is excreted unchanged.

Thiamazole crosses the placenta and passes into breast milk.

5.3 Preclinical safety data Acute toxicity

The LD50 in mice is 860 mg / kg body weight when administered orally, while in rats it is 2,250 mg / kg body weight.

Chronic toxicity

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Chronic toxicity of thiamazole in rats is 2,627 mg / kg body weight, roughly equivalent to acute toxicity.

Mutagenesis and tumor-producing potential Mutagenicity studies of thiamazole are limited. The available data did not reveal any evidence of mutagenic effects. After long-term oral administration of high doses of thiamazole in rats a high incidence of thyroid tumours was observed. Respective effects in humans following thyrostatic therapy are not known.

Reproductive toxicity See sections 4.3 and 4.6.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Lactose Monohydrate Sodium Starch Glycolate Talc Magnesium Stearate

6.2 Incompatibilities Not applicable.

6.3 Shelf life 5 years.

6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Store in the blister in the carton box in order to protect from light.

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6.5 Nature and contents of container The tablets are packaged in transparent PVC/Aluminum blisters. Pack sizes: 100, 105 or 125 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER []

8 MARKETING AUTHORISATION NUMBER(S) []

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: dd/mm/yyyy

10 DATE OF REVISION OF THE TEXT

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