Thimatrin 5 mg Tablet

THIMATRIN is indicated in the management of hyperthyroidism, thyrotoxicosis (including thyroid storm), and also for the preparation of patients for thyroidectomy. THIMATRIN can also be used for therapy prior to and post radio-active ablative therapy.

Posology
THIMATRIN should only be administered if hyperthyroidism has been confirmed by laboratory tests. 10 mg to 60 mg daily according to the severity of the disorder. The dose should be gradually reduced to the smallest amount which will control the disease. Daily dosage should be divided and titrated against thyroid function until the patient is euthyroid in order to reduce the risk of over-treatment and resultant hypothyroidism. Serial thyroid function monitoring is recommended, together with appropriate dosage modification in order to maintain a euthyroid state.

Method of administration
For oral use.

• Hypersensitivity to carbimazole, other thiourea antithyroid medicines, or to any of the excipients (see section 6.1).
• Serious, pre-existing haematological conditions.
• Severe hepatic insufficiency.
• Patients with a history of acute pancreatitis after administration of carbimazole or its active metabolite thiamazole.
• Tracheal obstruction.

Bone marrow depression including neutropenia, eosinophilia, leucopenia and agranulocytosis has been reported. Fatalities with carbimazole-induced agranulocytosis have been reported. Cases of pancytopenia/aplastic anaemia and isolated thrombocytopenia have also been reported. Additionally, cases of haemolytic anaemia have been reported. Patients should always be warned about the onset of sore throats, bruising or bleeding, mouth ulcers, fever and malaise and should be instructed to stop THIMATRIN and to seek medical advice immediately. In such patients, white blood cell counts should be performed immediately, particularly where there is any clinical evidence of infection.

There have been post-marketing reports of acute pancreatitis in patients receiving carbimazole or its active metabolite thiamazole. In case of acute pancreatitis, THIMATRIN should be discontinued immediately. THIMATRIN must not be given to patients with a history of acute pancreatitis after administration of carbimazole or its active metabolite thiamazole. Re-exposure may result in recurrence of acute pancreatitis, with decreased time to onset.

Following the onset of any signs and symptoms of hepatic disorder (pain in the upper abdomen, anorexia, general pruritus) in patients, THIMATRIN should be stopped and liver function tests performed immediately. Early withdrawal of THIMATRIN will increase the chance of complete recovery. THIMATRIN should be used with caution in patients with mild-moderate hepatic insufficiency. If abnormal liver function is discovered, the treatment should be stopped. The half-life may be prolonged due to the liver disorder.

THIMATRIN should be stopped temporarily at the time of administration of radio-iodine (to avoid thyroid crisis). Patients unable to comply with the instructions for use or who cannot be monitored regularly should not be treated with THIMATRIN. Regular full blood count checks should be carried out in patients who may be confused or have a poor memory.

Precaution should be taken in patients with intrathoracic goitre, which may worsen during initial treatment with THIMATRIN. Tracheal obstruction may occur due to intrathoracic goitre. There is a risk of cross-allergy between carbimazole, the active metabolite thiamazole (methimazole) and propylthiouracil.

Women of childbearing potential and pregnancy
Women of childbearing potential have to use effective contraceptive measures during treatment. If THIMATRIN 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).

Lactose
THIMATRIN contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency, glucose-galactose malabsorption should not take THIMATRIN.

Particular care is required in case of concurrent administration of medicine capable of inducing agranulocytosis. Since THIMATRIN is a vitamin K antagonist, the effect of anticoagulants could be intensified. Additional monitoring of prothrombin time/international normalised ratio (PT/INR) should be considered, especially before surgical procedures. The serum levels of theophylline can increase and toxicity may develop if hyperthyroidic patients are treated with antithyroid medicines without reducing the theophylline dosage.

Co-administration of prednisolone and THIMATRIN may result in increased clearance of prednisolone. THIMATRIN may inhibit the metabolism of erythromycin, leading to reduced clearance of erythromycin. Serum digoxin levels may be increased when hyperthyroid patients on a stable digoxin regimen become euthyroid; a reduced dosage of digoxin may be needed. Hyperthyroidism may cause an increased clearance of beta-adrenergic blockers with a high extraction ratio. A dose reduction of beta blockers may be needed when a hyperthyroid patient becomes euthyroid.

Laboratory value alterations
With diagnostic test results: THIMATRIN may decrease thyroidal uptake of sodium iodide I 123 or I 131, or pertechnetate, withdrawal of THIMATRIN 5 days or more before radioactive iodine uptake tests is necessary to prevent interference. With physiology laboratory test values: Alanine aminotransferase (ALT [SGPT]) serum concentrations, alkaline phosphatase serum concentrations, aspartate aminotransferase (AST [SGOT]) serum concentrations, bilirubin serum concentrations, lactate dehydrogenase (LDH) serum concentrations and prothrombin time (PT) may be increased, and may indicate hepatoxicity and be associated with splenomegaly.

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

Pregnancy
Safety in pregnancy and lactation has not been established. THIMATRIN may cause foetal or neonatal hypothyroidism and goitre. THIMATRIN crosses the placenta but, provided the mother's dose is within the standard range, and her thyroid status is monitored; there is no evidence of neonatal thyroid abnormalities. Cases of congenital malformations have been observed following the use of THIMATRIN or its active metabolite methimazole during pregnancy. A causal relationship of these malformations, especially choanal atresia and aplasia cutis congenital, to transplacental exposure to THIMATRIN and methimazole cannot be excluded. Therefore, the use of THIMATRIN in non-pregnant women of childbearing potential should be based on individual risk/benefit assessment. Cases of renal, skull, cardiovascular congenital defects, exomphalos, gastrointestinal malformation, umbilical malformation and duodenal atresia have also been reported.

Lactation
THIMATRIN is excreted in milk and if treatment is continued during lactation the patient should not continue to breastfeed her baby.

The effect on the ability to drive and use machines is not known.

a. Summary of the safety profile
Adverse reactions usually occur in the first eight weeks of treatment. The most frequent minor reactions are nausea, headache, arthralgia, mild gastrointestinal disturbance, skin rashes and pruritus. These reactions are usually self-limiting and may not require withdrawal of the medicine.

b. Tabulated summary of adverse reactions
The undesirable effects are listed below by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness

MedDRA system organ class Frequency Adverse reactions
Blood and lymphatic system disorders Less frequent Bone-marrow depression including neutropenia, eosinophilia, leukopenia. Fatalities with carbimazole-induced, agranulocytosis have been reported (see section 4.4).
Frequency unknown Pancytopenia/aplastic anaemia, thrombocytopaenia, haemolytic anaemia
Immune system disorders Less frequent Angioedema, multi-system hypersensitivity reactions such as cutaneous vasculitis, liver, lung and renal effects
Endocrine disorders Frequency unknown Insulin autoimmune syndrome (with pronounced decline in blood glucose level)
Nervous system disorders Frequent Headache
Frequency unknown Paraesthesias, neuritis, polyneuropathy
Vascular disorders Frequency unknown Vassculitis, bleeding
Gastrointestinal disorders Frequent Gastrointestinal disturbances (including nausea, vomiting and gastric discomfort)
Frequency unknown Taste disturbances, acute salivary gland swelling, acute pancreatitis
Hepato-biliary disorders Less frequent Jaundice, abnormal liver function tests, hepatitis, cholestatic jaundice; in these cases of hepatic disorder THIMATRIN should be withdrawn and not re-introduced.
Skin and subcutaneous tissue disorders Frequent Rash, pruritus, skin pigmentation, urticaria
Less frequent Severe cutaneous hypersensitivity reactions, including Stevens-Johnson syndrome (very rare including isolated reports: severe forms, including generalised dermatitis, have only been described in isolated cases).
Frequency unknown Abnormal hair loss
Musculoskeletal and connective tissue disorders Less frequent Myopathy, arthralgia. Patient experiencing myalgia after the intake of THIMATRIN should have their creatine phosphokinase levels monitored.
Frequency unknown Lupus-like syndrome
Renal and urinary disorders Frequency unknown Nephritis
General disorders and administration site conditions Frequency unknown Fever, malaise
Injury, poisoning and procedural complications Frequency unknown Bruising
Paediatric population Frequency, type and severity of adverse reactions in children appear to be comparable with those in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Signs and symptoms
Overdosage or accidental poisoning may result in hypothyroidism and goitre. If blood dyscrasias occur, the medicine should be withdrawn immediately.

Management of overdose
Treatment is symptomatic and supportive.