1. NAME OF THE MEDICINAL PRODUCT

Carbimazole Orifarm 5 mg, 10 mg, 15 mg and 20 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Carbimazole Orifarm 5 mg Each tablet contains 5 mg carbimazole.

Excipient with known effect: Lactose monohydrate 48.6 mg (see section 4.4).

Carbimazole Orifarm 10 mg Each tablet contains 10 mg carbimazole.

Excipient with known effect: Lactose monohydrate 97.2 mg (see section 4.4).

Carbimazole Orifarm 15 mg Each tablet contains 15 mg carbimazole.

Excipient with known effect: Lactose monohydrate 145.8 mg (see section 4.4).

Carbimazole Orifarm 20 mg Each tablet contains 20 mg carbimazole.

Excipient with known effect: Lactose monohydrate 194.4 mg (see section 4.4).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablets

Carbimazole Orifarm 5 mg Pink, mottled, round, biconvex uncoated tablets, debossed with "5" on one side and plain on the other side. Diameter 5 mm.

Carbimazole Orifarm 10 mg Pink, mottled, round, biconvex uncoated tablets, debossed with "10" on one side and plain on the other side. Diameter 6.5 mm.

Carbimazole Orifarm 15 mg Pink, mottled, round, biconvex uncoated tablets, debossed with "15" on one side and plain on the other side. Diameter 7.4 mm.

Carbimazole Orifarm 20 mg Pink, mottled, round, biconvex uncoated tablets, debossed with "2 and 0" separated by a score line on one side and plain on the other side. Diameter 8 mm. The 20 mg tablet can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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Long-term treatment of thyrotoxicosis, Basedow's disease (Graves' disease), especially cases with minor, diffuse goitre or without goitre. Therapy prior to radio-iodine treatment or preparation for thyroidectomy.

4.2 Posology and method of administration

The dosage is individual and dependent on the severity of the disease.

Carbimazole Orifarm should only be administered if hyperthyroidism has been confirmed by laboratory tests.

Posology

Adults Severe cases: The initial dose is in the range 20-60 mg (depending on the severity of hyperthyroidism), taken as 2-3 divided doses. The patient should be monitored clinically and the dose should be titrated against thyroid function until the patient is euthyroid in order to reduce the risk of over-treatment and resultant hypothyroidism.

Mild cases: Initially 20 mg daily.

Maintenance regimen: Following normalization of serum thyroxine treatment should be continued, but gradually reduced in steps of 5-20 mg daily, every 10 day until daily dose is 5-20 mg. Therapy should be continued for at least 6 months and up to 18 months with simultaneous control of serum thyroxine.

Maintenance dose should be determined according to clinical criteria and laboratory parameters.

In some cases, very large doses are required initially, e.g. 120 mg daily. This especially applies to very large goitre and if the patient has received iodine treatment.

Serial thyroid function monitoring is recommended, together with appropriate dosage modification in order to maintain an euthyroid state.

Blocking-replacement regimen: The treatment is initiated with carbimazole followed by concomitant L-thyroxine administration, in order to prevent hypothyroidism. Therapy should be continued for at least 6 months and up to 18 months.

Note that blocking-replacement therapy should not be used during pregnancy (see section 4.6).

Special populations

Elderly No special dosage regimen is required, but care should be taken to observe the contraindications and warnings as it has been reported that the risk of a fatal outcome to neutrophil dyscrasia may be greater in the elderly (aged 65 and over).

Paediatric population Use in children and adolescents (3-17 years of age) The dose of carbimazole ranges from 0.2-0.5 mg/kg body weight per day divided into 2 doses and is adjusted based on the circulating levels of T4 and T3.

For maintenance therapy, the daily dose can be reduced depending on the response of the patient to the treatment. Additional treatment with levothyroxine may be required to avoid hypothyroidism.

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5 mg tablets: The tablets are not suitable for children with a body weight below 20 kg. For children weighing 20-50 kg, the suitability of the 5 mg tablet depends of the dosage needed.

10 mg, 15 mg and 20 mg tablets: The tablets are not suitable for the small children.

The maximum recommended dose of carbimazole is 30 mg/day.

Use in children (2 years of age and under) Safety and efficacy of carbimazole in children below 2 years of age have not been evaluated systematically. Use of carbimazole in children below 2 years of age is not recommended.

Patients with mild to moderate hepatic impairment Patients with hepatic impairment, see section 4.4.

Method of administration Oral use.

4.3 Contraindications

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Serious, pre-existing haematological conditions (granulocytopenia).  Severe hepatic insufficiency.  Breast-feeding (see section 4.6).  Patients with a history of acute pancreatitis after administration of carbimazole or its active metabolite thiamazole.

4.4 Special warnings and precautions for use

Treatment with carbimazole is associated with a risk of inhibiting hematopoiesis (leucopenia, granulocytopenia, agranulocytosis, pancytopenia/aplastic anaemia, haemolytic anaemia, thrombocytopenia) and of liver damage. Agranulocytosis or aplastic anaemia may develop within a short period of time, from a few hours to a few days (see section 4.8).

Fatalities with carbimazole-induced agranulocytosis have been reported. As early treatment of agranulocytosis is essential, it is important that patients should always be warned about the onset of sore throats, bruising or bleeding, mouth ulcers, fever or malaise and should be instructed to stop the drug 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.

Considering the risk of agranulocytosis, particular following doses of over 40 mg/day and in patients aged over 40 and within the first two months of treatment, the blood picture should be closely monitored before and after initiation of treatment, especially in the case of existing mild granulocytopenia. Following the onset of agranulocytosis, aplastic anaemia (pancytopenia) or severe hepatic impairment, treatment should be discontinued immediately and appropriate treatment initiated if necessary. Patients treated with this medicine should be instructed to seek medical advice as soon as possible if fever, pharyngitis, stomatitis, furunculosis or any other infection occurs. Following the onset of any signs and symptoms of hepatic disorder (pain in the upper abdomen, anorexia, general pruritus) in patients, the drug should be stopped and liver function tests performed immediately.

Early withdrawal of the drug will increase the chance of complete recovery.

Carbimazole should be used with caution in patients with iodine level imbalance.

Carbimazole should be used with caution in patients with mild-moderate hepatic insufficiency. Carbimazole can cause liver disease. If abnormal liver function is discovered, the treatment should be stopped. The half- life may be prolonged due to liver disorder.

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Carbimazole should be stopped temporarily if radio-iodine is administered.

Should the volume of the goitre increase, the dose of carbimazole should not be increased, since growth in volume is more likely to occur following overdosing of the preparation.

As carbimazole can cause hypoprothrombinemia and clinical bleeding, thromboplastin time monitoring is recommended during treatment and especially prior to any surgery.

Patients unable to comply with the instructions for use or who cannot be monitored regularly should not be treated with carbimazole.

Regular full blood count checks should be carried out in patients who may be confused or have a poor memory.

Control of serum thyroxine is necessary. Precaution should be taken in patients with intrathoracic goitre, which may worsen during initial treatment with carbimazole. Tracheal obstruction may occur due to intrathoracic goitre.

Patients experiencing myalgia after the intake of carbimazole should have their creatine phosphokinase levels monitored.

Women of childbearing potential have to use effective contraceptive measures during treatment. The use of carbimazole in pregnant women must be based on the individual benefit/risk assessment. If carbimazole 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 is risk of cross-allergy between carbimazole, thiamazole (methimazole) and propylthiouracil.

There have been post-marketing reports of acute pancreatitis in patients receiving carbimazole or its active metabolite thiamazole. In case of acute pancreatitis, carbimazole should be discontinued immediately. Carbimazole 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.

Carbimazole Orifarm contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The effect of carbimazole is significantly reduced if the patient has undergone iodine treatment. Particular care is required in case of concurrent administration of medication capable of inducing agranulocytosis.

Since carbimazole is a vitamin K antagonist, the effect of anticoagulants could be intensified. Since thyroid hormones can alter the amount of vitamin K-dependent clotting factors and thus the extent of inhibition by oral anticoagulants, careful control of anticoagulant dosage is required as hyperthyroid patients are rendered euthyroid; additional monitoring of 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 medications without reducing the theophylline dosage.

Co-administration of prednisolone and carbimazole may result in increased clearance of prednisolone.

Carbimazole may inhibit the metabolism of erythromycin, leading to reduced clearance of erythromycin.

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Iodine deficiency will increase the response to carbimazole while an excess of iodine will attenuate it.

Serum digitalis levels may be increased when hyperthyroid patients become euthyroid. A reduced dosage of digitalis glycosides 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.

Paediatric population Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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

Pregnancy Carbimazole should only be used if clearly indicated during pregnancy, if the benefit outweighs the possible risk for the foetus.

Hyperthyroidism in pregnant women should be adequately treated to prevent serious maternal and foetal complications.

Carbimazole is able to cross the human placenta.

Based on human experience from epidemiological studies and spontaneous reporting, carbimazole 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.

Carbimazole 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 carbimazole is used during pregnancy, close maternal, foetal and neonatal monitoring is recommended (see section 4.4).

Methimazole, a metabolite of carbimazole, crosses the placenta and presents a risk of developing goitre, cretinism and other congenital malformations in the foetus. Studies have shown that the incidence of congenital malformations is greater in the children of mothers whose hyperthyroidism has remained untreated than in those who have been treated with carbimazole or the active metabolite during pregnancy. If the mother's carbimazole dose is within the standard range, and her thyroid status is monitored closely, there is a lower risk of developing neonatal thyroid abnormalities (see section 4.4). However, very rare cases of congenital malformations have been observed in newborns following the exposure of carbimazole or its active metabolite methimazole during pregnancy.

A causal relationship of these malformations to transplacental exposure to carbimazole and its metabolites cannot be excluded. Cases of renal, skull, cardiovascular and congenital defects, such as choanal atresia, aplasia cutis congenital, exomphalos, gastrointestinal malformation, umbilical malformation and duodenal atresia have also been reported. Therefore, carbimazole should be used in pregnancy only when propylthiouracil is not suitable.

If carbimazole is used in pregnancy the dose must be regulated by the patient’s clinical condition.

The thyroid gland of the foetus does not start to develop until week 11 of pregnancy and only becomes functional around week 18. The lowest dose possible should be used, and this can often be discontinued 3-4

5 weeks before term, in order to reduce the risk of neonatal complications (such as hypothyroidism in the foetus) precisely at a time when the brain of the foetus will be growing most.

The blocking-replacement regimen should not be used during pregnancy.

If a pregnant woman takes carbimazole or a female patient becomes pregnant during treatment, they must be informed of the possible risks for the unborn child. If antithyroid treatment with carbimazole of a pregnant women is nessecary, treatment should be continued at the lowest effective dose necessary to achieve a normal thyroid function for the mother, but without causing hypothyroidism of the foetus. In such cases, particularly careful monitoring is required in weeks 10-14 of pregnancy due to the fact that the foetus will start to produce the hormone in this period. Treatment with carbimazole should however be discontinued before the expected term due to the risk of hypothyroidism in the foetus when the brain of the foetus will be growing most. The possibility of replacing carbimazole with propylthiouracil should be taken into consideration.

Breast-feeding If treatment with carbimazole is necessary, breast-feeding should be ceased. Carbimazole is secreted in breast milk and can cause serious adverse reactions in the newborn. Switch to treatment with propylthiouracil should be taken into consideration if appropriate, since this passes into breast milk about ten times less freely than does thiamazole.

Fertility No special recommendations.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Adverse reactions usually occur in the first 8 weeks of treatment. The most frequently occurring mild reactions are fever, nausea, headache, arthralgia (especially in the joint of the thumb), mild dyspepsia, skin rashes and pruritus. Occasionally alopecia has been reported. These reactions are usually self-limiting and may not require withdrawal of the drug.

Paediatric population Frequency, type and severity of adverse reactions in children appear to be comparable with those in adults.

Adverse reactions are classified according to MedDRA system organ class and sorted by frequency, with the most frequent first using 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) or not known (cannot be estimated from the available data).

The following adverse reactions have been observed:

Blood and lymphatic system disorders Uncommon Bone marrow depression1, neutropenia1, eosinophilia1, leucopenia1, agranulocytosis1, pancytopenia/aplastic anaemia, haemolytic anaemia

Rare Blood disorders

Immune system disorders Not known

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Angioedema and skin reactions2, vasculitis, allergic dermatitis, generalised exfoliative dermatitis3, Stevens-Johnson syndrome3

Endocrine disorders Not known Goitre, hypothyroidism, insulin autoimmune syndrome, hypoglycemic coma

Nervous system disorders Common Headache, dizziness, paraesthesia, neuritis, polyneuropathy

Eye disorders Not known Exophthalmos

Gastrointestinal disorders Common Nausea, mild dyspepsia, abdominal pain

Uncommon Loss of sense of taste

Rare Sialoadenitis

Not known Mouth ulcers, vomiting, stomatitis, oropharyngeal pain, acute pancreatitis

Hepatobiliary disorders Not known Hepatobiliary disorders4, hepatitis, jaundice, cholestatic hepatitis, cholestatic jaundice, hepatic disorders including glomerulonephritis

Skin and subcutaneous tissue disorders Common Skin rashes, pruritus, urticaria

Uncommon Alopecia

Musculoskeletal and connective tissue disorders Common Arthralgia (especially in the joint of the thumb)

Very rare Myopathy

Not known Myalgia5, muscle diseases

General disorders and administration site conditions Not known Fever, malaise, fatigue

Investigations Not known Liver function test abnormal, creatine phosphokinase levels abnormal

1Patients should always be warned about the onset of sore throats, bruising or bleeding, mouth ulcers, fever, and malaise and should be instructed to stop the drug and to seek medical advice immediately. In such patients, white blood cell counts should be performed, particularly where there is any clinical evidence of infection. Agranulocytosis and thrombocytopenia may in some cases be fatal.

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2Severe cutaneous hypersensitivity reactions (skin reactions) have been reported in both adult and paediatric patients.

3Generalised exfoliative dermatitis and Stevens-Johnson syndrome have only been described in isolated cases.

4In case of jaundice, liver disease and cholestatic hepatitis, carbimazole should be withdrawn.

5Patients experiencing myalgia after the intake of carbimazole should have their creatine phosphokinase levels monitored to adjust the dose.

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

4.9 Overdose

Overdose may lead to hypothyroidism with similar symptoms of decreased metabolism and via the feedback effect, activation of adenohypophysis and consequently goitre enlargement. This can be prevented by dose reduction as soon as an euthyroid state is reached and, if necessary, with further administration of levothyroxine.

In case of manifest overdosing, the treatment must be discontinued and, if necessary, the symptoms treated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sulfur-containing imidazole derivatives, ATC code: H03BB01.

Mechanism of action Carbimazole, a thionamide, is a pro-drug which undergoes rapid and virtually complete metabolism to the active metabolite, thiamazole, also known as methimazole. The method of action is believed to be inhibition of the organification of iodide and the coupling of iodothyronine residues which in turn suppress the synthesis of thyroid hormones.

Alongside this effect, typical of all synthetic antithyroid agents, carbimazole also has another particular property: It blocks the enzyme dehalogenase, which enables recovery of any organic iodine that has not been distributed. Intrathyroid iodine is thus gradually eliminated, leading to iodine activity in the thyroid gland. This means that it is always possible to replace radio-iodine treatment with carbimazole.

5.2 Pharmacokinetic properties

Absorption Carbimazole is rapidly metabolised to methimazole. The mean peak plasma concentration of methimazole is reported to occur 1 hour after a single dose of carbimazole. The apparent plasma half-life of methimazole is reported as 6.4 hours.

After oral ingestion, about 90-100% of orally administred carbimazole is rapidly absorbed in the intestine and rapidly transformed to its active metabolite thiamazole in the blood by hydrolysis and enzymatic decarboxylation. The pharmacokinetic data therefore refers to this metabolite.

Peak plasma concentrations of thiamazole, 0.2-1.0 μg/l are reached within 1-2 hours following administration of a dose of 60 mg while the active moity occurs after 1-2 hours.

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Distribution The total volume of distribution of thiamazole is 0.5 l/kg and it binds with plasma proteins up to 40%. Thiamazole is concentrated in the thyroid gland following administration. This intrathyroidal concentration of thiamazole has the effect of prolonging the activity of carbimazole. However, thiamazole has a shorter half-life in hyperthyroid patients than in normal controls and so more frequent initial doses are required while the hyperthyroidism is active.

Biotransformation Thiamazole is moderately bound to plasma proteins. It undergoes oxidative decomposition in the liver and in the thyroid gland. There is 10% enterohepatic circulation.

Elimination Carbimazole has a half-life of 5.3-5.4 hours. It is possible that the plasma half-life may also be prolonged by renal or hepatic disease (see section 4.2). Thiamazole crosses the placenta and appears in breast milk (see section 4.6). The plasma:milk ratio approaches 1.

The retention time of thiamazole in the thyroid gland is approximately 20 hours which corresponds to the duration of the effect of a single dose. Over 90% of orally administered carbimazole is excreted in the urine as thiamazole or its metabolites. The remainder appears in faeces. Approximately 7% of methimazole is excreted unchanged.

5.3 Preclinical safety data

No significant preclinical data are available regarding the use of carbimazole.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Ferric oxide red (E172) Croscarmellose sodium Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

Container: After first opening the polyester filling should be discarded.

6.5 Nature and contents of container

Container (HDPE) with child resistant closure (PP), aluminum seal and polyester filling: 100 tablets.

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6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

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