NeoMercazole^® is an anti-thyroid agent. It is indicated in adults and children in all conditions where reduction of thyroid function is required.

Such conditions are:

·         Hyperthyroidism.

·         Preparation for thyroidectomy in hyperthyroidism.

·         Therapy prior to and post radio-iodine treatment.

Posology

NeoMercazole^® should only be administered if hyperthyroidism has been confirmed by laboratory tests.

 

Adults:

The initial dose is in the range 20 mg to 60 mg (four to twelve 5 mg tablets), per day taken as two to three divided doses. The regular checking of thyroid function is recommended and dose should be titrated against thyroid function until the patient is euthyroid in order to reduce the risk of over-treatment and resultant hypothyroidism.

 

Subsequent therapy may then be administered in one of two ways.

 

 

Maintenance regimen:

Final dosage is usually in the range 5 mg to 15 mg (one to three 5 mg tablets) per day, which may be taken as a single daily dose, preferably with meals. Therapy should be continued for at least six months and up to 18 months. Serial thyroid function monitoring is recommended, together with appropriate dosage modification in order to maintain a euthyroid state.

 

Blocking-replacement regimen:

Dosage is maintained at the initial level, i.e. 20 mg to 60 mg (four to twelve tablets of 5 mg tablets) per day, and supplemental L-thyroxine, 50 microgram to 150 microgram per day, is administered concomitantly, in order to prevent hypothyroidism. Therapy should be continued for at least six months and up to eighteen months. Where a single dosage of less than 20 mg is recommended, it is intended that carbimazole 5 mg tablets should be taken.

 

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 (e.g. neutropenia) may be greater in the elderly (aged 65 or over).

 

Paediatric population

Use in children and adolescents (3 to 17 years of age)

The usual initial daily dose is 15 mg per day adjusted according to response.

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 therefore not recommended.

 

Route of administration

For oral administration only.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Serious, pre-existing haematological conditions. Severe hepatic insufficiency • NeoMercazole® tablets are contraindicated in patients with a previous history of adverse reactions to carbimazole, thiamazole or to any of the excipients listed in section 6.1. • Breast feeding (see section 4.6). • Patients with a history of acute pancreatitis after administration of carbimazole or its active metabolite thiamazole.

·                     Bone marrow depression including neutropenia, eosinophilia, leucopenia and agranulocytosis has been reported. As fatal cases of agranulocytosis with carbimazole have been reported and 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, 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.

·                     Rare cases of pancytopenia/aplastic anaemia, isolated thrombocytopenia and very rare cases of haemolytic anaemia have been reported (see section 4.8).

·                     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.

·                     NeoMercazole^® tablets 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.

·                     NeoMercazole^® 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 NeoMercazole.

·                     Regular full blood count checks should be carried out in patients who may be confused or have a poor memory. Special precaution is recommended in the case of concurrent administration of medicinal products capable of inducing agranulocytosis.

·                     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

·                     Precaution should be taken in patients with intrathoracic goiter, which may worsen during initial treatment with NeoMercazole^®. Tracheal obstruction may occur due to intrathoracic goiter.

·                     Should the volume of the goiter increase, the dose of NeoMercazole^® should not be increased, since growth in volume is more likely to occur following overdosing of the preparation.

·                     The use of carbimazole in non-pregnant women of childbearing potential should be based on individual risk/benefit assessment (see section 4.6).

·                     There is a risk of cross-allergy between carbimazole, the active metabolite thiamazole (methimazole) and propylthiouracil.

·                     Not to be administered if hyperthyroidism has not been confirmed by laboratory tests.

·                     Since carbimazole is a vitamin K antagonist, the effect of anticoagulants could be intensified. An accurate control with regards to the anticoagulant dosage is required as hyperthyroid patients receiving treatment with carbimazole become euthyroid; additional monitoring of prothrombin time/international normalised ratio (PT/INR) should be considered, especially before surgical procedures. Carbimazole administration may itself, rarely, result in hypoprothrombinaemia, which may increase the risk of haemorrhagic events.

·         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).

 

NeoMercazole^® contains lactose

NeoMercazole^® contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Little is known about interactions.

Interaction studies have not been performed in paediatric patients.

 

Particular care is required in case of concurrent administration of medication capable of inducing agranulocytosis.

 

It is difficult to distinguish between the effect of corrected hyperthyroidism and the specific effects of synthetic antithyroid drugs.

 

Anticoagulants:

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 receiving treatment with carbimazole are rendered euthyroid; additional monitoring of PT/INR should be considered, especially before surgical procedures. Carbimazole administration can itself, rarely, result in hypoprothrombinaemia, which may increase the risk of haemorrhagic events.

 

Theophylline:

The serum levels of theophylline can increase and toxicity may develop if hyperthyroidic patients are treated with antithyroid medications without reducing the theophylline dosage.

 

Iodine deficiency:

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

 

Prednisolone:

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

 

Erythromycin:

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

 

Digitalis:

Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.

 

Beta-blockers:

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.

 

Interference with serological testing:

Hypoprothrombinemia and bleeding may be caused hence, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures.

 

Paediatric population:

Interaction studies have only been performed in adults.

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. Carbimazole is able to cross the human placenta.

 

Carbimazole and its active metabolite cross the placenta and may cause foetal hypothyroidism and thyroid hyperplasia. 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.

 

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).

 

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.

 

However, cases of congenital malformations have been observed following the use of

carbimazole or its active metabolite methimazole during pregnancy.

 

Transient thyroid function abnormalities have been reported in newborns born to mothers treated with carbimazole during pregnancy.

 

In humans, the foetal thyroid gland begins to trap iodine 10-12 weeks after conception.

 

However, cases of congenital malformations such as circumscribed aplasia of the scalp, choanal atresia, oesophageal atresia have been observed following the use of carbimazole or its active metabolite methimazole during pregnancy.

 

A causal relationship of these malformations, especially choanal atresia and aplasia cutis congenita (congenital scalp defects), to transplacental exposure to carbimazole and methimazole cannot be excluded.

 

Therefore, the use of NeoMercazole^® in non-pregnant women of childbearing potential should be based on individual risk/benefit assessment (see section 4.4).

 

Cases of renal, skull, cardiovascular congenital defects, 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 NeoMercazole^® is used in pregnancy the dose of NeoMercazole^® must be regulated by the patient's clinical condition. The lowest dose possible should be used, and this can often be discontinued three to four weeks before term, in order to reduce

the risk of neonatal complications.

 

If a pregnant woman takes NeoMercazole^® or a female patient becomes pregnant during treatment, they must be informed of the possible risks for the unborn child. If NeoMercazole^® is used in pregnancy, the dose must be regulated by the patient's clinical condition. The lowest dose possible should be used, and this can often be discontinued three or four weeks before term, in order to reduce the risk of neonatal complications.

·                     The posologies will need to be adjusted to obtain normal thyroid function or mild maternal hyperthyroidism in order to limit the risk of foetal hypothyroidism. Maternal supplementation with L-thyroxine might prove ineffective for the foetus because it barely crosses the placenta.

·                     A prenatal exam (ultrasound) should be considered in order to detect some of the above-cited malformations and to monitor the foetal thyroid gland.

·                     A neonatal thyroid function test should be performed.

 

The blocking-replacement regimen should not be used during pregnancy since very little thyroxine crosses the placenta in the last trimester.

 

Breast-feeding

Carbimazole is excreted in milk, due to the risk of neonatal hypothyroidism, breast-feeding is contraindicated and if treatment is continued during lactation the patient should not continue to breast-feed her baby. In the use of high doses there is a risk of hypothyroidism, as well as agranulocytosis in the infant.

 

If appropriate, switching to treatment with propylthiouracil should be considered, since the latter passes into breast milk about ten times less freely than does thiamazole.

 

Fertility

No special recommendations.

No studies on the effects on the ability to drive and use machines have been performed.

Adverse reactions generally usually occur in the first eight weeks of treatment. The most frequently occurring reactions are nausea, headache, arthralgia (especially in the joint of the thumb), mild gastrointestinal disorder, rash, pruritus and urticaria. These reactions are generally self-limiting and do not require withdrawal of the drug.

Unless otherwise stated, the frequency of undesirable effects is unknown.

 

Paediatric population

Frequency, type and severity of adverse reactions in children appear to be comparable

with those in adults.

 

Infections and infestations

Furuncle, sialoadenitis

 

Blood and lymphatic system disorders

Bone marrow failure including neutropenia, eosinophilia, leukopenia and agranulocytosis has been reported. Fatalities with carbimazole-induced agranulocytosis have been reported (see section 4.4).

 

Rare cases of hypoprothrombinaemia, pancytopenia/aplastic anaemia and isolated thrombocytopenia have also been reported. Additionally, lymphadenopathy and very rare cases of haemolytic anaemia have been reported (see section 4.4).

 

The occasional and usually sudden onset (in 0.5 to 1% of cases) of bone-marrow aplasia.

 

Patients should always be warned about the onset of oropharyngeal pain, contusion or haemorrhage, mouth ulceration, pyrexia, discomfort 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 immediately particularly where there is any clinical evidence of infection.

 

Generalised lymphadenopathy.

 

Immune system disorders

Angioedema and multi-system hypersensitivity reactions such as cutaneous vasculitis, hepatic, pulmonary and renal effects may occur.

 

Endocrine disorders

Insulin autoimmune syndrome (with pronounced decline in blood glucose level) may develop and could even lead to shock hypoglycaemic.

Hypothyroidism and worsening of goiter.

 

An increase in volume of the goiter may occur, in a manner similar to hypothyroidism following overdosage, worsening of goiter.

 

Nervous system disorders

Nervous system disorder, headache, neuritis, polyneuropathy, ageusia (rare cases), dizziness and paraesthesia.

 

Eye disorders

Exophthalmos.

 

Vascular disorders

Haemorrhage.

 

Gastrointestinal disorders

Stomatitis, nausea, moderate gastrointestinal disorder, abdominal pain and abdominal pain upper, Loss of sense of taste has been observed, acute salivary gland swelling.

 

Hepatobiliary disorders

Liver disorders, including, hepatitis, hepatitis cholestatic (rare cases), jaundice cholestatic, hepatic necrosis (rare cases) and most commonly jaundice have been reported; in these cases NeoMercazole^® tablets should be withdrawn. Jaundice may persist for several weeks after discontinuation of the treatment

 

Skin and subcutaneous tissue disorders

Rash, pruritus, urticaria have been reported commonly, alopecia has been occasionally reported. Pigmentation disorder, dermatitis and erythema may occur.

 

Severe dermatitis allergic reactions have been reported in both adult and paediatric patients, including Stevens-Johnson syndrome (very rare including isolated reports: severe forms, including generalised dermatitis, have only been described in isolated cases).

 

Musculoskeletal and connective tissue disorders

Arthralgia (especially in the joint of the thumb), isolated cases of myopathy and muscle disease have been reported. Patients experiencing myalgia after the intake of NeoMercazole^® tablets should have their creatine phosphokinase levels monitored.

 

General disorders and administration site conditions

Pyrexia, malaise and fatigue.

 

Investigations

Liver function test abnormal.

 

Injury, poisoning and procedural complications

Contusion.

 

Gastro-intestinal system disorders

Not known: Acute pancreatitis

 

-To reports any side effect(s):

 

o   The National Pharmacovigilance and Drug Safety Centre (NPC)

o   Fax: +966-11-205-7662

o   Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o   SFDA Call Center: 19999

o   E-mail: npc.drug@sfda.gov.sa

o   ebsite: http://ade.sfda.gov.sa

 

• Other GCC States: Please contact the relevant competent authority.

Symptoms

Normally no symptoms are likely from a single large dose. Onset of hypothyroidism with elevated TSH and increased goiter volume, as well as increasing the risk of agranulocytosis may occur.

 

Treatment

No specific treatment is indicated. In case of manifest overdosing, the treatment must be discontinued and, if necessary, the symptoms treated.

 

Forced diuresis, haemodialysis, peritoneal dialysis and haemoperfusion have not been found effective in the treatment of overdoses of carbimazole.

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Sulfur-containing imidazole derivatives (antithyroid preparation)

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, which has a prolonged antithyroid effect. 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.

 

Since carbimazole inhibits the action of thyroid peroxidase, it prevents the oxidation of iodides and their uptake by the tyrosyl radicals of thyroglobulin as well as the coupling of iodotyrosines with iodothyronines (T₃ and T₄).

 

Alongside these two effects, both 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 avidity in the thyroid gland. This means that it is always possible to replace radioactive iodine treatment with NeoMercazole^®.

Absorption

Between 90 and 100% of orally administered carbimazole is rapidly absorbed in the intestines within 15-30 minutes. Only its active metabolite, methimazole, can be identified in the blood. The mean peak plasma concentration of thiamazole is reported to occur one hour after a single dose of thiamazole.

 

After oral ingestion, peak plasma concentrations of thiamazole, the active moiety, occur at 1 to 2 hours

 

Distribution

The total volume of distribution of thiamazole is 0.5L/kg and is moderately (about 40%) bound to plasma proteins. Thiamazole is concentrated in the thyroid gland. This intra-thyroidal concentration of thiamazole has the effect of prolonging the activity of carbimazole. When low doses are administered the ratio of the thyroid to plasma is about 100, which drops as the dose is raised and as saturation of the transport system increases. 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.

 

Carbimazole and thiamazole cross the placenta and appear in breast milk. The plasma milk ratio for thiamazole approaches unity.

 

Biotransformation

Thiamazole is moderately (about 40%) bound to plasma proteins. Carbimazole has a half-life of 5.3 to 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. The plasma: milk ratio approaches unity.

Carbimazole is transformed into its active metabolite thiamazole in the blood by hydrolysis and enzymatic decarboxylation. Only its active metabolite thiamazole (methimazole) can be detected in the blood, so the pharmacokinetic data therefore refer to this metabolite.

 

Elimination

The blood half-life ranges from 4-12 hours depending on the person.

 

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. There is 10% enterohepatic circulation.

 

The dwell time of thiamazole in the thyroid amounts to about 20 hours, which corresponds to the duration of the effect of a single dose.

 

1. Characteristics in patients

The plasma half-life is longer in patients with disorders of the liver or kidney functions (see section 4.3).

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

Sucrose, lactose, acacia, talc, maize starch, magnesium stearate, gelatine and red iron oxide (E172)

None known

3 years

Do not store above 25°C.

Store in the original container away from heat.

Do not use after the expiry date which is printed on the carton after EXP. The expiry date refers to the last day of that month.

NeoMercazole® 5mg tablets are available in HDPE bottles with a polypropylene tamper-evident screw cap with integrated desiccant. Each bottle contains 100 Tablets.

No special requirements.