NeoMercazole 5 and NeoMercazole 20

1. Name Of The Medicinal Product

NeoMercazole^® 5 and NeoMercazole^® 20

2. Qualitative And Quantitative Composition

Each NeoMercazole 5 tablet contains carbimazole Ph. Eur. 5mg and each

NeoMercazole 20 tablet contains carbimazole Ph.Eur. 20mg.

3. Pharmaceutical Form

5 mg Tablet: Pink, circular biconvex tablet, imprinted with 'Neo 5' on the obverse and plain on the reverse.

20 mg Tablet: Pink, circular biconvex tablet, imprinted with 'Neo 20' on the obverse and plain on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

NeoMercazole is an anti-thyroid agent. It is indicated in all conditions where reduction of thyroid function is required.

1. Hyperthyroidism.

2. Preparation for thyroidectomy in hyperthyroidism.

[1]3. Therapy prior to and post radio-iodine treatment.

4.2 Posology And Method Of Administration

[2]NeoMercazole should only be administered if hyperthyroidism has been confirmed by laboratory tests.

Adults

The initial dose is in the range 20 - 60mg, and 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 - 15mg per day, which may be taken as a single daily dose. Therapy should be continued for at least six, 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 – 60 mg per day, and supplemental l-thyroxine, 50 – 150 mcg 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 20mg is recommended, it is intended that NeoMercazole 5 should be taken.

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 or over).

Children

The usual initial daily dose is 15mg per day.

4.3 Contraindications

NeoMercazole is contraindicated in patients with a previous history of adverse reactions to carbimazole or to any of the excipients in the composition. Serious, pre-existing haematological conditions, [3]severe hepatic insufficiency.

4.4 Special Warnings And Precautions For Use

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, blood cell counts should be performed immediately, particularly where there is any clinical evidence of infection.

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 should be used with caution in patients with [4]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.

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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

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, thiamazole and propylthiouracil.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Little is known about interactions.

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.

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

4.6 Pregnancy And Lactation

Carbimazole 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.

Studies have shown that the incidence of congenital malformations is greater in the children of mothers whose hyperthyroidism has remained untreated than in those to whom treatment with carbimazole has been given.

However, very rare cases of congenital malformations 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, to transplacental exposure to carbimazole and methimazole cannot be excluded. Therefore, the use of carbimazole 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.

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

NeoMercazole is secreted in breast milk and, if treatment is continued during lactation, the patient should not continue to breastfeed her baby.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Adverse reactions usually occur in the first eight weeks of treatment. The most frequently occurring reactions are nausea, headache, arthralgia, mild gastric distress, skin rashes and pruritus. These reactions are usually self-limiting and may not require withdrawal of the drug.

[8]Blood and lymphatic system disorders

Bone marrow depression including neutropenia, eosinophilia, leukopenia, agranulocytosis has been reported. Fatalities with carbimazole-induced agranulocytosis have been reported. Rare cases of pancytopenia/aplastic anaemia and isolated thrombocytopenia have also been reported. Additionally, very rare cases of haemolytic anaemia have been reported.

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, blood cell counts should be performed immediately, particularly where there is any clinical evidence of infection.

Nervous system disorders

Headache.

Gastrointestinal system disorders

Nausea, mild gastric distress.Loss of sense of taste has been observed.

General disorders and administration site conditions

Fever, Malaise

Hepatobiliary system disorders

Hepatic disorders, including abnormal liver function tests, hepatitis, cholestatic hepatitis, cholestatic jaundice and most commonly jaundice, have been reported; in these cases carbimazole should be withdrawn.

Injury, poisoning and procedural complications

Bruising

Skin and subcutaneous tissue disorders

Skin rashes, pruritus, urticaria. Hair loss has been occasionally reported.

Musculoskeletal system disorders

Isolated cases of myopathy have been reported. Patients experiencing myalgia after the intake of NeoMercazole should have their creatine phosphokinase levels monitored.

Hypersensitivity and allergic reaction

Angioedema and multi-system hypersensitivity reactions such as cutaneous vasculitis, liver, lung and renal effects occur.

Vascular Disorders

Bleeding

4.9 Overdose

No symptoms are likely from a single large dose and so no specific treatment is indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Carbimazole is a thyroid reducing agent.

5.2 Pharmacokinetic Properties

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

5.3 Preclinical Safety Data

Not relevant.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, Starch Maize, Gelatin, Magnesium Stearate, Sucrose, Acacia, Talc, Red Iron Oxide (E172). Microcrystalline Cellulose (NeoMercazole 20 only).

6.2 Incompatibilities

None known.

6.3 Shelf Life

[9]NeoMercazole 5: 3 years

NeoMercazole 20: 5 years

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original container.

6.5 Nature And Contents Of Container

NeoMercazole tablets are available in HDPE bottles with a low density polyethylene tamper evident snap-fit closure. Each bottle contains 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Amdipharm Plc

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

United Kingdom

8. Marketing Authorisation Number(S)

NeoMercazole 5: PL 20072/0013

NeoMercazole 20: PL 20072/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

NeoMercazole 5: 31 May 2004

NeoMercazole 20: 31 May 2004

10. Date Of Revision Of The Text

December 2007

NeoMercazole is a registered trade mark

[1] PL20072/0013-0012 & PL20072/0014-0017;13/12/2007

[2] PL20072/0013-0013 & PL20072/0014-0010;13/12/2007

[3] PL20072/0013-0014 & PL20072/0014-0011; 19/12/2007

[4] PL20072/0013-0015 & PL20072/0014-0012; 19/12/2007

[5] PL20072/0013-0016 & PL20072/0014-0013; 20/12/2007

[6] PL20072/0013-0017 & PL20072/0014-0015; 20/12/2007

[7] PL20072/0013-0018 & PL20072/0014-0015; 13/12/2007

[8] PL20072/0013-0019 & PL20072/0014-0016; 20/12/2007

[9] PL 20072/0013-0025; 21/04/2009