SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

COSURIC/Allopurinol 100 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Allopurinol BP 100 mg

3    PHARMACEUTICAL FORM

Tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

To reduce urate levels in conditions of excess body urate including gout. Hyperuricaemia and hyperuricosuria are manifestations of excess body urate. A concentration of 6.4-7.0 mg % is the urate concentration at which serum is theoretically saturated.

In the treatment of calcium kidney stones in patients with raised urinary or serum uric acid.

4.2    Posology and method of administration

Adults: Initially 100 mg daily, preferably after food, then adjusted according to plasma or urinary uric acid concentration; usual maintenance dose in mild conditions 100-200 mg daily, in moderately severe conditions 300-600 mg daily, in severe conditions 700-900 mg daily. Doses over 300 mg daily should be given in divided doses. It may take up to three weeks to adjust the dosage to the desired effect. This is achieved by regularly monitoring uric acid levels (serum or urinary).

Children: The daily dose is 10-20 mg per kilo bodyweight. The maximum dose is 400mg daily. Indicated for use in children is for neoplastic conditions and enzyme disorders.

Elderly: The dose should be maintained at the smallest necessary to maintain normal serum and urinary urate levels.

Commencing therapy: When commencing treatment with COSURIC then, as with all uricosuric agents, an acute attack of gout may be precipitated. It is recommended that a prophylactic dose of an anti-inflammatory agent or colchicine is given for at least one month after hyperuricaemia is corrected. Aspirin and salicylates are not recommended for prophylactic use.

Use with uricosurics: COSURIC may be given concurrently with uricoguric agents. However, when changing to COSURIC from uricosuric therapy it is advisable to overlap treatment for one to three weeks thus ensuring a continuous hypouricaemic effect.

In neoplastic conditions to avoid acute uric acid nephropathy COSURIC should precede any treatment with cytotoxic drugs.

Recommended dosage in impaired renal function: COSURIC and metabolites are excreted via the kidney therefore retention of the drug and its metabolites will occur in conditions where renal function to impaired. Prolongation of action of COSURIC may require reduction as indicated by regular monitoring of serum uric acid levels. For guidance, the following scheme provided relates to adults:

If renal creatinine is greater than 20 ml/per minute use a standard dose. When creatinine clearance is less than 10 ml/per minute then l00 mg may be given daily or at regular intervals.

In renal dialysis: Renal dialysis removes COSURIC and its metabolites. When frequent dialysis is required then 300 mg - 400 mg COSURIC should be given after each dialysis without any dosage in between.

Route of administration: Oral

4.3 Contraindications

This product is contra-indicated as a treatment for the acute phase of gout. Prophylactic therapy may be instituted when the acute gouty attack has completely subsided provided also that anti-inflammatory agents are also taken.

Sensitivity and intolerance to Allopurinol. In the presence of hepatic or renal disorders consideration should be given to a reduction of dosage.

4.4 Special warnings and precautions for use

Care should be taken when COSURIC is given together with anticoagulants and with Chlorpropamide (especially when renal function is impaired). There may be risk of increased hypoglycaemia.

Patients should ensure adequate intake of fluids of at least 2 litres per day.

When COSURIC is used prophylactically at the same time as anti-inflammatory treatment, for example with Azathioprine or 6-mercaptopurine, then only one quarter of the usual dose of these latter drugs should be given because xanthine oxidase inhibition will prolong their activity.

Hypersensitivity syndrome, SJS and TEN

Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS/TEN. These reactions are clinical diagnoses, and their clinical presentations remain the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately. Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.

HLA-B*5801 allele

The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese population, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the patient is a known carrier of HLA-B*5801, the use of allopurinol may be considered if the benefits are thought to exceed risks. Extra vigilance for signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately at the first appearance of symptoms, (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Potentiates Azathioprine causing increased toxicity; interacts with Cyclophosphamide causing increase of bone marrow toxicity. Causes potentiation of Warfarin and Nicoumalone.

4.6 Pregnancy and lactation

Although in human pregnancy there is no evidence that Allopurinol taken orally causes foetal abnormalities, due caution should be exercised in the use of COSURIC in pregnancy.

Allopurinol has been detected in breast milk and so should be used with caution in nursing mothers.

4.7 Effects on ability to drive and use machines

Does not effect ability to drive or operate machinery.

4.8 Undesirable effects

Skin reactions are the most common side effect and may occur at any time during treatment. They may be pruritic, macropapular, scaly or rarely exfoliative. Treatment should be withdrawn immediately if such reactions should occur. Re-introduction of Allopurinol at an initially low dose may be contemplated only if a mild skin reaction has occurred. If the rash recurs the drug should be withdrawn permanently.

Occasionally gastrointestinal disorders, general malaise, headache, vertigo, drowsiness, visual and taste disorders, hypertension, symptomless xanthine deposits in muscle, alopecia, hepatotoxicity, parasthesia and neuropathy, blood disorders (including leucopenia, thrombocytopenia, haemolytic anaemia and aplastic anaemia) have occur.

Other side effects which have been reported include fever, asthenia, ataxia, somnolence, coma, depression, paralysis, cataract, stomatitis, changed bowel habit, impotence, infertility, diabetes mellitus, hyperlipaemia, furunculosis, discoloured hair, angina, bradycardia, oedema, uraemia, haematuria, angioedema, gynaecomastia.

Immune system disorders

A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, and colon). If such reactions do occur, it may be at any time during treatment, allopurinol should be withdrawn immediately and permanently.

When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal, (see section 4.4).

4.9 Overdose

Institute adequate hydration in order to maintain optimum diuresis to produce excretion of Allopurinol and its metabolites. It may be necessary to resort to dialysis should this be considered necessary.

The risk of increased activity when there is concomitant use of Azathioprine, 6-mercaptopurine and Adenine Arabinoside.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Allopurinol inhibits the action of xanthine oxidase and reduces the oxidation of hypoxanthine and xanthine to uric acid. Allopurinol reduces the concentration of uric acid in plasma.

5.2    Pharmacokinetic properties

Allopurinol is absorbed from the gastrointestinal tract and has a plasma halflife of approximately one hour. It is rapidly converted in the body to oxypurinol which is also an inhibitor of xanthine oxidase which has a half-life of 18-30 hours. Allopurinol and oxypurinol are not bound to serum proteins and are excreted mainly in the urine. The oxypurinol is re-absorbed by the kidney tubules and is slowly excreted. The slow renal clearance of oxypurinal suggests that part of the therapeutic activity of Allopurinol may be due to the maintenance of adequate blood concentrations of oxypurinol.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Crospovidone Polyethylene glycol 6000 Dextrose monohydrate Stearic acid

Purified water

6.2 Incompatibilities

Azathioprine, 6-mercaptopurine, Adenine, Arabinoside, Warfarin, Nicoumalone and cyclophosphamide.

6.3 Shelf life

36 months for containers, 24 months for blister packs.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

High density polystyrene containers with polythene lids and/or polypropylene containers with polythene lids and polyurethane or polythene inserts. Pack sizes: 16, 21, 28, 30, 50, 56, 60, 84, 90, 112, 120, 140, 150, 168, 180, 250, 1000, 5000, 50000

PVC/Aluminium blister-packs.

Packsizes: 16, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 140, 150, 168, 180.

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

11 Boumpoulinas Street, 3^rd floor, 1060 Nicosia Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/10/1982    09/08/2001

10    DATE OF REVISION OF THE TEXT

19/12/2012