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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Allopurinol 100 mg Tablets B.P.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Allopurinol 100.0 mg

3. PHARMACEUTICAL FORM

Compressed tablet

4.    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

In the prophylactic management of gout and other conditions of excess body urate whose main clinical manifestations are gouty arthritis, skin tophi and/or renal involvement.

In the treatment of excess body urate associated with the treatment of neoplastic disease, certain enzyme disorders(in particular Lesch-Nyhan Syndrome), renal failure, renal calculus formation, diuretic therapy and psoriasis.

In the prophylaxis and treatment of patients with urate nephropathy with raised serum or urinary uric acid and calcium oxalate stones.

4.2. Posology and Method of Administration

Adult Dosage:

Initial: 100 - 300 mg daily as a single dose.

Maintenance:    Normally 200 - 600 mg, rarely 900 mg daily.

Doses over 300 mg should be given in divided doses, after meals. The dose should be adjusted by monitoring serum uric acid and/or

urinary uric acid levels at appropriate intervals until the desired effect is attained, which takes 1 to 3 weeks.

In impaired renal function the dose may need to be reduced and adjusted as indicated by serum uric acid levels.

The following maintenance schedule is for guidance;

If creatinine clearance exceeds 20 ml/minute give standard dose.

If creatinine clearance is between 20 and 10 ml/minute give 100 - 200 mg/day.

If creatinine clearance is less than 10 ml/minute give 100 mg/day or at longer intervals.

In renal dialysis: Allopurinol and its metabolites are removed by renal dialysis.

If frequent dialysis is required, an alternative schedule of 300 - 400 mg allopurinol after each dialysis, should be considered, with none in the intervening period.

In prevention of acute uric acid nephropathy in neoplastic conditions: treatment with allopurinol should precede treatment with cytotoxic drugs.

Use in the elderly:

The dose should be maintained at the minimum necessary to maintain normal plasma and uric acid levels.

Paediatric dosage:

Children: 10-20 mg/kg/day.

Use in children is mainly indicated in malignant conditions especially leukaemia, and certain enzyme disorders (e.g. Lesch-Nyhan Syndrome).

4.3 Contra-Indications

Known intolerance to allopurinol.

Should not be used for treatment of acute gout. It may be used for prophylaxis once an attack has completely subsided in conjunction with anti-inflammatory agents.

4.4 Special warnings and precautions for use

Treatment with allopurinol should not be started during an acute attack of gout. The dosage should be reduced in patients with renal or hepatic disorders. Prophylactic doses of a suitable anti-inflammatory (not aspirin or salicylates) should be given concurrently. Fluid intake should ensure adequate urinary output of not less than 2 litres a day and the urine rendered alkaline if uric acid overload is high.

In conditions where xanthine deposition may occur in the urinary tract (e.g. in malignant disease and its treatment, the Lesch-Nyhan syndrome) adequate hydration should be maintained, to give optimal urine dilution.

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

Allopurinol inhibits the metabolism of 6-mercaptopurine and azathioprine. The dosages of these drugs should be reduced to one third or one quarter of their usual dosage when concurrently administered with allopurinol.

Allopurinol may potentiate the effects of warfarin and nicoumalone when given concurrently.

When given concurrently with cyclophosphamide, adenine arabinoside, patients should be observed for enhanced toxic effects. The dose of theophylline and other xanthines may have to be adjusted to avoid toxicity. When given concurrently with chlorpropamide, there may be a risk of prolonged hypoglycaemia, if renal function is impaired.

When used with drugs which increase uricosuric activity (e.g. loop diuretics), allopurinol’s therapeutic effect may be decreased. Therefore the dose may have to be adjusted..

4.6. Pregnancy and Lactation

High dose intraperitoneal allopurinol in mice has been associated with foetal abnormalities but extensive animal studies with oral allopurinol have shown no such effects. In human pregnancy there is no evidence that allopurinol taken orally causes foetal abnormalities; however, as with all drugs, due caution should be exercised in the use of allopurinol in pregnancy. Allopurinol is excreted in breast milk and so should not be given to nursing mothers.

4.7. Effects on Ability to Drive and Use Machines

None Known.

4.8 Undesirable effects

Skin reactions, the most common side effect, may occur at any time during the treatment and are more frequent in patients with renal failure.

These may be pruritic, macropapular, sometimes scaly or purpuric and rarely, exfoliative. Treatment should be withdrawn immediately when such reactions occur and if desired, after recovery from mild reactions, re-introduced at a low dose (e.g.

50 mg / day) which may be gradually increased. If the rash recurs, allopurinol should be withdrawn permanently.

Generalised hypersensitivity reactions occur more rarely and are an indication to discontinue allopurinol immediately and permanently. These may occur at any time during treatment and include skin reactions associated with exfoliation, fever, lymphadenopathy and arthralgia and/or eosinophilia resembling Stevens-Johnson and/or Lyell’s syndrome. Associated vasculitis and tissue response may be manifest in various ways including hepatitis, interstitial nephritis, and, very rarely, epilepsy. When such reactions have occurred, a renal and/or hepatic disorder has usually been present, particularly when the outcome has been fatal. Corticosteroids may be beneficial in overcoming such reactions.

Liver damage has been reported. Very rarely, granulomatous hepatitis, without evidence of more generalised hypersensitivity, has been described, which appears to be reversible upon withdrawal of allopurinol.

Gastro-intestinal disturbances including nausea and vomiting have occurred and may be avoided by taking allopurinol after meals. Recurrent haematemesis and steatorrhoea have been reported very rarely.

There have been occasional reports of transient reduction in the number of circulating formed elements of the blood, usually in association with a renal and / or hepatic disorder. Vasculitis has also been reported.

Exacerbation of acute gouty attacks may occur in the early stages of hypouricaemic therapy.

In those conditions where the body’s miscible urate pool is greatly increased, the rise in the xanthine concentration resulting from the action of allopurinol may lead to tissue disposition of xanthine. Fluid intake to maintain adequate urinary output should be ensured.

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).

The following complaints have been reported occasionally, but do not appear to have clear cause and effect relationships with allopurinol: alopecia, angina, asthenia, ataxia, bradycardia, cataract, changed bowel habit, coma, depression, diabetes mellitus, discoloured hair, fever, furunculosis, general malaise, haematuria, headache, hyperlipidaemia, hypertension, impotence, infertility, macular changes, neuropathy, nocturnal emission, oedema, paraesthesia, paralysis, somnolence, stomatitis, taste disturbance, uraemia, vertigo and visual disorders.

4.9. Overdose

No reports of overdosage or acute intoxication are available. The most likely reaction would be gastro-intestinal intolerance. Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity. This should show no untoward effects unless 6-mercaptopurine, adenine arabinoside, and/or azathioprine, is being taken concomitantly. In this case, the risk of increased activity of these drugs must be recognised. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Dialysis may be necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Allopurinol and its major metabolite, oxypurinol, act by inhibiting the action of xanthine oxidase and thus reduce the oxidation of hypoxanthine and xanthine to uric acid. The urinary purine load, normally almost entirely uric acid, is thereby divided between hypoxanthine, xanthine, and uric acid, each with its independent solubility. The reduced concentration of uric acid in plasma facilitates the resolution of tophi and calculi. Hypoxanthine and xanthine may be re-utilised for nucleotide and nucleic acid syntheses, and purine biosynthesis may be reduced.

5.2. Pharmacokinetic Properties

Allopurinol is absorbed from the gastro-intestinal tract and is reported to have a plasma half-life of about 1 hour. It is rapidly converted in the body to oxypurinol (alloxanthine) which is also an inhibitor of xanthine oxidase with a

5.3. Pre-clinical Safety Data

Not relevant.

6. PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Each tablet contains: Lactose

Maize starch Povidone

Magnesium stearate Sodium starch glycollate

6.2.    Incompatibilities

None known.

6.3.    Shelf-Life

60 months.

6.4.    Special Precautions for Storage

Store in a cool dry place. Keep well closed.

6.5.    Nature and Contents of Container

Amber glass bottle with BK Steran faced plastic cap. Pack sizes:100, 250 and 1000 tablets.

Plastic securitainer tub and tamper-evident closure. Pack sizes:100, 250 and 1000 tablets.