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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Allopurinol Tablets BP 100mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg of Allopurinol BP. For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Allopurinol is indicated in:

1. Conditions of excess body urate including gout. Allopurinol is used to reduce urate levels in the body when these levels are excessive (serum is theoretically saturated with urate at a concentration between 0.38-0.42 mmol (6.4-7.0 mg%)). The higher levels seen in practice may be accounted for by (a) the formation of supersaturated solutions: (b) protein binding of urate. Excess body urate may be indicated by hyperuricaemia and /or hyperuricosuria. It may lead to deposition of urate in the tissues or it may be present with no obvious signs or symptoms. The main clinical manifestations of urate deposition are gouty arthritis, skin tophi and/or renal involvement. Excess body urate is frequently of idiopathic origin but may also be found in association with other conditions including the following: neoplastic disease and its treatment; certain enzyme disorders (in particular Lesch Nyhan syndrome); renal failure; renal calculus formation; diuretic therapy and psoriasis.

2. Calcium renal lithiasis: Allopurinol is of benefit in the prophylaxis and treatment of calcium renal lithiasis in patients with raised serum or urinary uric acid.

Allopurinol and its major metabolite, oxypurinol, act by inhibiting the enzyme xanthine oxidase which catalyses the end stage of the metabolism of purines to uric acid. Allopurinol and its metabolites are excreted by the kidney but the renal handling is such that allopurinol has a plasma half-life of about one hour whereas that of oxypurinol exceeds 18 hours. Thus therapeutic effect may be achieved by once-a-day dosage.

4.2 Posology and method of administration

Adults

The initial dosage should be in the range of 100-300mg per day, which may be taken as a single dose. Larger amounts should be taken in divided doses. It has rarely been found necessary to exceed 900mg per day. The dose should be adjusted by monitoring serum uric acid and/or urinary uric acid levels, until the desired effect is attained which may take one to three weeks. The maintenance level is normally 200600mg per day.

Children:    10-20mg/kgbody weight/day.

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

Elderly

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

Initiation of therapy

In early stages of treatment with allopurinol, an acute attack of gouty arthritis may be precipitated. Therefore; it is advisable to give a prophylactic dose of a suitable antiinflammatory agent or colchicine, for at least one month.

Use with uricosurics

Oxipurinol the major metabolite of allopurinol and itself therapeutically active is excreted by the kidney in a similar way to urate. Hence drugs with uricosuric activity such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic effect of allopurinol, but the significance needs to be assessed in each case.

Use with cytotoxic drugs

To prevent acute uric acid nephropathy in neoplastic conditions, treatment with allopurinol should precede treatment with cytotoxic drugs.

Dose recommendations in impaired renal function:

Since allopurinol and its metabolites are excreted via the kidney, impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action. Thus the amount and frequency of the dosage may require reduction as indicated by monitoring serum uric acid levels.

The following schedule is provided for guidance in adults:-

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

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

If creatinine clearance is less than 10ml/minute- give 100mg/day or at longer intervals. Dose recommendation in renal dialysis

Allopurinol and its metabolites are removed by renal dialysis. If frequent dialysis is required, an alternative schedule of 300-400mg allopurinol after each dialysis with none in the interim should be considered.

Dosage in hepatic impairment: Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.

Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.

Instructions for Use: Allopurinol tablets may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.

4.3 Contraindications

Known intolerance of allopurinol and as a treatment for acute attacks of gout. Prophylactic therapy may be started when the acute attack has completely subsided, provided anti inflammatory agents are also taken.

4.4 Special warnings and precautions for use

Hypersensitivity syndrome, SJS and TEN

Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) andStevens-Johnson Syndrome (SJS) /toxic epidermal necrolysis (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.

Chronic renal impairment

Patients with chronic renal impairment may be at increased risk of developing hypersensitivity reactions including SJS/TEN associated with allopurinol. Extra vigilance for the signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately and permanently at the first appearance of symptoms (see section 4.8)

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).

Hepatic or renal impairment

Reduced doses should be used in patients with hepatic or renal impairment. (See Section 4.2) Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and allopurinol should be used with care in this group.

Asymptomatic hyperuricaemia per se is generally not considered an indication for use of Allopurinol. Fluid and dietary modification with management of the underlying cause may correct the condition.

Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.

In the early stages of treatment with Allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for at least one month. The literature should be consulted for details of appropriate dosage and precautions and warnings.

If acute attacks develop in patients receiving allopurinol, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.

Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be minimised by adequate hydration to achieve optimal urine dilution.

Impaction of uric acid renal stones: Adequate therapy with Allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Lactose intolerance: Allopurinol tablets contain lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

6-mercaptopurine andazathioprine: Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given concurrently with Allopurinol only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.

Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of vidarabine is increased in the presence of allopurinol. When the two products are used concomitantly extra vigilance is necessary, to recognise enhanced toxic effects.

Salicylates and uricosuric agents: oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of Allopurinol , but the significance needs to be assessed in each case.

Chlorpropamide: If Allopurinol is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycaemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.

Coumarin anticoagulants: There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with allopurinol therefore, all patients receiving anticoagulants must be carefully monitored.

Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Theophylline: Inhibition of the metabolism of theophylline has been reported.

The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man. Theophylline levels should be monitored in patients starting or increasing allopurinol therapy.

Ampicillin/Amoxicillin: An increase in frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to

patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol an alternative to ampicillin or amoxicillin is used where available.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.

Cyclosporin: Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced cyclosporin toxicity should be considered if the drugs are co-administered.

ACE Inhibitors and Angiotensin II Antagonists: Increased risk of toxicity with captopril, especially in renal impairment

4.6    Fertility, pregnancy and lactation

High dose intraperitoneal allopurinol in mice has been associated with foetal abnormalities but extensive animal studies with oral allopurinol have shown none. 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. Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from woman taking Allopurinol 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

4.7    Effects on ability to drive and use machines

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that allopurinol does not adversely affect performance

4.8 Undesirable effects

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency:

>1/10 (>10%)

>1/100 and <1/10 (>1% and <10%)

>1/1000 and <1/100 (>0.1% and <1%) >1/10,000 and <1/1000 (>0.01% and <0.1%) <1/10,000 (<0.01%)

Adverse reactions in association with Allopurinol are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.

Infections and infestations

Very rare    Furunculosis

Blood and lymphatic system disorders

Very rare    Agranulocytosis, aplastic anaemia, thrombocytopenia

Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.

Immune system disorders

Uncommon    Hypersensitivity reactions

Very rare    Angioimmunoblastic lymphadenopathy

Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis occur rarely (see Skin and subcutaneous tissue disorders). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment, Allopurinol tablets should be withdrawn immediately and permanently.

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) Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.

Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Allopurinol tablets.

Metabolism and nutrition disorders

Very rare    Diabetes mellitus, hyperlipidaemia

Psychiatric disorders

Very rare    Depression

Nervous system disorders

Very rare Coma, paralysis, ataxia, neuropathy, paraesthesiae, somnolence, headache, taste perversion

Eye disorders

Very rare    Cataract, visual disorder,    macular changes

Ear and labyrinth disorders

Very rare    Vertigo

Cardiac disorders

Very rare    Angina, bradycardia

Vascular disorders

Very rare    Hypertension

Gastrointestinal disorders

Uncommon    Vomiting, nausea

Very rare    Recurrent haematemesis,    steatorrhoea, stomatitis, changed bowel

habit

In early clinical studies, nausea and vomiting were reported. Further reports suggest that this reaction is not a significant problem and can be avoided by taking Allopurinol tablets after meals.

Hepatobiliary disorders

Uncommon    Asymptomatic increases    in liver function tests

Rare    Hepatitis (including hepatic necrosis and granulomatous hepatitis)

Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.

Skin and subcutaneous tissue disorders

Common    Rash

Stevens-Johnson syndrome/toxic epidermal necrolysis Angioedema, fixed drug eruption, alopecia, discoloured hair

Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).

Allopurinol tablets should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Allopurinol tablets may, if desired, be reintroduced at a small dose (e.g. 50mg/day) and gradually increased. If the rash recurs, Allopurinol tablets should be permanently withdrawn as more severe hypersensitivity may occur (see Immune system disorders).

The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.

Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.

Renal and urinary disorders

Very rare    Haematuria, uraemia

Reproductive system and breast disorders

Very rare    Male infertility, erectile dysfunction, gynaecomastia

General disorders and administration site conditions

Very rare    Oedema, general malaise, asthenia, fever

Fever has been reported to occur with and without signs and symptoms of a more generalised Allopurinol tablets hypersensitivity reaction (see Immune system disorders).

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

No reports of overdosage or acute intoxication are available. The most likely effect of overdosage would be gastro intestinal disturbance. Massive absorption of allopurinol may lead to marked xanthine oxidase inhibition. This should have no untoward effect unless 6-mercaptopurine, adenine

arabinose and/or azathioprine is being taken concurrently when the activity of these drugs may be increased. 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 resorted to if considered necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Allopurinol inhibits the action of xanthine oxidase thus reducing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. This results in a reduction of uric acid in both plasma and urine. Plasma concentrations of xanthine and hypoxanthine increase only slightly during treatment because renal clearance is rapid.

5.2 Pharmacokinetic properties

Allopurinol is absorbed from the gastro-intestinal tract after oral administration. The plasma half-life is 1-3 hours. It is converted primarily in the liver to oxipurinol which has a plasma half-life of 18-30 hours. Allopurinol and oxipurinol are not bound to plasma proteins. Excretion is mainly through the kidney.

Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of Allopurinol tablets, but fall rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after 3-5 hours after oral administration of Allopurinol tablets and are much more sustained.

Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 litre/kg which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.

Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine. Allopurinol has a plasma half-life of about 1 to 2 hours.

Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma

half-life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of Allopurinol tablets. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10 mg/litre.

Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.

Pharmacokinetics in patients with renal impairment:

Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20ml/min, showed plasma oxipurinol concentrations of approximately 30mg/litre after prolonged treatment with 300 mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of Allopurinol tablets is therefore required in patients with renal impairment.

Pharmacokinetics in elderly patients:

The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see Pharmocokinetics in patients with renal impairment).

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC

A.    Mutagenicity

Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600 mg/day for mean period of 40 months.

Allopurinol does not produce nitraso compounds in vitro or affect lymphocyte transformation in vitro.

Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.

B.    Carcinogenicity

No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.

C. Teratogenicity

One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.

An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose, soluble starch, maize starch, polyvinyl pyrrolidone K25, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store in a cool, dry place below 25°C.

Nature and contents of container