INFORMATION FOR HEALTH PROFESSIONALS
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Allopurinol in :
100mg Tablets: Circular, white, flat, bevel-edged tablets with a bisecting score on one face and a diameter of 9mm.
300mg Tablets: Circular, white, flat, bevel-edged tablets with a bisecting score on one face and 11mm in diameter.
Allopurinol inhibits the enzyme xanthine oxidase, thus reducing the oxidation of hypoxanthine to xanthine to uric acid. The reduction in plasma uric acid concentration facilitates resolution of tophi and calculi. Due to the slow excretion of the active metabolite the inhibition lasts for over 24 hours.
A significant reduction of serum uric acid occurs within 2 or 3 days.
90% of the allopurinol from tablets is absorbed in the gastrointestinal tract. The allopurinol is rapidly metabolised to the active metabolite oxypurinol (alloxanthine). After allopurinol tablet administration, peak plasma levels occur generally at 1.5 hours and 4.5 hours for allopurinol and oxypurinol respectively. Allopurinol has a volume of distribution of approximately 0.6l/kg, and neither allopurinol nor oxypurinol are protein bound. Apart from metabolism to oxypurinol, allopurinol is eliminated through the kidneys and some through the gastrointestinal tract.
Allopurinol has a plasma half-life of approximately 1 hour. Oxypurinol has a longer plasma half-life of over 15 hours and is excreted renally. As a result the activity of allopurinol is independent of its plasma concentration. Renal failure may cause accumulation of both allopurinol and oxypurinol so that toxicity is more likely to occur. In such cases the dose of allopurinol should be lowered.
Allopurinol should be administered with care in patients with hepatic dysfunction or in elderly patients where age-related renal function impairment is a possibility.
Allopurinol is indicated for the treatment of chronic gout and hyperuricaemia associated with leukemia, radiotherapy or chemotherapy.
ALLORIN tablets are for oral administration. ALLORIN may be taken after food, to lessen gastrointestinal irritation.
Gout: 100mg daily initially increasing by 100mg increments at weekly intervals to a maintenance dose of 400-600mg daily. Doses over 300mg should be taken as divided doses.
Hyperuricaemia: 200mg daily initially increasing to maintenance doses of 300-400mg daily. Doses of up to 900mg daily may be necessary in some patients with very severe hyperuricaemia. Doses larger than 300mg daily should be taken in divided doses.
Administration in Renal Failure: Patients receiving dialysis may require usual therapeutic doses. However in patients not receiving dialysis, two types of dosage regimens have been suggested.
Firstly monitoring creatinine clearance with respect to the following schedule.
| Creatinine clearance ml/min |
Dose |
|---|---|
| 10 to 20 | 200mg daily |
| 3 to 10 | no more than 100mg daily |
| < 3 | 100mg at intervals of more than 24 hours may be necessary |
However, because of the possible imprecision of low creatinine clearance values, an alternative method, if available, is to monitor the level of plasma-oxypurinol. The dose should be adjusted accordingly to maintain the concentration below 100µmol per litre.
Dosage for patients with either gout or neoplastic disease can be adjusted according to serum uric acid concentration to give the desired level.
Children: Initially 8mg/kg/day increasing to 20mg/kg/day in single or divided doses.
During initial ALLORIN therapy prophylactic colchicine or NSAID may be required in order to prevent acute episodes of gout at this time. Also throughout ALLORIN therapy a fluid intake of no less than 2 litres per day is required. A neutral or slightly alkaline urine is also recommended.
Acute gout and allergy to allopurinol.
If a rash appears when ALLORIN therapy is occurring, ALLORIN should be discontinued.
Administration of allopurinol is not advisable immediately after an acute attack of gout. Allopurinol can increase the frequency of acute attacks of gout during the early months of therapy.
The occurrence of such reactions can be reduced by initiating allopurinol therapy at a low dose then gradually increasing the dosage to obtain the desired effect. Prophylactic doses of colchicine or a non-steroidal anti-inflammatory agent may be administered concurrently during the first 3 to 6 months of allopurinol therapy.
Aplastic anaemia has developed in several patients taking allopurinol, most of the patients also having impaired renal function.
Caution is required in the presence of renal or hepatic impairment. If the creatinine clearance is between 10-20ml per minute the dose should be reduced to 100-200mg daily. The dose should not be more than 100mg daily if the creatinine clearance is less than 10ml per minute.
When uricosuric therapy is being changed to allopurinol therapy, the dose of uricosuric agent should be decreased gradually over a period of several weeks and the dose of allopurinol increased gradually to the appropriate maintenance dose.
Parenteral administration of allopurinol in mice has been shown to cause foetal abnormalities. However, oral administration of allopurinol during both animal and human pregnancy have not led to abnormalities. Should ALLORIN be indicated for a pregnant woman, any risk to the foetus must be considered with the disease process in the mother.
Allopurinol should not be given to nursing mothers as both allopurinol and oxypurinol are excreted in breast milk.
Skin: Reactions affecting skin have a general incidence of 10%, being more common in renal patients and in patients receiving thiazide diuretics. Rash, urticaria, erythematous eruptions, papulovesicular reactions and pruritis may be the only sign of hypersensitivity or may be part of a generalised reaction. Rarely exfoliative dermatitis, Lyell's syndrome and the Stevens-Johnson syndrome can develop. Loosening of finger nails has also been reported.
Nervous system: More common effects are headache and vertigo, fever and chills. Rarely peripheral neuropathy and seizures can occur.
Haematological: Eosinophilia and leukocytosis are part of a hypersensitivity reaction. Leukopenia, neutropenia and aplastic anaemia are sometimes associated with allopurinol treatment. Agranulocytosis is extremely rare. Thrombocytopenia and unexplained nose bleeds have been reported rarely.
Hepatic system: Hepatitis ranging from mild granulomatous hepatitis to severe hepatocellular necrosis can be part of a generalised hypersensitivity reaction. Renal impairment appears to be a prerequisite for a severe hepatic reaction.
Urinary system: Vasculitis due to a general hypersensitivity reaction can cause renal failure, oliguria and decreased creatinine clearance. Acute renal failure, nephrolithiasis and granulomatous interstitial nephritis have been reported.
Hypersensitivity reactions can be severe, even fatal and patients with hepatic or renal impairment are at special risk. It is, therefore, recommended that allopurinol be withdrawn immediately if a rash occurs or other symptoms of hypersensitivity are observed.
Allopurinol inhibits the metabolism of mercaptopurine. The dosage of azathioprine or mercaptopurine must be reduced if they are to be given concomitantly with allopurinol.
Allopurinol may increase the incidence of skin rash in patients taking ampicillin.
Severe neurotoxicity has been reported with concomitant vidarabine therapy.
Allopurinol may increase the plasma half-life of chlorpropamide, possibly by inhibiting its renal excretion. This may require a decrease in hypoglycaemic dose.
The plasma half-life of some oral anticoagulants is increased during allopurinol therapy. It is believed allopurinol interferes with the metabolism. Anticoagulant activity may be enhanced.
Inconclusive results about the effect of allopurinol on theophylline metabolism have been produced experimentally. There does not appear to be any clinical significance.
Medicines that increase serum uric acid may require adjustments to the dose of allopurinol.
Aluminium hydroxide, as the antacid, can reduce the absorption of allopurinol.
Accidental or deliberate ingestion of up to 5g of allopurinol or very rarely 20g has been reported. Symptoms include nausea, vomiting, diarrhoea and dizziness.
Recovery followed general supportive measures. Massive absorption of ALLORIN may lead to considerable inhibition of xanthine oxidase activity which should have no untoward effects unless 6-mercaptopurine and/or azathiaprine is being taken concomitantly. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary, haemodialysis may be used. Allopurinol and its metabolites are removed by renal dialysis.
Store at room temperature. Protect from light and moisture. Keep out of reach of children.
Prescription Medicine.
ALLORIN 100mg tablets: Quantities of 100 tablets packed in HDPE bottles.
ALLORIN 300mg Tablets: Quantities of 30 tablets packed in calendar packs and HDPE bottles and 90 tablets packed in calendar packs.
Allopurinol is 1H-Pyrazolo(3,4-d)pyrimidin-4-ol. It has a chemical formula and molecular weight of C5H4N4O and 136.1 respectively.
Other ingredients of the tablets are: lactose, maize cornflour, polyvinylpyrrolidinone and magnesium stearate.
Douglas Pharmaceuticals Ltd,
PO Box 45-027,
AUCKLAND 8
Ph: (09) 835-0660,
Fax: (09) 835-0665
2 December 1998