Aspen

Zyloric 100mg Tablets

Each tablet contains 100mg of allopurinol.

In addition each tablet also contains 50mg of the excipient lactose monohydrate

For a full list of excipients, see section 6.1.

Tablet

White to off-white, biconvex, scored tablets coded “GXCM2”.

The score line is only to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses.

Zyloric is indicated for reducing urate/uric acid formation in conditions where urate/uric acid deposition has already occurred (e.g. gouty arthritis, skin tophi, nephrolithiasis) or is a predictable clinical risk (e.g. treatment of malignancy potentially leading to acute uric acid nephropathy).

The main clinical conditions where urate/uric acid deposition may occur are:

• idiopathic gout;

• uric acid lithiasis;

• acute uric acid nephropathy;

• neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy;

• certain enzyme disorders which lead to overproduction of urate, for example:

− hypoxanthine-guanine phosphoribosyltransferase, including Lesch-Nyhan syndrome;

− glucose-6-phosphatase including glycogen storage disease;

− phosphoribosylpyrophosphate synthetase;

− phosphoribosylpyrophosphate amidotransferase;

− adenine phosphoribosyltransferase;

Zyloric is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltranferase.

Zyloric is indicated for the management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

Dosage in adults:-

Zyloric should be introduced at low dosage e.g. 100mg/day to reduce the risk of adverse reactions and increased only if the serum urate response is unsatisfactory. Extra caution should be exercised if renal function is poor (see Dosage in renal impairment). The following dosage schedules are suggested:

100 to 200mg daily in mild conditions,

300 to 600mg daily in moderately severe conditions,

700 to 900mg daily in severe conditions.

Dosage higher than 300mg should be given in divided doses not exceeding 300mg at any time. If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be used. Where available, Zyloric granules should be used in preference to the halving of tablets.

Dosage in children:-

Children under 15 years: 10 to 20mg/kg bodyweight/day up to a maximum of 400mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.

Dosage in the elderly:-

In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice in Dosage in renal impairment and Special Warnings and Precautions for Use.

Dosage in renal impairment:-

Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of plasma half-lives. In severe renal insufficiency, it may be advisable to use less than 100mg per day or to use single doses of 100mg at longer intervals than one day.

If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels below 100 µmol/litre (15.2mg/litre).

Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required two to three times a week consideration should be given to an alternative dosage schedule of 300-400mg Zyloric immediately after each dialysis with none in the interim.

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.

Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome:-

It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with Zyloric before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum diuresis and to attempt alkalinisation of urine to increase solubility of urinary urate/uric acid. Dosage of Zyloric should be at the lower end of the recommended dosage schedule.

If urate nephropathy or other pathology has compromised renal function, the advice given in Dosage in renal impairment should be followed.

These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. See also Interaction with Other Medicaments and Other Forms of Interaction and Undesirable Effects.

Monitoring Advice:-

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

Instructions for Use:-

Zyloric may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300mg and gastrointestinal intolerance be manifested, a divided dose regimen may be appropriate.

Zyloric should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation.

- Use in patients who are breast-feeding infants.

- Use in acute gout.

Zyloric should be withdrawn immediately if a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see Adverse Reactions – Immune system disorders and Skin and subcutaneous tissue disorders).

Reduced doses should be used in patients with hepatic or renal impairment. 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 Zyloric. Fluid and dietary modification with management of the underlying cause may correct the condition.

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

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 Zyloric, 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 Zyloric will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

6 -mercaptopurine and azathioprine

Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given concurrently with Zyloric, 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 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 Zyloric, but the significance needs to be assessed in each case.

Chlorpropamide

If Zyloric 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 the 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 (mustine 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.

Didanosine

In healthy volunteers and HIV patients receiving didanosine, plasma didanosine C_max and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half life. Therefore, dose reductions of didanosine may be required when used concomitantly with allopurinol.

There is inadequate evidence of safety of Zyloric in human pregnancy, although it has been in wide use for many years without apparent ill consequence.

Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child.

Lactation

Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7mg/litre oxipurinol have been demonstrated in breast milk from a woman taking Zyloric 300mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

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.

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:

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.

Symptoms and Signs

Ingestion of up to 22.5g allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20g allopurinol. Recovery followed general supportive measures.

Management

Massive absorption of Zyloric may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary haemodialysis may be used.

Pharmacotherapeutic group

Allopurinol is a xanthine-oxidase inhibitor.

Mode of Action

Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine catabolism, in some but not all hyperuricaemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.

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 Zyloric, but fall rapidly and are barely detectable after 6 hours. Peak plasma levels of oxipurinol generally occur after 3-5 hours after oral administration of Zyloric 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 Zyloric. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10mg/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.

Pharmocokinetics 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 300mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600mg/day in those with normal renal function. A reduction in the dose of Zyloric is therefore required in patients with renal impairment.

Pharmocokinetics in elderly patients

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

Mutagenicity

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

Allopurinol does not produce nitroso 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.

Carcinogenicity

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

Teratogenicity

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

Lactose monohydrate

Maize starch

Povidone

Magnesium stearate

Not applicable.

5 years.

Do not store above 25°C.

Store in the original package.

Zyloric 100mg tablets are packed in PVC/aluminium foil blister packs containing 100 tablets.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Aspen Pharma Trading limited

12/13 Exchange Place

I.F.S.C

Dubline 1, Ireland

PA 1691/2/1

1^st April 1978/1^st April 2008

January 2011