Zyloric

Allopurinol.

Allopurinol inhibits xanthine oxidase (XO). The enzyme which catalyses the following reactions.


Click on icon to see table/diagram/image

Allopurinol decreases urate formation in 2 ways.
The inhibition of xanthine oxidase reduces the amount of hypoxanthine and xanthine converted to urate/uric acid.
This action makes more hypoxanthine and xanthine available for re-utilisation in the purine metabolic cycle, which in turn, by a feedback mechanism, decreases overall de novo purine formation. Since allopurinol decreases urate formation, it reduces urate/uric acid concentrations in both body fluids and urine. In contrast, the uricosuric agents which increase urate/uric acid excretion via the kidney will reduce the urate concentration in body fluids, but increase urate/uric acid concentrations in urine. Reduction of the urate concentrations in body fluids by allopurinol permits mobilisation and dissolution of urate deposits anywhere in the body, the commonest sites being those in the skin, bones, joints and kidney interstitial tissue.
Therapeutic effects therefore include: The resolution of skin tophi and the healing of urate sinuses; eventual reduction in the frequency of attacks of acute gouty arthritis; improvement in joint mobility; reduction of the urate load to be excreted via the kidney; prevention and treatment of acute uric acid nephropathy; and, in the long term, reduced risk of renal impairment by urate/uric acid and prevention and dissolution of uric acid renal stones.

Zyloric is used to reduce urate concentrations in body fluids and/or urine to prevent or reverse the deposition of urate/uric acid.
Zyloric is indicated for the main clinical manifestations of urate/uric acid deposition. These are gouty arthritis, skin tophi and/or renal involvement through crystal deposition or stone formation.
Such clinical manifestations occur in: 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 and involve hypoxanthine guanine phosphoribosyl transferase including Lesch-Nyhan syndrome; glucose-6-phosphatase glycogen storage disease; phosphoribosylpyrophosphate synthetase; phosphoribosylpyrophosphate amidotransferase; adenine phosphoribosyltransferase; glutathione reductase; glutamate dehydrogenase.
Zyloric is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.
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.

The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Dose Frequency: Zyloric may be taken orally once a day after a meal. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided dose regimen may be appropriate.
Adults: 2-10 mg/kg body weight/day or 100-200 mg daily in mild conditions; 300-600 mg daily in moderately severe conditions. Maximum Daily Dose: 800 mg.
Children <15 years: 100-300 mg daily.
Use in children is rarely indicated, except in malignant conditions (especially leukaemia and certain enzyme disorders eg, Lesch-Nyhan syndrome).
Elderly: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used.
Particular attention should be paid to dosage advice in renal disorder and Precautions.
Dosage Recommendations: Renal Disorder: 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 the presence of impaired renal function, serious consideration should be given to initiating treatment with a maximum dose of 100 mg/day and increasing it only if the serum and/or urinary urate response is unsatisfactory.
In severe renal insufficiency, it may be advisable to use <100 mg/day or to use single doses of 100 mg at longer intervals than 1 day.
Alternative schedules based on creatinine clearances are unsatisfactory because of the imprecision of low clearance values.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels <100 mmol/L (15.2 mcg/mL).
Renal Dialysis: Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required 2-3 times a week, consideration should be given to an alternative dosage schedule of Zyloric 300-400 mg immediately after each dialysis with none in the interim.
Treatment of High Urate Turnover Conditions eg, 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.
Dosage of Zyloric should be in the lower range.
If urate nephropathy or other pathology has compromised renal function, the advice given in "Dosage Recommendations in Renal Disorder" should be followed. These steps may reduce the risk of xanthine and/or oxypurinol deposition complicating the clinical situation. (See Adverse Reactions and Interactions.)

Symptoms and signs included nausea, vomiting, diarrhoea and dizziness. Recovery followed general supportive measures.
Massive absorption of Zyloric may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless 6-mercaptopurine and/or azathioprine is being taken concomitantly.
Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary, haemodialysis may be used.

Other than known intolerance of allopurinol, there appear to be no absolute contraindications to the use of Zyloric.

Zyloric should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs.
Dosage reduction should be considered in the presence of severe hepatic or renal disorder.
Asymptomatic hyperuricaemia is not an indication for use of Zyloric. Fluid and dietary modification with management of the underlying cause may correct the condition. If other clinical conditions suggest a need for Zyloric, it must be introduced at low dosage (50-100 mg/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 also Dosage Recommendations in Renal Disorder under Dosage & Administration).
Zyloric must be withdrawn immediately and permanently at the first sign of intolerance.
Acute Gouty Attacks: 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 (0.5 mg 3 times a day) for at least 1 month.
Xanthine Deposition: In conditions where the rate of urate formation is greatly increased (eg, 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.
Use in pregnancy: There is no adequate evidence of safety of Zyloric in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
Use Zyloric in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or child.
Use in lactation: Based on data from a single individual, oxypurinol (126 micromole/L, 19.2 mcg/mL), allopurinol (4.4 micromole/L, 0.6 mcg/mL) and allopurinol riboside (5.6 micromole/L, 1.5 mcg/mL) have been demonstrated in human breast milk 4 hrs after a single dose of allopurinol 300 mg.

Use in pregnancy: There is no adequate evidence of safety of Zyloric in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
Use Zyloric in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or child.
Use in lactation: Based on data from a single individual, oxypurinol (126 micromole/L, 19.2 mcg/mL), allopurinol (4.4 micromole/L, 0.6 mcg/mL) and allopurinol riboside (5.6 micromole/L, 1.5 mcg/mL) have been demonstrated in human breast milk 4 hrs after a single dose of allopurinol 300 mg.

Adverse reactions in association with Zyloric 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.
Skin Reactions: These 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.
Zyloric should be withdrawn immediately if reactions occur. After recovery from mild reactions, Zyloric may, if desired, be reintroduced at a small dose (eg, 50 mg/day) and gradually increased. If the rash recurs, Zyloric should be permanently withdrawn.
Generalised Hypersensitivity: Skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-Johnson and/or Lyell's syndrome, occur rarely. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, interstitial nephritis and very rarely, epilepsy.
If such reactions do occur, which may be at any time during treatment, Zyloric should be withdrawn immediately and permanently.
Corticosteroids may be beneficial in overcoming them. When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
Angio-immunoblastic Lymphadenopathy: Has been described rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.
Granulomatous Hepatitis: Very rarely, granulomatous hepatitis, without overt evidence of more generalised hypersensitivity, has been described. It appears to be reversible on withdrawal of Zyloric.
Gastrointestinal Disorders: In early clinical studies, nausea and vomiting were reported. Further reports suggest that these reactions are not a significant problem and can be avoided by taking Zyloric after meals. Recurrent haematemesis has been reported as an extremely rare event as has steatorrhoea.
Blood and Lymphatic System: There have been occasional reports of transient reduction in the numbers of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal function, reinforcing the need for particular care in this group of patients.
Miscellaneous: The following complaints have been reported occasionally: Fever, general malaise, asthenia, headache, vertigo, ataxia, somnolence, coma, depression, paralysis, paraesthesiae, neuropathy, visual disorder, cataract, macular changes, taste perversion, stomatitis, changed bowel habit, infertility, impotence, nocturnal emission, diabetes mellitus, hyperlipaemia, furunculosis, alopecia, discoloured hair, angina, hypertension, bradycardia, oedema, uraemia, haematuria, gynaecomastia.

6-Mercaptopurine and Azathioprine: When 6-mercaptopurine or azathioprine is given by mouth concurrently with Zyloric, only ¼ of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.
Adenine Arabinoside: Evidence suggests that the plasma half-life of adenine arabinoside is increased in the presence of allopurinol. When the 2 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 eg, 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.
Coumarin Anticoagulants: There is no evidence that interaction between allopurinol and the coumarins seen under experimental conditions has any clinical significance. However, 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: Experimental studies of the effect of allopurinol on theophylline metabolism have produced contradictory findings. There have been no clinical reports of interactions.

Hyperuricemia & Gout Preparations

M04AA01 - allopurinol ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.

G

Tab 100 mg x 60's, 200's. 300 mg x 30's, 100's.