Class: Musculoskeletal System
Dosage Form: Tablets
Description: Hypoxanthine oxidase inhibitor for treatment of gout
Manufacturer: GlaxoSmithKline (GSK)
Allopurinol………….100 or 300 mg
Allopurinol is a xanthine-oxidase inhibitor.
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.
Zyloric is indicated for reducing urate/uric acid formation in conditions where urea/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:
- Idopathic 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 synthetase
- 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 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
Zyloric should not be administered in individuals known to be hypersensitive to allopurinol or to any of the components of the formulation.
The following interactions are to be noted:
1. 6-Mercaptopurine and Azathioprine:
Azathioprine is metabolised to6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given concurrently with Zylroic, only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.
2. Vidarabine (Adenine Arabinoside):
Evidence suggests taht 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 recognize enhanced toxic effects.
3. Salicylates and Uricosuric Agents:
Oxipurinol, teh 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 Zyloric, but the significance needs to be assessed in each case.
If Zyloric is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypogylcaemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.
5. 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.
Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
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.
An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxycillin 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 alterantive to ampicillin or amoxicillin be used where available.
9. Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamine:
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, belomycin, procarbazine and/or mechloroethamine (mustine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
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.
Adverse reactions in associated with Zyloric are rare in the overall treated population and are mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorders.
1. Skin and hypersensitivity reactions:
These are the most common reactions and may occur at any time druing treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative. Fixed drug eruption occurs very rarely.
Zyloric should be withdrawn immediately should reactions occur. After recovery from mild reactions, Zyloric may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually increased. If the rash recurs, Zyloric should be permanently withdrawn as more severe hypersensitivity reactions may occur.
Skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson syndrome and Toxic Epidermal Necrolysis occur rarely. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and, very rarely, seizures. If such reactions do occur, it may at any time during treatment. Zyloric should be withdrawn immediately and permanently.
Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal. Very rarely acute anaphylactic shock has been reported.
2. Angioimmunoblastic lymphadenopathy:
Angioimmunoblastic lymphadenopathy has been described rarely following biopsy of a generalized lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.
3. Hepatic function:
Rare reports of hepatic dysfunction ranging from asymptomatic rises in liver function tests to hepatitis (including hepatic necrosis and granulomatous hepatitis) have been reported without overt evidence of more generalised hypersensitivity.
4. Gastrointestinal disorders:
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 Zyloric after meals. Recurrent haematemesis has been reported as an extremely rare event, as has steatorrhoea.
Blood and lymphatic system:
Occasional reports have been received of thrombocytopenia, agranulocytosis and aplastic anemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
The following complaints have been reported occasionally; fever, general malaise, asthenia, headache, vertigo, ataxia, somnolence, coma, depression, paralysis, parasthesiae, neuropathy, visual disorder, cataract, macular changes, taste perversion, stomatitis, changed bowel habit, infertility, impotence, diabetes mellitus, amd hyperlipaemia.
Dosage and Administration:
1. Dosage in adults:
Zyloric should be introduced at a low dosage, e.g. 100 mg/day to reduce the risk of adverse reactions and increased only if the serium 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 200 mg daily in mild conditions
- 300 to 600 mg daily in moderately severe conditions
- 700 to 900 mg daily in severe conditions
If a dosage on a mg/kg body weight basis is required, 2 to 10 mg/kg body weight/day should be used.
2. Dosage in children:
Children under 15 years: 10 to 20 mg/kg body weight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukemia) 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.”
3. 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 100 mg per day or to use single doses of 100 mg 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 micromole/liter (15.2 mg/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 300-400 mg Zyloric immediately after each dialysis with none in the interim.
4. Dosage in hepatic impairment:
Reduced doses should be used in patients with hepatic impairment.
Periodic liver functions 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. Adequate hydration is important to maintain optimum diruesis and alkalanisation of the urine is advisable 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 the “Dosage in renal impariment section” should be followed. These steps may reduce the risk of zantine and/or oxipurinol deposition complicating the clinical situation.
The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Zyloric 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 by manifested, a divided dose regimen may be appropriate.
Symptoms and Signs
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20 g allopurinol. 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 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.
Pregnancy and Lactation:
One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalilities. 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 inidicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.
Pregnancy and Fertility
There is inadequate evidence of safely 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 the risks for the mother or unborn child.
Reports indicated that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from a woman taking Zyloric 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
Zyloric should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs.
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.
a) 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 a few months. 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.
b) 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 is 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.
c) 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.
d) Effects on ability to drive and use machinery:
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.
Pack of 3 strips of 10 tablets each.
Store at room temperature, below 25°C.