- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsZyloric should be introduced at low dosage e.g. 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 Patients with 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 dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be used.
Paediatric populationChildren under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.
Older peopleIn the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice in Patients with renal impairment and section 4.4.
Patients with renal impairmentSince 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 micromol/litre (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.
Patients with hepatic impairmentReduced 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 syndromeIt 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 Patients with renal impairment should be followed.These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. See also section 4.5 and section 4.8.
Monitoring AdviceThe dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Method of administrationZyloric 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.
Hypersensitivity syndrome, SJS and TENAllopurinol should be withdrawn IMMEDIATELY when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions, (including Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)) and hypersensitivity syndrome (also known as Drug Rash with Eosinophilia and Systemic Symptoms, DRESS) (see section 4.8).
HLA-B*5801 alleleThe HLA-B*58:01 allele has been identified as a genetic risk factor for allopurinol associated SJS/TEN (and possibly other serious hypersensitivity reactions) in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Thai, Korean, Japanese and European descent. Up to 20-30% of people of Han Chinese, African and Indian ancestry carry the HLA-B*58:01 allele whereas only 1-2% of Northern European, US European and Japanese are estimated to be HLA-B*58:01 carriers. Screening for HLA-B*58:01 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high. If these individuals test positive, allopurinol should not be started unless there are no other reasonable therapeutic options and the benefits of use outweigh the potential associated risks. Patients who are found to be negative for HLA-B*58:01 still have a low risk of SJS/TEN. The clinical diagnosis of SJS/TEN, and other hypersensitivity reactions, remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. (See Adverse Reactions Immune system disorders and Skin and subcutaneous tissue disorders).
Chronic renal impairmentPatients with chronic renal impairment and concomitant diuretic use, in particular thiazides,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).
Hepatic or renal impairmentReduced 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 Zyloric. Fluid and dietary modification with management of the underlying cause may correct the condition.
Acute gouty attacksAllopurinol 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 depositionIn 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 stonesAdequate therapy with Zyloric will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Lactose intoleranceZyloric 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.
6-mercaptopurine and azathioprineAzathioprine 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 agentsOxipurinol, 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 Zyloric, but the significance needs to be assessed in each case.
ChlorpropamideIf 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 anticoagulantsThere 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.
PhenytoinAllopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
TheophyllineInhibition 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/AmoxicillinAn 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, mechloroethamineEnhanced 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.
CiclosporinReports suggest that the plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are co-administered.
DidanosineIn healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half life. Co-administration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.
DiureticsAn interaction between allopurinol and furosemide that results in increased serum urate and plasma oxypurinol concentrations has been reported. An increased risk of hypersensitivity has been reported when allopurinol is given with diuretics, in particular thiazides, especially in renal impairment.
Angiotensin-converting-enzyme (ACE) inhibitorsAn increased risk of hypersensitivity has been reported when allopurinol is given with ACE inhibitors especially in renal impairment.
PregnancyThere 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.
Breast-feedingReports indicate 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.
|Very common Common Uncommon Rare Very rare||≥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%)|
|Table 1 Undesirable effects|
|System Organ Class||Frequency||Adverse reaction|
|Infections and infestations||Very rare||Furuncle|
|Blood and lymphatic system disorders||Very rare||Agranulocytosis1 Aplastic anaemia1 Thrombocytopenia1|
|Immune system disorders||Uncommon||Hypersensitivity 2|
|Very rare||Angioimmunoblastic T-cell lymphoma 3|
|Metabolism and nutrition disorders||Very rare||Diabetes mellitus Hyperlipidaemia|
|Psychiatric disorders||Very rare||Depression|
|Nervous system disorders||Very rare||Coma Paralysis Ataxia Neuropathy peripheral Paraesthesia Somnolence HeadacheDysgeusia|
|Eye disorders||Very rare||Cataract Visual impairment Maculopathy|
|Ear and labyrinth disorders||Very rare||Vertigo|
|Cardiac disorders||Very rare||Angina pectoris Bradycardia|
|Vascular disorders||Very rare||Hypertension|
|Gastrointestinal disorders||Uncommon||Vomiting4 Nausea4|
|Very rare||Haematemesis Steatorrhoea Stomatitis Change of bowel habit|
|Hepatobiliary disorders||Uncommon||Liver function test abnormal5|
|Rare||Hepatitis (including hepatic necrosis and granulomatous hepatitis) 5|
|Skin and subcutaneous tissue disorders||Common||Rash|
|Rare||Stevens-Johnson syndrome/toxic epidermal necrolysis 6|
|Very rare||Angioedema7 Drug eruption Alopecia Hair colour changes|
|Renal and urinary disorders||Very rare||Haematuria Azotaemia|
|Reproductive system and breast disorders||Very rare||Infertility male Erectile dysfunction Gynaecomastia|
|General disorders and administration site conditions||Very rare||Oedema Malaise Asthenia Pyrexia 8|
Reporting of suspected adverse reactionsReporting 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 SchemeWebsite: www.mhra.gov.uk/yellowcard
AbsorptionAllopurinol 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.
DistributionAllopurinol 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.
BiotransformationThe main metabolite of Zyloric is oxipurinol. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
EliminationApproximately 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 0.5 to 1.5 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 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 impairmentAllopurinol 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 20 ml/min, showed plasma oxipurinol concentrations of approximately 30 mg/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 Zyloric is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patientsThe 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).
MutagenicityCytogenetic 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 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.
CarcinogenicityNo evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.
TeratogenicityOne 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.
Zyloric 100 mg TabletsPVC/aluminium foil blister packs of 100 tablets.
Zyloric-300 TabletsPVC/aluminium foil blister packs (2 strips of 14 tablets).
|Date of first authorisation: Renewal: Date of latest renewal:||Zyloric 100 mg Tablets 20.03.80 06.06.90 14.11.95||Zyloric-300 Tablets 14.07.80 18.02.91 25.11.98|
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