Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aspen Pharma Trading Limited 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Zyloric should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation, listed in section 6.1.
Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS/TEN. These reactions are clinical diagnoses, and their clinical presentations remain the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately. Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese population, 8-15% in the Thai, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. Screening for HLA-B*5801 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high. Chronic kidney disease may increase the risk in these patients additionally In case that no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or Korean descent the benefits should be thoroughly assessed and considered outweigh the possible higher risks before starting therapy. The use of genotyping has not been established in other patient populations. If the patient is a known carrier of HLA-B*5801 (especially in those who are from Han Chinese, Thai or Korean descent), allopurinol should not be started unless there are no other reasonable therapeutic options and the benefits are thought to exceed risks. Extra vigilance for signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be informed of the need to stop treatment immediately at the first appearance of symptoms.
SJS/TEN can still occur in patients who are found to be negative for HLA-B*5801 irrespective of their ethnic origin.
Patients 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).
Reduced 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.
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.
In conditions where the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, LeschNyhan 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.
Adequate therapy with Zyloric will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with allopurinol (5.8%) in a long term open label extension study. Caution is required when allopurinol is used in patients with alteration of thyroid function.
Zyloric 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
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.
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.
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 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 hypoglycaemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.
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 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.
With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halogenides), blood dyscrasias occur more frequently than when these active substances are administered alone.
Blood count monitoring should therefore be performed at regular intervals.
Reports 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.
In 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. Coadministration 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.
An 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.
An increased risk of hypersensitivity has been reported when allopurinol is given with ACE inhibitors especially in renal impairment.
If aluminium hydroxide is taken concomitantly, allopurinol may have an attenuated effect. There should be an interval of at least 3 hours between taking both medicines.
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 (see section 5.3). Use in pregnancy only when there is no safer alternative and when the disease itself carries risks for the mother or unborn child.
Allopurinol and its metabolite oxipurinol is excreted in the 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. Allopurinol during breastfeeding is not recommended.
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:
Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1000 to <1/100
Rare ≥1/10,000 to <1/1000
Very rare <1/10,000
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.
Table 1. Tabulated summary of adverse reactions:
Very rare: Furuncle
Very rare: Agranulocytosis1, Aplastic anaemia1, Thrombocytopenia1
Uncommon Hypersensitivity2
Very rare: Angioimmunoblastic, T-cell lymphoma3
Very rare: Diabetes mellitus, Hyperlipidaemia
Very rare: Depression
Very rare: Coma Paralysis, Ataxia, Neuropathy peripheral, Paraesthesia, Somnolence, Headache, Dysgeusia
Very rare: Cataract, Visual impairment, Maculopathy
Very rare: Vertigo
Very rare: Angina pectoris, Bradycardia
Vascular disorders
Very rare: Hypertension
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
Common: Rash
Rare: Stevens-Johnson syndrome/toxic epidermal necrolysis6
Very rare: Angioedema7, Drug eruption, Alopecia, Hair colour changes
Very rare: Haematuria, Azotaemia
Very rare: Infertility male, Erectile dysfunction, Gynaecomastia
Very rare: Oedema, Malaise, Asthenia, Pyrexia8
Common: Blood thyroid stimulating hormone increased9
1 Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
2 A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, rashes, vasculitis,lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia hepato-splenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, and colon). If such reactions do occur, it may be at any time during treatment, allopurinol should be withdrawn IMMEDIATELY AND PERMANENTLY.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. 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.
3 Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.
4 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.
5 Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.
6 Skin reactions 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, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the first weeks of treatment. The best results in managing such reactions come from early diagnosis and immediate discontinuation of any suspect drug. Zyloric should be withdrawn immediately should such 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. The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN.
The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the rash recurs, Zyloric should be permanently withdrawn as more severe hypersensitivity may occur (see section 4.8 Immune system disorders). If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce allopurinol due to the potential for a severe or even fatal reaction. The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.
7 Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.
8 Fever has been reported to occur with and without signs and symptoms of a more generalised Zyloric hypersensitivity reaction (see section 4.8 Immune system disorders).
9 The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did not report any impact on free T4 levels or had TSH levels indicative of subclinical hypothyroidism.
Reporting 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 Scheme Website: www.mhra.gov.uk/yellowcard
Not applicable.
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