Allopurinol Tablets Bp 300mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Allopurinol 300mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Tablet contains 300mg of Allopurinol For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet.
White circular biconvex tablet with “300” on one face and plain on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
As a xanthine oxidase inhibitor in the management of conditions of excess body urate, including gout, neoplastic disease and associated treatment, enzyme disorders such as the Lesch-Nyhan syndrome, renal calculi, renal failure, diuretic therapy and psoriasis.
In the prophylaxis and treatment of calcium renal lithiasis in patients with raised serum or urinary uric acid.
4.2 Posology and method of administration
Dosage in Adults: Allopurinol 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 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.
Dosage in children: Children 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.
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 Precautions and Warnings.
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 100mg at longer intervals than one day (alternate days).
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 Allopurinol 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 Allopurinol 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 Allopurinol 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 Drug Interactions and Adverse Reactions.
Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals. Instructions for Use: Allopurinol 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.
4.3 Contraindications
• Allopurinol should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation.
• Not a treatment for acute gout but continue if attack develops when already receiving allopurinol and treat attack separately
4.4 Special warnings and precautions for use
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 allopurinol, 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 (not aspirin or salicylates) or colchicine for at least one month after hyperuricaemia corrected. Ensure adequate fluid intake (2-3 litres/day) is maintained.
For hyperuricaemia associated with cancer therapy, allopurinol treatment should be started before the commencement of cancer therapy.
Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs.
Hypersensitivity syndrome, SJS and TEN
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.
HLA-B*5801 allele
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, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the patient is a known carrier of HLA-B*5801, the use of allopurinol may be considered if 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 (see section 4.8)
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 allopurinol. Fluid and dietary modification with management of the underlying cause may correct the condition.
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 allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
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 allopurinol, 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.
Capecitabine: Avoidance of allopurinol advised by the manufacturer of Capecitabine.
Diuretics, Thiazide and related products: Allopurinol given with thiazides and related diuretics especially in renal impairment.
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 such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of allopurinol, but the significance needs to be assessed in each case.
Chlorpropamide: If allopurinol 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.
Captopril: increased risk of toxicity when allopurinol given with captopril especially in renal failure.
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 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 echloroethamine (chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
Ciclosporin: 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.
Didanosine: 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. 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.
4.6 Fertility, Pregnancy and lactation
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 risk for the mother or unborn child.
Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from woman taking Allopurinol 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
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 (A 10%)
Common ^ 1/100 and <1/10 (A 1% and <10%)
Uncommon ^ 1/1000 and <1/100 (A 0.1% and <1%)
Rare > 1/10,000 and <1/1000 (>0.01% and <0.1%)
Very rare <1/10,000 (<0.01%)
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.
Infections and infestations
Very rare Furunculosis
Blood and lymphatic system disorders
Very rare Agranulocytosis, aplastic anaemia, thrombocytopenia, leucopenia and haemolytic anaemia.
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.
Immune system disorders
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.
When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal (see section 4.4)
Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.
Metabolism and nutrition disorders
Very rare Diabetes mellitus, hyperlipidaemia
Psychiatric disorders
Very rare Depression
Nervous system disorders
Very rare Coma, paralysis, ataxia, neuropathy, paraesthesiae, somnolence, headache, taste perversion
Eye disorders
Very rare Cataract, visual disorder, macular changes
Ear and labyrinth disorders
Very rare Vertigo
Cardiac disorders
Very rare Angina, bradycardia
Vascular disorders
Very rare Hypertension
Gastrointestinal disorders
Uncommon Vomiting, nausea
Very rare Recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit
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 allopurinol after meals.
Hepatobiliary disorders
Uncommon Asymptomatic increases in liver function tests Rare Hepatitis (including hepatic necrosis and granulomatous hepatitis) Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.
Skin and subcutaneous tissue disorders
Common Rash
Very rare Angioedema, fixed drug eruption, alopecia, discoloured hair 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. Alopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions, allopurinol may,if desired, be re-introduced at a small dose (e.g. 50mg/day) and gradually increased. If the rash recurs, allopurinol should be permanently withdrawn as more severe hypersensitivity may occur (see Immune system disorders).
Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.
Renal and urinary disorders
Very rare Haematuria, uraemia
Reproductive system and breast disorders
Very rare Male infertility, erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Very rare Oedema, general malaise, asthenia, fever
Fever has been reported to occur with and without signs and symptoms of a more generalised allopurinol hypersensitivity reaction (see Immune system disorders).
4.9 Overdose
Accidental or deliberate ingestion of up to 5g of allopurinol, or very rarely 20g, has been reported. Symptoms include nausea, vomiting, diarrhoea, and dizziness. Recovery followed general supportive measures. The most likely reaction would be gastrointestinal intolerance. Massive absorption may lead to considerable inhibition of xanthine oxidase activity. However, this should have no untoward effects unless mercaptopurine, adenine arabinoside and/or azathioprine is being taken concomitantly. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Dialysis could be utilised.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Xanthine oxidase inhibitor ATC code: M0 4AA01
Allopurinol has no other important effects in man other than through inhibition of xanthine oxidase. Lowering uric acid concentrations in tissues leads to gradual dissolution of gouty tophi and halts the progression of gouty arthritis. Acute attacks of gout may be precipitated by allopurinol in the initial stages of treatment and this possibility should be covered by the use of a non-steroidal anti-inflammatory drug. The urinary excretion of xanthine is increased and in patients with very high uric acid production rates xanthine stones may be formed in the urine. This is very unusual and the risk can be minimized by alkalinising the urine and increasing the fluid intake.
5.2 Pharmacokinetic properties
Allopurinol is well absorbed from the gastrointestinal tract. It has a half-life of one hour but is converted to an active metabolite, oxipurinol, which has a half-life of 18 to 30 hours. Both parent drug and metabolite are poorly protein bound and are excreted via the kidney.
5.3 Preclinical safety data
Not available.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, maize starch, povidone, crospovidone, magnesium stearate.
6.2 Incompatibilities
None known.
6.3 Shelf life
Container
Blister
: 36 months. : 36 months
6.4 Special precautions for storage
Containers: Do not store above 25°C. Store in the original container. Blister packs: Store in the original package.
6.5 Nature and contents of container
Polypropylene tablet containers closed with low density polyethylene tamper-evident lids and containing either 28,100, 500 or 1000 tablets.
Al/PVC Blisters of 7, 14 and 28 tablets Pack size: 28 tablets
(or)
Al/PVDC coated PVC Blisters of 7, 14 and 28 tablets Pack size: 28 tablets
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Special Concept Development (UK) Limited,
Unit 1-7 Colonial Way,
Watford, Hertfordshire,
WD24 4YR United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 36722/0035
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13 January 2003
10 DATE OF REVISION OF THE TEXT
09/04/2014