Allopurinol 300mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS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 allopurinol 300mg Also contains Lactose monohydrate 70.80 mg For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet.
White, round, biconvex, uncoated tablets marked with '300' on one face and 'BL' on the other
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Allopurinol and its major metabolite, oxipurinol, act by inhibiting the enzyme xanthine oxidase, which catalyses the end stage of the metabolism of purines to uric acid. Allopurinol and its metabolites are excreted by the kidney but the renal handling is such that allopurinol has a plasma half-life of about 1 hour whereas that of oxipurinol exceeds 18 hours. Thus therapeutic effect may be achieved by once-a-day dosage.
1) Prophylactic management of gout and other conditions of excess body urate: Allopurinol is used to reduce excessive urate levels (serum is theoretically saturated with urate at a concentration between 0.38-0.42mmol/l). The higher levels seen in practice may be accounted for by: a) the formation of saturated solutions; b) protein binding of urate. Excess body urate may be indicated by hyperuricaemia and/or hyperuricosuria. It may lead to disposition of urate in the tissues or it may be present with no obvious signs or symptoms.
The main clinical manifestations of urate disposition are gouty arthritis, skin tophi and/or renal involvement: Excess body urate is frequently of idiopathic origin but may also be found in association with the following other conditions: neoplastic disease and its treatment; certain enzyme disorders (especially Lesch-Nyhan syndrome); renal failure; renal calculus formation; diuretic therapy and psoriasis.
2) Calcium renal lithiasis: Allopurinol is of benefit 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
Posology
Initiation of therapy: In the initial stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. It is therefore advisable to give a suitable anti-inflammatory agent or colchicine for at least one month prophylactically.
Adults: Initially 100-300mg daily which may be given as a single dose. Doses in excess of 300mg should be administered in divided doses. It has rarely been necessary to exceed 900mg daily. The dose should be adjusted by monitoring serum uric acid and urinary uric acid levels at appropriate intervals in order that the dose may be adjusted until the desired effect is attained (this may take 1-3 weeks). The maintenance dose is usually 200-600mg daily.
Children: Use in children is mainly indicated for malignant conditions especially leukaemia, and certain enzyme disorders (eg Lesch-Nyhan syndrome) when the dosage is 10-20mg/kg bodyweight daily.
Use in the elderly: Dosage should be the minimum necessary to maintain normal serum and urinary urate levels.
Use with uricosurics: Oxipurinol, allopurinol's major metabolite which is itself therapeutically active, is excreted by the kidney in a similar way to urate. Drugs with uricosuric activity (eg probenecid or large doses of salicylate) may therefore accelerate the excretion of oxipurinol. This may decrease the therapeutic effect of allopurinol, however, the significance should be assessed on an individual basis.
In order to prevent acute uric acid nephropathy in neoplastic conditions, treatment with allopurinol should precede treatment with cytotoxic drugs.
Dose recommendations with impaired renal function: Impairment of renal function may lead to retention of allopurinol and its metabolites (which are excreted via the kidney) with consequent prolongation of action. Serum uric acid levels should therefore be monitored and the dose adjusted accordingly. The following dose recommendation is for use in adults:
|
Creatinine clearance: |
Dosage: |
|
Over 20ml/minute |
Standard dose |
|
10-20ml/minute |
100-200mg daily |
|
Under 10ml/minute |
100mg daily or less frequently |
Dose recommendations in renal disease: Allopurinol and it metabolites are removed by renal dialysis. If frequent dialysis is required, an alternative schedule of 300400mg after each dialysis, with none in the interim, should be considered.
Method of Administration
For oral administration
4.3 Contraindications
Known hypersensitivity to allopurinol or any of the components of the formulation. Treatment for an acute attack of gout; prophylactic therapy may be commenced when the acute attack has completely subsided, provided anti-inflammatory agents are also taken.
4.4 Special warnings and precautions for use
Hypersensitivity syndrome, SJS and TEN
Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (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.
Chronic renal impairment
Patients with chronic renal impairment 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).
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.
Allopurinol 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 and toxic epidermal necrolysis) (see section 4.8).
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Allopurinol tablets. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Allopurinol treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Allopurinol tablets, Allopurinol tablets must not be re-started in this patient at any time.
Hepatic or renal impairment
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.
Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has been 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 or colchicines 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 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.
Lactose intolerance: Allopurinol 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
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. There is no unequivocal evidence that allopurinol potentiates the activity of other cytotoxic drugs.
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 hypoglycaemia activity.
Antibacterials: 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.
Coumarin Anticoagulants: Although there is no evidence that an interaction between allopurinol and the coumarins seen under experimental conditions has any clinical significance, this possibility should be borne in mind when a patient on oral anticoagulants is given allopurinol.
Antivirals: 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.
Ciclosporin: Reports suggest that the plasma concentration of ciclosporin (risk of nephrotoxicity) may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are coadministered.
Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.
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 mechloroethamine (chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
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.
Antacids: Allopurinol may fail to reduce the blood-uric-acid concentrations when given at the same time as aluminium hydroxide. Intake of antacids and allopurinol should not seperated by 3 hours.
Ace inhibitors: Concurrent use of allopurinol and ACE inhibitors may lead to an increased risk of haematological reactions such as leucopenia, especially if there is pre-existing renal failure.
4.6 Fertility, pregnancy and lactation
High dose intraperitoneal Allopurinol in mice has been associated with foetal abnormalities, but extensive animal studies with oral Allopurinol have shown none. In human pregnancy, there is no evidence that Allopurinol taken orally causes foetal abnormalities, however, as with all drugs, due caution should be exercised in the use of Allopurinol in pregnancy.
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, Nausea 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
These are usually rare and mostly of a minor nature; the incidence is higher in the presence of renal and/or hepatic disorders.
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(^10%)
Common £ 1/100 and <1/10 (£1% and <10%)
Uncommon ^ 1/1000 and <1/100 (^0.1% and <1%)
Rare
> 1/10,000 and <1/1000 (>0.01% and <0.1%)
Very rare <1/10,000 (<0.01%)
Infections and infestations
Very Rare: furunculosis
Blood and lymphatic system disorders
Very rare: thrombocytopenia, aplastic anaemia, agranulocytosis
Frequency not known: leucopenia, eosinophilia, haemolytic anaemia
Reports of transient reduction in the number of circulating formed elements of the blood, are usually in association with a renal and/or hepatic disorder reinforcing the need for particular care in this group of patients.
Immune system disorders
Uncommon: Hypersensitivity reactions
Very rare: Angioimmunoblastic lymphadenopathy, anaphylaxis
Frequency not known: arthralgia
Associated vasculitis and tissue response may be manifested in various ways including hepatitis, interstitial nephritis and, very rarely, epilepsy. Corticosteroids may be beneficial in overcoming them.
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, a renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
Metabolism and nutrition disorders
Very rare: diabetes mellitus, hyperlipidaemia
Frequency not known: exacerbation of gouty attacks (see section 4.4)
Psychiatric disorders Very rare: depression
Nervous system disorders
Very rare: ataxia, coma, headache, neuropathy, paraesthesia, paralysis,
somnolence, taste perversion
Frequency not known: dizziness
Eye disorders
Very rare: cataract, macular changes, visual disorders
Ear and labyrinth disorders
Very rare: vertigo
Cardiac disorders
Very rare: angina, bradycardia
Vascular disorders
Very rare: hypertension
Frequency not known: vasculitis
Gastrointestinal disorders
Uncommon: nausea, vomiting
Very rare: changed bowel habit, stomatitis, steatorrhoea, haematemisis
Frequency not known: diarrhoea, abdominal pain
Hepatobiliary disorders
Uncommon: asymptomatic increases in liver function tests
Rare: Hepatitis (including hepatic necrosis and granulomatous hepatitis)
Skin and subcutaneous tissue disorders
Common: rash
Very Rare: alopecia, angioedema, discoloured hair, fixed drug eruptions,
Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)
Frequency not known: skin reaction associated with eosinophilia, urticaria
Skin reactions are the most common reactions and may occur at any time during treatment.
They may be pruritic, maculopapular, sometimes scaly or purpuric, associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and/or Lyell's. Allopurinol should be withdrawn immediately should such reactions occur.
If desired, after recovery from mild reactions, allopurinol may be reintroduced at a low dose (e.g. 50mg/day) which may be gradually increased. If the rash recurs, allopurinol should be permanently withdrawn.
Reporting of Suspected Adverse Reactions
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 the Yellow Card Scheme at: www.mhra.gov.uk/vellowcard
4.9 Overdose
No reports of overdosage or acute intoxication are available.
Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with 6-mercaptopurine, adenine arabinoside, and/or azathioprine is being taken concurrently. In this case, the risk of increased activity of these drugs must be recognised.
Symptoms
Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and abdominal pain. Rarely, there may be renal insufficiency and hepatitis.
Treatment
The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50 g for adults; 1 g/ kg for children) if the patient presents within 1 hour of ingestion of more than 50 mg/kg. If more than 50 mg/kg has been ingested check U&Es and LFTs.
Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Other measures as indicated by the patient’s clinical condition. Haemodialysis is unlikely to be required. Haemodialysis may be considered in patients with severe renal or hepatic impairment.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Xanthine-oxidase inhibitor ATC CODE: M04AA01
Allopurinol is used in the prevention and treatment of gout
5.2 Pharmacokinetic properties
Allopurinol is absorbed from the GI tract and is reported to have a plasma half life of about one hour. It is rapidly converted in the body to oxipurinol (alloxanthine) which is also an inhibitor of xanthine oxidase with a reported half life of 18-30 hours. Allopurinol and oxipurinol are not bound to serum proteins and are excreted mainly in the urine.
5.3 Preclinical safety data
Not applicable
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Allopurinol 300mg tablets:
Lactose Maize starch Povidone
Magnesium stearate Sodium starch glycolate.
6.2 Incompatibilities
None known.
6.3 Shelf life
60 months.
6.4 Special precautions for storage
Securitainers: Store in a cool, dry place and protect from light.
Blister packs: Do not store above 25°C. Keep the blister in the outer carton to protect from light and moisture.
6.5 Nature and contents of container
Allopurinol 300mg tablets:
Blister strips comprising 250pm PVC film and 20pm Aluminium foil packed into an outer carton.
Pack sizes: 28, 30, 56, 60, 100 Securitainer with polyethylene closures.
Pack sizes: 28, 30, 56, 60 and 100.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd
Unit 3, Canalside
Northbridge Road
Berkhamsted
Herts
HP4 1EG
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0140
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/03/2009
10 DATE OF REVISION OF THE TEXT
12/12/2014