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Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS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
Allopurinol BP 300.00mg
3 PHARMACEUTICAL FORM
Oral Tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Gout prophylaxis
Allopurinol is used to treat primary or secondary hyperuricaemia, associated with chronic gout, uric acid nephropathy, recurrent uric acid stone formation, enzyme disorders, blood disorders, calcium oxalate renal lithiasis, renal failure, diuretic therapy, psoriasis and neoplastic disease and its treatment.
Allopurinol is not used to treat acute gout.
4.2 Posology and method of administration
Adults:
Initially 100mg daily as a single dose, after food, gradually increased over 1 to 3 weeks according to the plasma and/or urinary uric acid concentration.
The average daily dose is 200 to 300mg for mild gout and 400 to 600mg for moderately severe gout. Up to 300mg may be taken as a single daily dose; larger amounts should be taken in divided doses preferably after food.
Hyperuricaemia associated with cancer therapy: 600 to 800mg daily in divided doses for 2 or 3 days, starting 1 or 2 days before the cancer treatment.
Maintenance doses are then given according to response. When given concurrently with azothiaprine or mercaptopurine the dose of the antineoplastic agent should be reduced to one third to one quarter of the usual dose. Treatment with allopurinol should precede treatment with cytotoxic drugs.
Dose in impaired renal function: amount and frequency of the dosage may require reduction as indicated by monitoring serum uric acid levels. As a guide, if the creatinine clearance is between 10 and 20ml per minute (moderate impairment), 100 to 200mg daily should be given, if the creatinine clearance is less than 10ml/minute (severe impairment) 100mg on alternate days, maximum 100mg daily, should be given.
Dose in renal dialysis: If frequent dialysis is required, doses should be adjusted accordingly as its metabolites are removed by dialysis, or else a single dose of 300 to 400mg should be given after each dialysis with no interim doses.
Dose in impaired hepatic function: Reduce dose in hepatic impairment.
Use with uricosurics: Drugs with uricosuric activity, e.g. probenecid or large doses of salicylate, may accelerate the excretion of oxypurinol, the major metabolite of allopurinol. This may decrease the therapeutic affect of allopurinol but the significance in each case needs to be assessed.
Children:
In neoplastic conditions and enzyme disorders, a dose of 10-20 mg/kg bodyweight daily.
Use in the elderly:
Maintain dose at the minimum necessary to keep serum and urine urate levels normal.
4.3 Contraindications
Allopurinol should not be used for the treatment of an acute attack of gout; additionally, allopurinol therapy should not be initiated for any purpose during an acute attack (see also 4.4 Special warnings and precautions for use). Allopurinol is contraindicated where there is known intolerance to allopurinol.
4.4 Special warnings and precautions for use
In the first few months of therapy, there may be an increase in active attacks of gout.
It is advisable therefore to give a prophylactic dose of a suitable anti-inflammatory agent or colchicine for that period (at least one month). Allopurinol may be continued when acute attacks occur in patients already receiving the drug, while the acute attack is treated separately.
Allopurinol should be administered with care to patients with renal or hepatic impairment and doses may need to be reduced. (see section 4.2 Posology - Dose in impaired renal function & Dose in impaired hepatic function). Liver function should be monitored, especially during the first few months, in patients with hepatic impairment.
A urinary output of not less than 2 litres a day must be maintained in all patients receiving allopurinol and the urine rendered neutral or slightly alkaline if uric acid overload is high. To reduce the risk of renal xanthine deposition, an adequate fluid intake is required. Allopurinol should be used with care in patients under treatment for any illness that may predispose to impairment of renal function such as hypertension, cardiac insufficiency, diabetes mellitus.
In neoplastic conditions, treatment with allopurinol (if required) should be commenced before cytotoxic drugs are given.
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.
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).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
ACE inhibitors: There is an increased risk of toxicity with captopril, especially in renal impairment.
Antacids: Concurrent administration (within 3 hours) with aluminium hydroxide in patients on chronic haemodialysis has been reported to result in no change to the concentration of uric acid in blood.
Antibacterials: Increased risk of rash with concominant ampicillin, and amoxycillin.
Anticoagulants: Effects of dicoumarol, phenprocoumon and warfarin may be enhanced. Patients receiving anticoagulants should be carefully monitored.
Antidiabetic agents: An increase in the half-life of chloropropamide, and a decrease in the half-life of tolbutamide have been described, but the effect on the hypoglycaemic response is uncertain.
Antiepileptics: Allopurinol possibly inhibits the metabolism of phenytoin. Plasma carbamazepine concentrations can be gradually increased and the dose of carbamazepine may need to be reduced.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300mg daily) without affecting terminal half life. Coadministration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose of didanosine may be required, and patients should be closely monitored.
Ciclosporin: Plasma ciclosporin concentrations possibly increased (risk of nephrotoxicity).
Cytotoxics: The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one quarter to one third of the usual dose when either of them is given with allopurinol. Allopurinol may enhance the activity of, and possibly increase the toxicity of some other cytotoxics (pentostatin, cyclophosphamide). Concomitant use of allopurinol and capecitabine (prodrug of fluorouracil) should be avoided because allopurinol may decrease the activity of capecitabine.
Theophylline: Plasma theophylline concentrations possibly increased.
Thiazide diuretics: An increase in hypersensitivity reactions, and possibly also other adverse effects, has been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function.
Uricosurics, such as salicylates (see Section 4.2 Posology, Use with Uricosurics): Drugs with uricosuric activity may accelerate the excretion of oxypurinol, the major metabolite of allopurinol. This may decrease the therapeutic affect of allopurinol. Salicylates can also increase uric acid concentrations. These effects may require adjustment of the dose of allopurinol.
4.6 Pregnancy and lactation
There is inadequate evidence of safety of allopurinol in human pregnancy. Allopurinol should only be used during pregnancy when there is no safer alternative and when the disease itself carries risk for the mother or unborn child.
Allopurinol and its metabolite, oxipurinol, are excreted in human milk. There is insufficient information on the effects of allopurinol in newborns and infants. Allopurinol should not be used during breast feeding.
4.7 Effects on ability to drive and use machines
Occasionally drowsiness, dizziness or vertigo and visual disturbances, may occur when taking allopurinol. Patients affected should not drive or operate machinery.
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 though post-marketing surveillance were considered to be rare, very rare or not known. The following convention has been used for the classification of frequency:
Very common Common Uncommon Rare
Very rare Not known
> 1/10 (> 10%)
> 1/100 and <1/10 (> 1% and < 10%)
> 1/1,000 and < 1/100 (> 0.1% and <1%)
> 1/10,000 and < 1/1,000 (> 0.01% and < 0.1%) < 1/10,000 (<0.01%)
Cannot be estimated from the available data
Infections and infestations
Very rare Furunculosis
Blood and lymphatic system disorders
Very rare Agranulocytosis, aplastic anaemia, thrombocytopenia
Not known Haemolytic anaemia, clotting disorders
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
Uncommon Hypersensitivity reactions
Very rare Angioimmunoblastic lymphadenopathy
Not known Chills, leucopenia, leucocytosis
Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis occur rarely (see Skin and subcutaneous tissue disorders). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and, very rarely, seizures. Very rarely acute anaphylactic shock has been reported.
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 Allopurinol.
Metabolism and nutrition disorder
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
Not known Dizziness
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
Not known Diarrhoea, abdominal pain, gastrointestinal bleeding 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
Rare Stevens-Johnson syndrome/toxic epidermal necrolysis
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, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).
Allopurinol should be withdrawn immediately should such reactions occur.
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).
In addition to these adverse effects patients may experience an increase in acute gout attacks during the first few months of treatment.
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/yellowcard.
4.9 Overdose
The most likely reaction would be gastrointestinal intolerance. Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity which should have no untoward effect unless 6-mercaptopurine and/or azathioprine is being taken concomitantly. In this case, the risk of increased activity of these drugs must be recognised. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Dialysis may be resorted to if necessary.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Allopurinol and its major metabolite, oxypurinol, act by inhibiting the enzyme xanthine oxidase which catalyses the end stage of metabolism of purines to uric acid.
5.2 Pharmacokinetic properties
Allopurinol is absorbed from the gastrointestinal tract after oral administration and is reported to have a plasma half life of about 1 - 3 hours. It is converted primarily in the liver to oxypurinol (alloxanthine) which is also an inhibitor of xanthine oxidase with a reported half life of 12 - 30 hours (average 15 to 18 hours) in patients with normal renal function, although this is prolonged by renal impairment. Both allopurinol and oxypurinol are conjugated to form their respective ribonucleosides. Allopurinol and oxypurinol are not bound to plasma proteins. Excretion is mainly through the kidney, but it is slow since oxypurinol undergoes glomerular filtration as well as tubular reabsorption. About 70% of a daily dose may be excreted in the urine as oxypurinol and up to 10% as allopurinol; prolonged administration may alter these proportions due to allopurinol inhibiting its own metabolism. The remainder of the dose is excreted in the faeces. Allopurinol and oxypurinol have also been detected in breast milk.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Maize starch Povidone
Sodium starch glycolate Magnesium stearate Water
6.2 Incompatibilities
No major incompatibilities known.
6.3 Shelf life
36 months in polypropylene or polyethylene containers. 24 months in blister packaging.
6.4
6.5
Nature and contents of container
28, 60, 100 or 1000 tablets in polypropylene/polyethylene containers or 28 or 56 tablets in blister packaging of opaque or clear PVC with 20 micron foil.
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MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham Industrial Estate Wrexham LL13 9UF United Kingdom
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08/05/2015