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Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS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. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Uncoated Tablets
White, biconvex tablets. Embossed ‘PV’ on one face and ‘A’ and ‘300’ on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Allopurinol is indicated for the main clinical manifestation of urate/uric acid deposition, these are gouty arthritis, skin tophi and/or renal involvement.
In the treatment of excess body urate associated with neoplastic disease, and its treatment, certain enzymes disorders (in particular Lesch-Nyhan syndrome) renal failure, renal calculus formation, diuretic therapy and psoriasis. In the prophylaxis and in the treatment of calcium renal lithiasis in patients with raised serum or urinary uric acid.
Primary hyperuricaemia. Secondary hyperuricaemia. Prophylaxis of calcium oxalate stones.
4.2 Posology and method of administration
The dosage should be adjusted by monitoring serum urate concentration and urinary urate/uric acid levels.
Route of administration: oral
Adults: Initial dose in the range 100mg to 200mg per day which may be taken as a single dose. Maintenance dose is 200mg to 600mg per day. Maximum single dose is 300mg. Doses in excess of 300mg should be administered in divided
doses. It has rarely been found necessary to exceed 900mg per day. The dose should be adjusted by monitoring serum uric acid and/or urinary uric acid levels at appropriate intervals until the desired effect is attained, which may take 1 to 3 weeks.
Children: 10-20mg/kg body weight/day use is mainly indicated in leukaemia and other malignant conditions and enzyme disorder such as Lesh-Nyhan syndrome.
Elderly: The dose should be maintained at the minimum, necessary to maintain normal serum and urinary urate levels.
Initiation of therapy: In the early stages of treatment with Allopurinol, as with uricosuric agents, an acute attack of gout arthritis may be precipitated . Therefore it is advisable to give a prophylactic dose of a suitable anti-inflammatory agent or colchicine (0.5mg, 3 times a day) for at least one month.
Use with Uricosurics: Allopurinol does not interfere with the action of uricosuric agents. When changing from uricosuric therapy to Allopurinol 1-3 weeks overlap of treatment is recommended to ensure a continuous hypouricaemic effect.
Use in Neoplasia: When giving Allopurinol to prevent uric acid in nephropathy in neoplastic condition, it is advisable to start treatment with Allopurinol before cytotoxic therapy.
Patients with hepatic disease: The dosage of allopurinol should be reduced in patients with hepatic disease.
Dose recommended in impaired renal function: Allopurinol and its metabolites are excreted via the kidney. Impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action The amount and frequency may require reduction as indicated by monitoring serum uric acid levels. The following schedule is provided for guidance in adults:
If creatinine clearance exceeds 20ml/min - give standard dose
If creatinine clearance is between 20ml and 10ml/min - give 100 - 200mg/day.
If creatinine clearance is less than 10ml/min - give 100mg/day at longer intervals
Dose recommended in renal dialysis: Allopurinol and its metabolites are removed by renal dialysis. If frequent dialysis is required an alternative schedule of 300 -400mg Allopurinol after each dialysis with none in the interim should be considered.
4.3 Contraindications:
Should not be used in patients with a known intolerance to Allopurinol or to any other ingredients. Should not be used for treatment for acute attack of gout, nor immediately after an acute attack.
Use in the elderly: the dose should be maintained at the minimum necessary to
maintain serum and urinary urate levels.
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-B15801 allele
The HLA-B15801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B15801 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-B15801, 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).
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)
• Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of allopurinol.
• 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. (Adoption to individual drug if such data are available)
• 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.
• If the patient has developed SJS or TEN with the use of allopurinol, allopurinol must not be re-started in this patient at any time.
Acute gouty attacks: Treatment with Allopurinol should not be started during an acute attack of gout has been completely subsided, as further attacks may be precipitated
Dosage should be reduced in the patients with renal or hepatic disorders. Prophylactic doses of a suitable anti-inflammatory (not aspirin or salicylates) should be given concurrently. Fluid intake should ensure a urinary output of not less than 2 litres a day and the urine rendered alkaline if uric acid overload is high.
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.
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 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 antiinflammatory 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
Coumarin anticoagulants: Allopurinol may potentiate the effect of warfarin nicoumalone Azathioprine and 6-mercaptopurine: Allopurinol inhibits the metabolism of 6 - mercaptopurine, therefore, all patients receiving anticoagulants must be carefully monitored. The dosage of these should be reduced when given concurrently.
Adenine: Evidence suggests that the plasma half-life of vidarabine (adenine arabinoside) is increased in the presence of allopurinol. When given concurrently, patients should be observed for enhanced toxic effect.
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. When used with drugs which increase uricosuric activity such as probenecid or large doses of salicylates, Allopurinol therapeutic effect may be decreased, therefore the dose may have to be adjusted.
Chlorpropamide: when given concurrently with chlorpropramide, there may be a risk of prolonged hypoglycaemia if renal function is impaired.
ACE Inhibitors: increased risk of toxicity when allopurinol given with captopril especially in renal impairment.
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 the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared with 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.
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 coadministered.
Diuretics: Increased risk of hypersensitivity when allopurinol given with thiazides and related diuretics especially in renal impairment.
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. 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.
Cytotoxics: allopurinol enhances effects and increase toxicity of azathioprine and mercaptopurine (reduce dose of azathioprine and mercaptopurine) avoidance of allopurinol advised by the manufacturer of capecitabine.
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.
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.
4.6 Fertility, pregnancy and lactation
There is no evidence that Allopurinol taken orally causes fatal abnormalities; however, as with all drugs, 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.
Allopurinol is excreted in breast milk and should not be given to nursing mothers. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
4.7 Effect 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
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 (i 0.01% and <0.1%)), Very rare (<1/10,000 (<0.01%))
Adverse reactions in association with allopurinol are usually rare and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorders.
Infections and infestations
Very rare Furunculosis
Blood and lymphatic system disorders
Very rare Agranulocytosis, aplastic anaemia, thrombocytopenia.
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. Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
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).
Serious hypersensitivity reactions, Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis occur rarely (see Skin and subcutaneous tissue disorders). Associated tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment, Allopurinol should be withdrawn immediately and permanently.
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. (see section 4.4).
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
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) have been reported (see section 4.4)
Allopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Allopurinol may, if desired, be reintroduced 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).
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 (see section 4.4).
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, nocturnal emission
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)
Miscellaneous: exacerbation of acute gouty attacks may occur in the early stages of hypouricaemic therapy, see sub-section 4.2 Posology and Method of Administration. In those conditions where the body’s miscible urate pool is greatly increased (eg malignant disease and its treatment; Lesch-Nyhan syndrome), the rise in the xanthine concentration resulting from the action of allopurinol may lead to tissue deposits of xanthine. Fluid intake should ensure adequate urinary output. Xanthine crystals have been seen in the muscle tissue of patients receiving allopurinol, but this appears to have no clinical significance.
4.9 Overdose:
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported.
The most likely reaction would be gastro-intestinal intolerance. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20 g allopurinol.
A considerable inhibition of xanthine oxidase activity may occur, which should have no untoward effects unless 6-mercaptopurine, adenine arabinoside and/or azathioprine is being taken concomitantly, which should lead to the risk of increased activity of these drugs. Adequate hydration to maintain optimum diuresis facilitates excretion of Allopurinol and its metabolites. Dialysis may be considered necessary.
Pharmacotherapeutic Group: Antigout preparations inhibiting uric acid production
ATC code: M04 AA01
Allopurinol inhibits the action of xanthine oxidase and thus reduces the oxidation of hypoxanthine and xanthine to uric acid. The urinary purine load, normally almost entirely uric acid, is divided between hypoxanthine, xanthine and uric acid. The reduced concentration of uric acid in plasma facilitates the resolution of tophi and calculi. Hypoxanthine and xanthine may be re-utilized for nucleotide and nucleic acid synthesis, and purine biosynthesis may be reduced.
5.2 Pharmacokinetic Properties
Allopurinol is absorbed from the gastro-intestinal tract and is reported to have a plasma half life of about 1 hour. It is rapidly converted in the body into oxypurinol (alloxanthine) which is also an inhibitor of xanthine oxidase with a reported half life of 18 to 30 hours. Allopurinol and oxypurinol are not bound to serum proteins and are excreted mainly in the urine.
Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. A reduction in the dose of Allopurinol is therefore required in patients with renal impairment.
5.3 Preclinical safety data
A. Mutagenicity
Cytogenetic 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 mean period of 40 months.
Allopurinol does not produce nitraso 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.
B. Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.
C. Teratogenicity
One 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.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Lactose_
Starch_
Polyethylene Glycol 4000
Povidone_
Magnesium Stearate_
Colloidal Silicon Dioxide Microcrystalline Cellulose Sodium Starch Glycollate
6.2. Incompatibilities
No major incompatibilities have been reported.
6.3. Shelf life
5 years
6.4. Special precautions for storage
Protect from light heat and moisture. Store below 25°C.
6.5 Nature and contents of container
Plastic securitainer with snap secure polypropylene lids containing Allopurinol Tablets. (Material of the container complies to EEC directives for plastic in contact with drugs and food stuff). Pack size available 14, 28, 30, 50, 56, 100, 250, 500 and 1000 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Pharmvit limited 117 Bilton Road Perivale Greenford
Middlesex UB6 7HQ
8. MARKETING AUTHORISATION NUMBER
PL 04556/0006
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29 July 1983 / 25 March 1993
10 DATE OF REVISION OF THE TEXT
20/11/2014
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.