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1. NAME OF THE MEDICINAL PRODUCT
Allopurinol 100 mg tablets Allopurinol 300 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Allopurinol 100 mg tablets Each tablet contains 100 mg allopurinol.
Allopurinol 300 mg tablets Each tablet contains 300 mg allopurinol.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet Allopurinol 100 mg tablets White, round, biconvex tablets with a single-sided score notch. The tablet can be divided into equal halves.
Allopurinol 300 mg tablets White to off-white, biconvex oblong tablet with both-sided breaking notch. The tablet can be divided into equal halves.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications Allopurinol 100 mg Adults All forms of hyperuricaemia not controllable by diet, with serum uric acid values in the range of 535 µmol/l (9 mg/100 ml) and above and in clinical complications of
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hyperuricaemic states, particularly manifest gout, urate nephropathy, for the dissolution and prevention of uric acid stones as well as for the prevention of the formation of calcium oxalate stones in concurrent hyperuricaemia
Adults, children and adolescents ≥ 15 kg bodyweight Secondary hyperuricaemia of differing origin
Children and adolescents ≥ 15 kg bodyweight Uric acid nephropathy during treatment of leukaemia Hereditary enzyme deficiency disorders, Lesch-Nyhan syndrome (partial or total hypoxanthin-guanin phosphoribosyl transferase deficiency) and adenine phosophoribosyl transferase deficiency.
Allopurinol 300 mg Adults All forms of hyperuricaemia not controllable by diet, with serum uric acid values in the range of 535 µmol/l (9 mg/100 ml) and above and in clinical complications of hyperuricaemic states, particularly manifest gout, urate nephropathy, for the dissolution and prevention of uric acid stones as well as for the prevention of the formation of calcium oxalate stones in concurrent hyperuricaemia
Adults, children and adolescents ≥ 45 kg bodyweight Secondary hyperuricaemia of differing origin
Children and adolescents ≥ 45 kg bodyweight Uric acid nephropathy during treatment of leukaemia Hereditary enzyme deficiency disorders, Lesch-Nyhan syndrome (partial or total hypoxanthin-guanin phosphoribosyl transferase deficiency) and adenine phosophoribosyl transferase deficiency.
4.2 Posology and method of administration
Allopurinol 100 mg tablets
Dosage in adults Allopurinol should be introduced at a low dosage e.g. 100 mg/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 impaired renal function”).
The following dosage schedules are suggested: 100 mg to 200 mg daily in mild conditions, 300 mg to 600 mg in moderately severe conditions, 700 mg to 900 mg daily in severe conditions. Dosage higher than 300 mg should be given in divided doses not exceeding 300 mg at any time. If dosage on a mg/kg bodyweight basis is required, 2-10 mg/kg bodyweight/day should be used.
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Dosage in children and adolescents ≥ 15 kg bodyweight The daily dose is 10 mg allopurinol per kilogram bodyweight (maximum 400 mg daily) given in 3 divided doses.
Dosage in older people As there are no specific data available on the use of allopurinol in elderly patients, this patient group should be treated with the lowest therapeutically justifiable dosage. Furthermore, the possibility of impaired renal function should be considered, especially in older patients.
Dosage in impaired renal function As allopurinol and its metabolites are excreted via the kidney, overdose can occur in cases of impaired renal function if the dosage is not adjusted appropriately.
For this reason, an adjustment of the recommended dosage is indicated to minimise this risk. In cases of severe impairment of kidney function, a maximum of 100 mg allopurinol should be administered daily, or single doses of 100 mg should be administered at intervals of more than a day. The respective dose should be raised only if the effects are inadequate. The level of oxypurinol in the serum should not exceed a value of 15.2 g/ml.
The following table provides guidance for the dosage in case of renal insufficiency:
Creatinine Clearance Daily Dose > 20 ml/min standard dose 10 to 20 ml/min 100 to 200 mg < 10 ml/min 100 mg or 100 mg every 2 or 3 days
In case of haemodialysis 300 mg to 400 mg allopurinol can be administered immediately after every treatment session (i.e. 2 or 3 times weekly).
Dosage in impaired hepatic function Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy. Allopurinol 300 mg tablets
Dosage in adults
Allopurinol should be introduced at a low dosage e.g. 100 mg/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 patients with impaired renal or hepatic function).
The following dosage schedules are suggested: 100 mg to 200 mg daily in mild conditions, 300 mg to 600 mg in moderately severe conditions, 700 mg to 900 mg daily in severe conditions.
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Dosage higher than 300 mg should be given in divided doses not exceeding 300 mg at any time. If dosage on a mg/kg bodyweight basis is required, 2-10 mg/kg bodyweight/day should be used.
Dosage in children and adolescents ≥ 45 kg bodyweight The daily dose is 10 mg allopurinol per kilogram bodyweight (maximum 400 mg daily) given in 3 divided doses.
Dosage in older people As there is no specific data available on the use of allopurinol in elderly patients, this patient group should be treated with the lowest therapeutically justifiable dosage. Furthermore, the possibility of impaired renal function should be considered, especially in older patients.
Dosage in patients with impaired renal or hepatic function Due to the high content of active substance, Allopurinol 300 mg is not suitable for patients with impaired renal or hepatic function.
In case of haemodialysis 300 mg to 400 mg allopurinol can be administered immediately after every treatment session (i.e. 2 or 3 times weekly).
Allopurinol 100 mg and Allopurinol 300 mg Method and duration of treatment The tablets should be taken unchewed with plenty of liquid after a meal. If the daily dose of 300 mg allopurinol is exceeded or if symptoms of gastrointestinal intolerance occur, the dose should be divided and administered over the course of the day.
The duration of treatment depends upon the underlying disorder. In order to prevent formation of calcium oxalate and uric acid stones and in cases of primary hyperuricaemia and gout, long-term therapy is necessary in most cases. In cases of secondary hyperuricaemia, transient treatment in accordance with the duration of raised uric acid values is recommended.
4.3 Contraindications
Allopurinol 100 mg: Hypersensitivity to the active substance allopurinol or to any of the excipients listed in section 6.1. Children < 15 kg bodyweight
Allopurinol 300 mg: Hypersensitivity to the active substance allopurinol or to any of the excipients. Severe renal dysfunction with a creatinine clearance of below 20 ml/min
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Children < 45 kg bodyweight
4.4 Special warnings and precautions for use
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. 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, Allopurinol must not be re-started in this patient at any time.
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.
According to recent recommendations expressed in the literature, treatment with medicinal products is unnecessary if uric acid levels are below 535 mol/l (equivalent to 9 mg/100 ml), providing dietary recommendations are followed and there is no kidney damage. Foods with high purine content (e.g. offal such as sweetbread, kidney, brain, liver, heart and tongue as well as meat extract) and alcohol (particularly beer, as this leads to uptake of guanosine, a ribonucleoside which profoundly raises the level of uric acid) should be avoided.
If hypersensitivity reactions occur (e.g. exanthema) Allopurinol should be discontinued immediately.
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Particularly close monitoring by the physician is necessary in cases of impaired renal or hepatic function or pre-existing haematopoiesis disorders. In patients with impaired renal or hepatic function the relevant dosage recommendations must be taken into account (see section 4.2). Especially in patients treated e.g. with ACE inhibitors or diuretics because of high blood pressure or cardiac insufficiency, allopurinol should be administered with caution, as patients in this group can suffer from impaired renal function.
In the treatment of renal gout and uric acid stones, the volume of urine produced should be at least 2 liters per day.
In order to avoid raised concentrations of uric acid in the serum or the urine (as can occur in radiotherapy or chemotherapy of neoplasms as well as in Lesch-Nyhan-syndrome) in addition to administration of allopurinol, plenty of liquids should be taken to assure sufficient diuresis. Furthermore, alkalisation of the urine leading to improved dissolution of urate/uric acid can contribute to increased excretion of these substances.
If urate nephropathy or any other pathological alteration has already caused impairment of renal function, the dosage must be adjusted according to the renal function parameters (see section 4.2).
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 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 the case of large uric acid stones in the renal pelvis, it cannot be excluded that parts of the stones dissolved during treatment with allopurinol could become trapped in the ureter.
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.
Salicylates and uricosuric agents
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Oxipurinol, the 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.
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 the 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 mechloroethamine (mustine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.
Cyclosporin
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Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced cyclosporin 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. Therefore, dose reductions of didanosine may be required when used concomitantly with allopurinol.
Captopril With concomitant administration of allopurinol and captopril, the risk of skin reactions can be raised, especially in cases of chronic renal failure.
4.6 Fertility, pregnancy and lactation
Pregnancy: There are insufficient data available regarding use of allopurinol in pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). As allopurinol interferes with purine metabolism and the potential risk for humans is not known, allopurinol should not be used during pregnancy, unless it is explicitly necessary.
Breast-feeding: Allopurinol and oxipurinol are secreted in small amounts into the mother’s milk. The dose to which the infant can then be exposed may approach the therapeutic level, however, effects on the infant have not been shown. Because of very limited experience, allopurinol should not be used during the lactation period.
4.7 Effects on ability to drive and use machines
While taking allopurinol undesirable effects as drowsiness, dizziness and ataxia might occur. The use of allopurinol may reduce the ability to react thus impairing the ability to drive and the ability to operate machinery.
4.8 Undesirable effects
The evaluation of undesirable effects is based on the following frequency conventions: Very common (1/10) Common (1/100 to <1/10)
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Uncommon (1/1,000 to <1/100) Rare (1/10,000 to <1/1,000) Very rare (<1/10,000), Not known (cannot be estimated from the available data)
Skin and subcutaneous tissue disorders Of the undesirable effects observed, skin reactions are the most common (approx. 4%); these can occur at any time during the treatment and are manifested as pruritus, in maculopapular, sometimes squamous, sometimes purpura-like and rarely exfoliative form.
At the first sign of these types of reaction, Allopurinol should be discontinued immediately. After mild symptoms have subsided, therapy can be recommenced at a low dose (e.g. 50 mg daily). This dose can be increased gradually if necessary. If the skin rash reappears, the preparation should be discontinued completely, as severe generalised hypersensitivity reactions can occur.
Very rare: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4) alopecia furunculosis Quincke’s oedema discoloured hair
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.
Hepatobiliary disorders Rare: disorders of hepatic function, ranging from an asymptomatic rise in liver function parameters to hepatitis (including hepatic necrosis and granulomatous hepatitis) in extreme cases
Gastrointestional disorders Uncommon: nausea vomiting
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diarrhoea
Very rare: haematemesis steatorrhea stomatitis
Not known: gastrointestinal bleeding
Blood and lymphatic system disorders Uncommon: thrombocytopenia agranulocytosis aplastic anaemia especially in patients with renal dysfunction. Particularly careful monitoring of this patient group is therefore necessary.
Very rare: altered blood counts such as leukopenia, leukocytosis, granulocytosis and eosinophilia pure red cell aplasia
General disorders and administration site conditions:
Very rare: general malaise asthenia oedema
Respiratory, thoracic and mediastinal disorders Very rare: angina
Nervous system disorders Very rare: ataxia peripheral neuritis change in taste perception coma headache neuropathy paralysis dizziness somnolence paraesthesia
Cardiac disorders Very rare: bradycardia
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Metabolism and nutrition disorders Very rare: diabetes mellitus, hyperlipidaemia
Psychiatric disorders Very rare: depression
Reproductive system and breast disorders Very rare: gynaecomastia impotence infertility
Renal and urinary disorders Very rare: haematuria uraemia
Not known: renal failure
Vascular disorders Very rare: hypertension
Eye disorders Very rare: cataract macular degeneration visual impairment
Musculoskeletal and connective tissue disorders Very rare: muscle pain
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 national reporting system listed in Appendix V.
4.9 Overdose There is no known specific antidote. After taking a single dose of 20 g, symptoms such as nausea, vomiting, diarrhoea and dizziness occurred in one patient. In another patient a dose of 22.5 g resulted in no undesirable effects. If intoxication is suspected, especially in cases of co-medication with azathioprine or 6- mercaptopurine, the patient can be helped by administering activated coal (only when the intake is not longer than an hour before).
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Extensive absorption of allopurinol can considerably inhibit the activity of xanthine-oxidase, which would not lead to adverse effects, unless it effects simultaneous applied medicines, especially azathioprine or 6-mercaptopurine. In such a case, the risk of an increased activity should be recognized. Maximal diuresis stimulates the excretion of allopurinol and its metabolites. When necessary, haemodialysis can be applied.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antigout preparations; preparations inhibiting uric acid production, ATC code: M04 AA01
Allopurinol, and its main metabolite oxypurinol, reduce the production of uric acid through inhibition of the enzyme xanthine oxidase, which plays an important role in the oxidation of hypoxanthine to uric acid. As a result, uric acid and urate levels in the body fluids and in urine are lowered.
In addition to inhibition of the metabolism of purine, the de novo biosynthesis of purine is suppressed in some patients through inhibition of hypoxanthine guanine phosphoribosyl transferase.
5.2 Pharmacokinetic properties
Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67 % to 90 %. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of allopurinol, but fall rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after 3-5 hours after oral administration of allopurinol and are much more sustained. Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.3 liter/kg which suggests relatively extensive uptake by tissues. Approximately 20 % of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10 % of the unchanged drug excreted in the urine. Allopurinol has a plasma half-life of about 1 to 2 hours.
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Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half- life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of allopurinol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10 mg/liter. Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.
Pharmacokinetics in patients with renal impairment Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20 ml/min, showed plasma oxipurinol concentrations of approximately 30 mg/liter after prolonged treatment with 300 mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the allopurinol dose is therefore required in patients with renal impairment.
Pharmacokinetics in older people The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see Pharmacokinetics in patients with renal impairment).
5.3 Preclinical safety data After prolonged use of allopurinol in animal studies, precipitation of xanthine precipitates occurred with high doses, and this led to changes in the efferent urinary organs.
The in-vitro and in-vivo studies carried out to date revealed no evidence of a mutagenic or carcinogenic potential.
In animal studies, teratogenic effects occurred from day 10 of gestation onwards in mice at high doses. No teratogenic effects were shown in rats and rabbits.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose powdered Povidone K25)
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Macrogol 4000 Crospovidone Talc Magnesium stearate Microcrystalline cellulose
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
Shelf life after first opening of the HDPE container: 6 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Allopurinol 100 mg PVC/aluminium and PP/aluminium blisters with 1, 7, 10, 25, 28, 30, 50, 90, 100 tablets HDPE tablet containers with PE lid closures with 50, 100, 250, 500, 1000 tablets
Not all pack sizes may be marketed.
Allopurinol 300 mg PVC/aluminium and PP/aluminium blisterswith 1, 7, 10, 20, 28, 30, 50, 90, 100, 105 tablets HDPE tablet containers with PE lid closures with 20, 30, 50, 100, 105, 250, 500, 1000 tablets
Not all pack sizes may be marketed.
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6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
<{MM/YYYY}>
<[To be completed nationally]>