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1.

Name of the medicinal product


Allopurinol 300mg Tablets
2. Qualitative and quantitative composition
Each tablet contains Allopurinol 300mg.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
White to off white, round, biconvex with beveled edge uncoated tablet with inscription
"AX' on one side and plain on the other side
4. Clinical particulars
4.1 Therapeutic indications
Allopurinol is indicated for reducing urate/uric acid formation in conditions where
urate/uric acid deposition has already occurred (e.g. gouty arthritis, skin tophi,
nephrolithiasis) or is a predictable clinical risk (e.g. treatment of malignancy potentially
leading to acute uric acid nephropathy). The main clinical conditions where urate/uric acid
deposition may occur are: idiopathic gout; uric acid lithiasis; acute uric acid nephropathy;
neoplastic disease and myeloproliferative disease with high cell turnover rates, in which
high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme
disorders which lead to overproduction of urate, for example: hypoxanthine-guanine
phosphoribosyltransferase, including Lesch-Nyhan syndrome; glucose-6-phosphatase
including glycogen storage disease; phosphoribosylpyrophosphate synthetase,
phosphoribosylpyrophosphate amidotransferase; adenine phosphoribosyltransferase.
Allopurinol is indicated for management of 2,8-dihydroxyadenine (2,8-DHA) renal stones
related to deficient activity of adenine phosphoribosyltransferase.
Allopurinol is indicated for the management of recurrent mixed calcium oxalate renal
stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have
failed.

4.2 Posology and method of administration


Posology
Adults: Allopurinol should be introduced at low dosage e.g. 100mg/day to reduce the risk
of adverse reactions and increased only if the serum urate response is unsatisfactory. Extra
caution should be exercised if renal function is poor (see Patients with renal impairment).
The following dosage schedules are suggested:
100 to 200 mg daily in mild conditions,
300 to 600 mg daily in moderately severe conditions,
700 to 900 mg daily in severe conditions.
If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should
be used.

Paediatric population:
Children under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily.
Use in children is rarely indicated, except in malignant conditions (especially leukaemia)
and certain enzyme disorders such as Lesch-Nyhan syndrome.
Older people: In the absence of specific data, the lowest dosage which produces
satisfactory urate reduction should be used. Particular attention should be paid to advice in
patients with renal impairment and section 4.4.
Patients with renal impairment: Since allopurinol and its metabolites are excreted by the
kidney, impaired renal function may lead to retention of the drug and/or its metabolites
with consequent prolongation of plasma half-lives. In severe renal insufficiency, it may be
advisable to use less than 100 mg per day or to use single doses of 100mg at longer
intervals than one day.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be
adjusted to maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre).
Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required two to
three times a week consideration should be given to an alternative dosage schedule of 300-
400 mg Allopurinol immediately after each dialysis with none in the interim.
Patients with hepatic impairment: Reduced doses should be used in patients with hepatic
impairment. Periodic liver function tests are recommended during the early stages of
therapy.
Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome: It is
advisable to correct existing hyperuricaemia and/or hyperuricosuria with Allopurinol before
starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum
diuresis and to attempt alkalinisation of urine to increase solubility of urinary urate/uric
acid. Dosage of Allopurinol should be at the lower end of the recommended dosage
schedule.
If urate nephropathy or other pathology has compromised renal function, the advice given
in Patients with renal impairment should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the
clinical situation. See also sections 4.5 and 4.8.
Monitoring Advice: The dosage should be adjusted by monitoring serum urate
concentrations and urinary urate/uric acid levels at appropriate intervals.
Method of administration: Allopurinol may be taken orally once a day after a meal. It is
well tolerated, especially after food. Should the daily dosage exceed 300 mg and
gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.
4.3 Contraindications
Allopurinol should not be administered to individuals known to be hypersensitive to
allopurinol or to any of the components of the formulation listed in section 6.1.
4.4 Special warnings and precautions for use

.
Lactose :
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: There have been rare reports of increased effect of warfarin and
other coumarin anticoagulants when coadministered with allopurinol, therefore, all patients
receiving anticoagulants must be carefully monitored.
Azathioprine and 6-mercaptopurine: 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 halflife 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:Oxipurinol, the major active metabolite of allopurinol, is
excreted by the kidney in a similar way to urate. Hence drugs with uricosuric activity such
as probenecid or large doses of salicylates 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.
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 co-administered.
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.
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.
Diuretics
An interaction between allopurinol and furosemide that results in increased serum urate and
plasma oxypurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with
diuretics, in particular thiazides, especially in renal impairment.
Angiotensin-converting-enzyme (ACE) inhibitors
An increased risk of hypersensitivity has been reported when allopurinol is given with ACE
inhibitors especially in renal impairment
.
4.6 Pregnancy and lactation
Pregnancy:
There is inadequate evidence of safety of Allopurinol in human pregnancy, although it has
been in wide use for many years without apparent ill consequence.
Use in pregnancy only when there is no safer alternative and when the disease itself carries
risk for the mother or unborn child.
Breast-feeding:
Reports indicate that allopurinol and oxipurinol are excreted in human breast milk.
Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been
demonstrated in breast milk from woman taking Allopurinol 300 mg/day. However, there
are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
4.7 Effects on ability to drive and use machines
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in
patients receiving allopurinol, patients should exercise caution before driving, using
machinery or participating in dangerous activities until they are reasonably certain that
allopurinol does not adversely affect performance.
4.8 Undesirable effects
For this product there is no modern clinical documentation which can be used as support
for determining the frequency of undesirable effects. Undesirable effects may vary in their
incidence depending on the dose received and also when given in combination with other
therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for
most reactions, suitable data for calculating incidence are not available. Adverse drug
reactions identified through post-marketing surveillance were considered to be rare or very
rare. The following convention has been used for the classification of frequency:
Very common 1/10
Common 1/100 and <1/10
Uncommon 1/1000 and <1/100
Rare 1/10,000 and <1/1000
Very rare <1/10,000
Adverse reactions in association with Allopurinol are rare in the overall treated population
and mostly of a minor nature. The incidence is higher in the presence of renal and/or
hepatic disorder.
Table 1 Undesirable effects
System Organ Class Frequency Adverse reaction
Infections and infestations Very rare Furuncle
Blood and lymphatic system Very rare Agranulocytosis1
disorders Aplastic anaemia1
Thrombocytopenia1
Immune system disorders Uncommon Hypersensitivity 2
Very rare Angioimmunoblastic T-c
lymphoma 3
Metabolism and nutrition disorders Very rare Diabetes mellitus
Hyperlipidaemia
Psychiatric disorders Very rare Depression
Nervous system disorders Very rare Coma
Paralysis
Ataxia
Neuropathy peripheral
Paraesthesia
Somnolence
HeadacheDysgeusia
Eye disorders Very rare Cataract
Visual impairment
Maculopathy
Ear and labyrinth disorders Very rare Vertigo
Cardiac disorders Very rare Angina pectoris
Bradycardia
Vascular disorders Very rare Hypertension
Gastrointestinal disorders Uncommon Vomiting4
Nausea4
Very rare Haematemesis
Steatorrhoea
Stomatitis
Change of bowel habit
Hepatobiliary disorders Uncommon Liver function test abnormal5
Rare Hepatitis (including hepatic necro
and granulomatous hepatitis) 5
Skin and subcutaneous tissue Common Rash
disorders Rare Stevens-Johnson syndrome/tox
epidermal necrolysis 6
Very rare Angioedema7
Drug eruption
Alopecia
Hair colour changes
Renal and urinary disorders Very rare Haematuria
Azotaemia
Reproductive system and breast Very rare Infertility male
disorders Erectile dysfunction
Gynaecomastia
General disorders and Very rare Oedema
administration site conditions Malaise
Asthenia
Pyrexia 8
1 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.
2 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.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and
SJS/TEN. 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.
3 Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy
of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Allopurinol
tablets.
4 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 tablets
after meals.
5 Hepatic dysfunction has been reported without overt evidence of more generalised
hypersensitivity.
6 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). The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is
within the first weeks of treatment. The best results in managing such reactions come from
early diagnosis and immediate discontinuation of any suspect drug. Allopurinol tablets
should be withdrawn immediately should such reactions occur. After recovery from mild
reactions, Allopurinol tablets may, if desired, be re-introduced at a small dose (e.g. 50
mg/day) and gradually increased. If the rash recurs, Allopurinol tablets should be
permanently withdrawn as more severe hypersensitivity may occur (see Immune system
disorders). If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO
NOT re-introduce allopurinol due to the potential for a severe or even fatal reaction. 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.
7 Angioedema has been reported to occur with and without signs and symptoms of a more
generalised hypersensitivity reaction.
8 Fever has been reported to occur with and without signs and symptoms of a more
generalised Allopurinol tablets hypersensitivity reaction (see Immune system disorders).
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 Yellow
Card Scheme.
Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms
and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a
patient who ingested 20 g allopurinol. Recovery followed general supportive measures.
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 and/or azathioprine. Adequate hydration to maintain
optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered
necessary haemodialysis may be used.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antigout preparations inhibiting uric acid production
ATC code: M04 AA01
Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol
lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the
enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In
addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients,
de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine
phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside
and oxipurinol-7 riboside.
5.2 Pharmacokinetic properties
Absorption:
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.
Distribution:
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 1.6 litre/kg which suggests relatively extensive uptake by
tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is
likely that allopurinol and oxipurinol will be present in the highest concentrations in the
liver and intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of Allopurinol tablets is oxipurinol. Other metabolites of allopurinol
include allopurinol-riboside and oxipurinol-7-riboside.
Elimination:
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.
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/litre.
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 20ml/min, showed plasma oxipurinol
concentrations of approximately 30mg/litre 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 dose of
Allopurinol is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients.
The kinetics of the drug are not likely to be altered other than due to deterioration in renal
function (see Pharmocokinetics 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
Maize starch
Povidone K-30
Crospovidone
Magnesium stearate
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Container pack: Do not store above 25C. Store in the original container. Keep the
container tightly closed.
Blister pack: Do not store above 25C. Store in the original package.
6.5 Nature and contents of container
Polypropylene tablet containers fitted with low density polyethylene caps.
Pack sizes: 28,100,500 and 1000 tablets.
Blister pack (clear PVC 250 micron and plain aluminium foil 20 micron)
Pack size: 28 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Not applicable.

ALLOPURINOL TABLETS BP 100mg


2. Qualitative and quantitative composition
Each tablet contains 100mg Allopurinol PhEur
Excipient with known effect: Each table contains 130.66 mg of lactose monohydrate
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
White uncoated tablets
White, circular, biconvex, uncoated tablets impressed C and the identifying letters AD
on either side of a central division line on one face.
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 which lead to overproduction of urate and involving:
hypoxanthine guanine phosphoribosyl transferase, such as Lesch-Nyhanb syndrome,
glucose-6-phosphatase, as in von Gierke's disease or fosforibosylpyrofosfaatsynthetase;
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.
Paediatric population: 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 300-400mg after
each dialysis, with none in the interim, should be considered.
Method of Administration
For oral administration
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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
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).
Chronic renal impairment
Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides,
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).
A reduction in dosage should be considered in the presence of severe renal or hepatic
disorders.
Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic
epidermalnecrolysis (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.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has also been reported
with the use of allopurinol. DRESS is characterised by fever, eosinophilia, atypical
circulating lymphocites, lymphadenopathy and hepatitis.
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.
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 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.
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. 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
6-mercaptopurine and azathioprine: If azathioprine or 6-mercaptopurine is given
concurrently with allopurinol, the dose of these agents should only be one quarter of that
usually given as inhibition of xanthine oxidase will prolong their activity.
Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of adenine
arabinoside is increased in the presence of allopurinol and hence when these two agents are
administered concomitantly, extra vigilance is required 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 Zyloric, but the
significance needs to be assessed in each case.
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.
Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal
function is poor, there may be an increased risk of prolonged hypoglycaemic activity.
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 (chlormethine
hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic
agents.
Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased
during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin
toxicity should be considered if the drugs are co-administered.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma
didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol
treatment (300 mg daily) without affecting terminal half life. Co-administration of these 2
drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of
didanosine may be required, and patients should be closely monitored.
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
separated 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 Pregnancy and lactation
Pregnancy
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, caution should be exercised in the use of allopurinol during pregnancy.
Breast-feeding
Reports indicate that allopurinol and oxipurinol are excreted in human breast milk.
Concentrations of 1.4mg/litre allopurinol and 53.7mg/litre oxipurinol have been
demonstrated in breast milk from women taking allopurinol 300mg/day. However, there is
no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
4.7 Effects on ability to drive and use machines
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in
patients receiving allopurinol, patients should exercise caution before driving, using
machinery or participating in dangerous activities until they are reasonably certain that
allopurinol does not adversely affect performance.
4.8 Undesirable effects
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
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 tablets 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.
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. 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
toxicepidermal necrolysis (TEN) have been reported (see section 4.4).
Frequency not known: skin reaction associated with eosinophilia, urticaria.
Drug Rash with Eosinophilia and Systemic Symptoms has been reported. Some cases have
had a fatal outcome.
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 (eg 50mg/day) which may be gradually increased. If the rash recurs, allopurinol
should be permanently withdrawn.
The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol
associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of
Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African
and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern
European, US European and Japanese patients are estimated to be HLA-B*5801 carriers.
However, the use of genotyping as a screening tool to make decisions about treatment with
allopurinol has not been established.
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.
Renal and urinary disorders
Very rare: haematuria, uraemia
Frequency not known: nephrolithiasis
Reproductive system and breast disorders
Very rare: gynaecomastia, impotence, infertility
Frequency not known: nocturnal emissions
General disorders and administration site conditions
Very rare: asthenia, fever, general malaise, oedema
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; website: www.mhra.gov.uk/yellowcard
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 adenine arabinoside, azathioprine or 6-mercaptopurine 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. Hameodialysis may be considered in patients with
severe renal or hepatic impairment.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antigout preparations inhibiting uric acid production
ATC code M04 AA01
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
Also contains:
Maize starch
Carmellose sodium
Cellulose
Sodium lauryl sulfate
Lactose
Magnesium stearate
6.2 Incompatibilities
None known
6.3 Shelf life
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution
Not applicable
Shelf-life after first opening
Not applicable
6.4 Special precautions for storage
Store below 25C in a dry place.
6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-
moulded polyethylene containers with snap-on polyethylene lids; in case any supply
difficulties should arise the alternative is amber glass containers with screw caps.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250m white rigid PVC. (ii) Surface printed 20m hard temper
aluminium foil with 5-7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse
side.
Pack sizes: 28's, 30's, 56's, 60's, 84's, 90's, 100's, 112's, 1000's.
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags
contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk
packs are included for temporary storage of the finished product before final packaging into
the proposed marketing containers.
Maximum size of bulk packs: 25,000.
6.6 Special precautions for disposal and other handling
Not applicable
1. Name of the medicinal product
Allopurinol 100mg Tablets
2. Qualitative and quantitative composition
Allopurinol BP 100.00mg
3. Pharmaceutical form
Oral Tablet
4. Clinical particulars
4.1 Therapeutic indications
Allopurinol is indicated for reducing urate/uric acid formation in conditions where
urate/uric acid deposition has already occurred (e.g. gouty arthritis, skin tophi,
nephrolithiasis) or is a predictable clinical risk (e.g. treatment of malignancy potentially
leading to acute uric acid nephropathy). The main clinical conditions where urate/uric acid
deposition may occur are: idiopathic gout; uric acid lithiasis; acute uric acid nephropathy;
neoplastic disease and myeloproliferative disease with high cell turnover rates, in which
high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme
disorders which lead to overproduction of urate, for example: hypoxanthine-guanine
phosphoribosyltransferase, including Lesch-Nyhan syndrome; glucose-6-phosphatase
including glycogen storage disease; phosphoribosylpyrophosphate synthetase,
phosphoribosylpyrophosphate amidotransferase; adenine phosphoribosyltransferase.
Allopurinol is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal
stones related to deficient activity of adenine phosphoribosyltransferase.
Allopurinol is indicated for the management of recurrent mixed calcium oxalate renal
stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have
failed.
4.2 Posology and method of administration
Posology
Adults
Allopurinol should be introduced at 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 section 4.2 Renal impairment).
The following dosage schedules are suggested:
100 to 200 mg daily in mild conditions,
300 to 600 mg daily in moderately severe conditions,
700 to 900 mg daily in severe conditions.
If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should
be used.
Paediatric population
Children under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily.
Use in children is rarely indicated, except in malignant conditions (especially leukaemia)
and certain enzyme disorders such as Lesch-Nyhan syndrome.
Older people
In the absence of specific data, the lowest dosage which produces satisfactory urate
reduction should be used. Particular attention should be paid to advice in section 4.2 Renal
impairment and section 4.4.
Renal impairment
Since allopurinol and its metabolites are excreted by the kidney, impaired renal function
may lead to retention of the drug and/or its metabolites with consequent prolongation of
plasma half-lives. In severe renal insufficiency, it may be advisable to use less than 100 mg
per day or to use single doses of 100 mg at longer intervals than one day. If facilities are
available to monitor plasma oxipurinol concentrations, the dose should be adjusted to
maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre). Allopurinol
and its metabolites are removed by renal dialysis. If dialysis is required two to three times a
week consideration should be given to an alternative dosage schedule of 300-400 mg
allopurinol immediately after each dialysis with none in the interim.
Hepatic impairment
Reduced doses should be used in patients with hepatic impairment. Periodic liver function
tests are recommended during the early stages of therapy.
Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome
It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with allopurinol
before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain
optimum diuresis and to attempt alkalinisation of urine to increase solubility of urinary
urate/uric acid. Dosage of allopurinol should be at the lower end of the recommended
dosage schedule.
If urate nephropathy or other pathology has compromised renal function, the advice given
in section 4.2 Renal impairment should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the
clinical situation. See also section 4.5 and section 4.8.
Monitoring Advice
The dosage should be adjusted by monitoring serum urate concentrations and urinary
urate/uric acid levels at appropriate intervals.
Method of administration
Allopurinol may be taken orally once a day after a meal. It is well tolerated, especially after
food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested,
a divided doses regimen may be appropriate.
4.3 Contraindications
Allopurinol should not be administered to individuals known to be hypersensitive to the
active substance or to any of the excipients listed in section 6.1.
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 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.
Chronic renal impairment
Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides,
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).
Hepatic or renal impairment
Reduced doses should be used in patients with hepatic or renal impairment (see section 4.2).
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
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 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.
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.
Thyroid disorders
Increased TSH values (>5.5 IU/mL) were observed in patients on long-term treatment
with allopurinol (5.8%) in a long term open label extension study.
Lactose
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
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 the enhanced toxic effects.
Salicylates and uricosuric agents
Oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted
by the kidney in a similar way to urate. Hence, drugs with uricosuric activity such as
probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may
decrease the therapeutic activity of allopurinol, but the significance needs to be assessed in
each case.
Chlorpropamide
If allopurinol is given concomitantly with chlorpropamide when renal function is poor,
there may be an increased risk of prolonged hypoglycaemic activity because allopurinol
and chlorpropamide may compete for excretion in the renal tubule.
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 and carbamazepine
Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not
been demonstrated. Plasma carbamazepine concentrations can be gradually increased and
the dose of carbamazepine may need to be reduced.
Theophylline
Inhibition of the metabolism of theophylline has been reported. The mechanism of the
interaction may be explained by xanthine oxidase being involved in the biotransformation
of theophylline in man. Theophylline levels should be monitored in patients starting or
increasing allopurinol therapy.
Ampicillin/Amoxicillin
An increase in frequency of skin rash has been reported among patients receiving
ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not
receiving both drugs. The cause of the reported association has not been established.
However, it is recommended that in patients receiving allopurinol an alternative to
ampicillin or amoxicillin is used where available.
Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine
Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has
been reported among patients with neoplastic disease (other than leukaemia), in the
presence of allopurinol. However, in a well-controlled study of patients treated with
cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine
(chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of
these cytotoxic agents.
Ciclosporin
Reports suggest that the plasma concentration of ciclosporin may be increased during
concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity
should be considered if the drugs are co-administered.
Didanosine
In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and
AUC values were approximately doubled with concomitant allopurinol treatment (300mg
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.
Diuretics
An interaction between allopurinol and furosemide that results in increased serum urate and
plasma oxypurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with
diuretics, in particular thiazides, especially in renal impairment.
Angiotenstin-converting-enzyme (ACE) inhibitors
An increased risk of hypersensitivity has been reported when allopurinol is given with ACE
inhibitors especially in renal impairment.
Capecitabine
Concomitant use of allopurinol and capecitabine (prodrug of fluorouracil) should be
avoided because allopurinol may decrease the activity of capecitabine.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of safety of allopurinol in human pregnancy, although it has
been in wide use for many years without apparent ill consequence (see section 5.3).
Use in pregnancy only when there is no safer alternative and when the disease itself carries
risk for the mother or unborn child.
Breast-feeding
Reports indicate that allopurinol and oxipurinol are excreted in human breast milk.
Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxypurinol have been
demonstrated in breast milk from a woman taking allopurinol 300 mg/day. However, there
are no data concerning the effects of allopurinol or its metabolites in the breast-fed baby.
4.7 Effects on ability to drive and use machines
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in
patients receiving allopurinol, patients should exercise caution before driving, using
machinery or participating in dangerous activities until they are reasonably certain that
allopurinol does not adversely affect performance.
4.8 Undesirable effects
For this product there is no modern clinical documentation which can be used as support
for determining the frequency of undesirable effects. Undesirable effects may vary in their
incidence depending on the dose received and also when given in combination with other
therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for
most reactions, suitable data for calculating incidence are not available. Adverse drug
reactions identified though 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
Common 1/100 to <1/10
Uncommon 1/1,000 to < 1/100
Rare 1/10,000 to < 1/1,000
Very rare < 1/10,000
Adverse reactions in association with allopurinol are rare in the overall treated population
and mostly of a minor nature. The incidence is higher in the presence of renal and/or
hepatic disorder.
Table 1 Tabulated summary of adverse reactions
System Organ Class Frequency Adverse Reaction
Infections and infestations Very rare Furuncle
Blood and lymphatic system disorders Very rare Agranulocytosis1
Aplastic anaemia1
Thrombocytopenia1
Not known Haemolytic anaemia
Immune system disorders Uncommon Hypersensitivity2
Very rare Angioimmunoblastic T-cell lymphoma3
Metabolism and nutrition disorders Very rare Diabetes mellitus
Hyperlipidaemia
Psychiatric conditions Very rare Depression
Nervous system disorders Very rare Coma
Paralysis
Ataxia
Neuropathy peripheral
Paraesthesiae
Somnolence
Headache
Dysgeusia
Eye disorders Very rare Cataract
Visual impairment
Maculopathy
Ear and labyrinth disorders Very rare Vertigo
Cardiac disorders Very rare Angina pectoris
Bradycardia
Vascular disorders Very rare Hypertension
Gastrointestinal disorders Uncommon Vomiting4
Nausea4
Very rare Haematemesis
Steatorrhoea
Stomatitis
Changed bowel habit
Hepatobiliary disorders Uncommon Liver function test abnormal5
Rare Hepatitis (including hepatic necrosis a
granulomatous hepatitis)5
Skin and subcutaneous tissue disorders Common Rash
Rare Stevens-Johnson syndrome/toxic epiderm
necrolysis6
Very rare Angioedema7
Drug eruption
Alopecia
Hair colour changes
Renal and urinary disorders Very rare Haematuria
Azotaemia
Reproductive and breast disorders Very rare Infertility male
Erectile dysfunction
Gynaecomastia
General disorders and administration Very rare Oedema
site conditions Malaise
Asthenia
Pyrexia8
Not known Chills
1
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.
2
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). 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.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and
SJS/TEN. 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.
3
Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy of
a generalised lymphadenopathy. It appears to be reversible on withdrawal of Allopurinol.
4
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.
5
Hepatic dysfunction has been reported without overt evidence of more generalised
hypersensitivity.
6
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).
The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the
first weeks of treatment. The best results in managing such reactions come from early
diagnosis and immediate discontinuation of any suspect drug. Allopurinol should be
withdrawn immediately should such reactions occur. After recovery, from mild reactions
allopurinol may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually
increased. The HLA-B*5801 allele has been shown to be associated with the risk of
developing allopurinol related hypersensitivity syndrome and SJS/TEN. The use of
genotyping as a screening tool to make decisions about treatment with allopurinol has not
been established. If the rash recurs, allopurinol should be permanently withdrawn as more
severe hypersensitivity may occur (see section 4.8 Immune system disorders). If SJS/TEN,
or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce
allopurinol due to the potential for a severe or even fatal reaction. 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.
7
Angioedema has been reported to occur with and without signs and symptoms of a more
generalised hypersensitivity reaction.
8
Fever has been reported to occur with and without signs and symptoms of a more
generalised Allopurinol hypersensitivity reaction (see section 4.8 Immune system
disorders).
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
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms
and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a
patient who ingested 20 g allopurinol. Recovery followed general supportive measures.
Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase
activity which should have no untoward effect unless affecting concomitant medication,
especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain
optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered
necessary haemodialysis may be used.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Preparations inhibiting uric acid production. ATC code:
M04AA01.
Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and
urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of
hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine
catabolism in some but not all hyperuricaemic patients, de novo purine biosynthesis is
depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase.
Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
5.2 Pharmacokinetic properties
Absorption
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 plasma levels of oxipurinol
generally occur after 3-5 hours after oral administration of allopurinol and are much more
sustained.
Distribution
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 1.6 litre/kg which, suggests relatively extensive uptake by
tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is
likely that allopurinol and oxipurinol will be present in the highest concentrations in the
liver and intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of allopurinol is oxipurinol. Other metabolites of allopurinol include
allopurinol-riboside and oxipurinol-7-riboside.
Elimination
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 0.5 to 1.5 hours.
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/litre.
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/litre 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 dose of
allopurinol is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients
The kinetics of the drug are not likely to be altered other than due to deterioration in renal
function (see section 5.2 Pharmacokinetics in patients with renal impairment).
5.3 Preclinical safety data
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 a mean period of 40 months.
Allopurinol does not produce nitroso 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.
Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for
up to 2 years.
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
Maize starch
Povidone
Sodium starch glycolate
Magnesium stearate
Water
6.2 Incompatibilities
No major incompatibilities known.
6.3 Shelf life
3 years in polypropylene or polyethylene containers
3 years in blister packaging.
6.4 Special precautions for storage
Store in a cool dry place
Protect from light
6.5 Nature and contents of container
100 tablets in polypropylene/polyethylene containers or 28 or 56 tablets in blister
packaging of opaque or clear PVC with 20 micron foil.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
N/A
7. Marketing authorisation holder
Wockhardt UK Ltd
Ash Road North
Wrexham Industrial Estate
Wrexham LL13 9UF
United Kingdom
8. Marketing authorisation number(s)
PL 29831/0004
9. Date of first authorisation/renewal of the authorisation
30/10/2007
10. Date of revision of the text
29/08/2017
1. Name of the medicinal product
Zyloric 100 mg Tablets
Zyloric 300 mg Tablets
2. Qualitative and quantitative composition
Allopurinol 100 mg (Zyloric Tablets)
Allopurinol 300 mg (Zyloric-300 Tablets)
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Tablet.
Each 100 mg tablet is round, white to off-white, biconvex, bisected tablet, debossed with
Z1 on one side.
Each 300 mg tablet is round, white to off-white, biconvex, bisected tablet, debossed with
Z3 on one side.
The score line is only to facilitate breaking for ease of swallowing and not to divide the
tablet into equal doses.
4. Clinical particulars
4.1 Therapeutic indications
Zyloric is indicated for reducing urate/uric acid formation in conditions where urate/uric
acid deposition has already occurred (e.g. gouty arthritis, skin tophi, nephrolithiasis) or is a
predictable clinical risk (e.g. treatment of malignancy potentially leading to acute uric acid
nephropathy). The main clinical conditions where urate/uric acid deposition may occur are:
idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and
myeloproliferative disease with high cell turnover rates, in which high urate levels occur
either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to
overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase,
including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage
disease; phosphoribosylpyrophosphate synthetase, phosphoribosylpyrophosphate
amidotransferase; adenine phosphoribosyltransferase.
Zyloric is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones
related to deficient activity of adenine phosphoribosyltransferase.
Zyloric is indicated for the management of recurrent mixed calcium oxalate renal stones in
the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.
4.2 Posology and method of administration
Posology
Adults
Zyloric should be introduced at 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 section 4.2 Renal impairment). The
following dosage schedules are suggested:
100 to 200 mg daily in mild conditions,
300 to 600 mg daily in moderately severe conditions,
700 to 900 mg daily in severe conditions.
If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should
be used.
Paediatric population
Children under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily.
Use in children is rarely indicated, except in malignant conditions (especially leukaemia)
and certain enzyme disorders such as Lesch-Nyhan syndrome.
Older people
In the absence of specific data, the lowest dosage which produces satisfactory urate
reduction should be used. Particular attention should be paid to advice in section 4.2 Renal
impairment and section 4.4.
Renal impairment
Since allopurinol and its metabolites are excreted by the kidney, impaired renal function
may lead to retention of the drug and/or its metabolites with consequent prolongation of
plasma half-lives. In severe renal insufficiency, it may be advisable to use less than 100 mg
per day or to use single doses of 100 mg at longer intervals than one day. If facilities are
available to monitor plasma oxipurinol concentrations, the dose should be adjusted to
maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre). Allopurinol
and its metabolites are removed by renal dialysis. If dialysis is required two to three times a
week consideration should be given to an alternative dosage schedule of 300-400 mg
Zyloric immediately after each dialysis with none in the interim.
Hepatic impairment
Reduced doses should be used in patients with hepatic impairment. Periodic liver function
tests are recommended during the early stages of therapy.
Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome
It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with Zyloric
before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain
optimum diuresis and to attempt alkalinisation of urine to increase solubility of urinary
urate/uric acid. Dosage of Zyloric should be at the lower end of the recommended dosage
schedule.
If urate nephropathy or other pathology has compromised renal function, the advice given
in section 4.2 Renal impairment should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the
clinical situation. See also section 4.5 and section 4.8.
Monitoring Advice
The dosage should be adjusted by monitoring serum urate concentrations and urinary
urate/uric acid levels at appropriate intervals.
Method of administration
Zyloric may be taken orally once a day after a meal. It is well tolerated, especially after
food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested,
a divided doses regimen may be appropriate.
4.3 Contraindications
Zyloric should not be administered to individuals known to be hypersensitive to allopurinol
or to any of the components of the formulation, listed in section 6.1.
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
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.
Chronic renal impairment
Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides,
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).
Hepatic or renal impairment
Reduced doses should be used in patients with hepatic or renal impairment (see Section
4.2). 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
Asymptomatic hyperuricaemia per se is generally not considered an indication for use of
Zyloric. 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 completely
subsided, as further attacks may be precipitated.
In the early stages of treatment with Zyloric, 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.
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 Zyloric will lead to dissolution of large uric acid renal pelvic stones,
with the remote possibility of impaction in the ureter.
Thyroid disorders
Increased TSH values (>5.5 IU/mL) were observed in patients on long-term treatment
with allopurinol (5.8%) in a long term open label extension study.
Lactose
Zyloric 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
Zyloric, 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
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 Zyloric, but the significance needs to be assessed in
each case.
Chlorpropamide
If Zyloric 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 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
(chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of
these cytotoxic agents.
Ciclosporin
Reports suggest that the plasma concentration of ciclosporin may be increased during
concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity
should be considered if the drugs are co-administered.
Didanosine
In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and
AUC values were approximately doubled with concomitant allopurinol treatment (300 mg
daily) without affecting terminal half life. Co-administration of these 2 drugs is generally
not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may
be required, and patients should be closely monitored.
Diuretics
An interaction between allopurinol and furosemide that results in increased serum urate and
plasma oxypurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with
diuretics, in particular thiazides, especially in renal impairment.
Angiotensin-converting-enzyme (ACE) inhibitors
An increased risk of hypersensitivity has been reported when allopurinol is given with ACE
inhibitors especially in renal impairment.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of safety of Zyloric in human pregnancy, although it has been
in wide use for many years without apparent ill consequence (see section 5.3).
Use in pregnancy only when there is no safer alternative and when the disease itself carries
risks for the mother or unborn child.
Breast-feeding
Reports indicate that allopurinol and oxipurinol are excreted in human breast milk.
Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxipurinol have been
demonstrated in breast milk from a woman taking Zyloric 300 mg/day. However, there are
no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
4.7 Effects on ability to drive and use machines
Since adverse reactions such as somnolence, vertigo and ataxia have been reported in
patients receiving allopurinol, patients should exercise caution before driving, using
machinery or participating in dangerous activities until they are reasonably certain that
allopurinol does not adversely affect performance.
4.8 Undesirable effects
For this product there is no modern clinical documentation which can be used as support
for determining the frequency of undesirable effects. Undesirable effects may vary in their
incidence depending on the dose received and also when given in combination with other
therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for
most reactions, suitable data for calculating incidence are not available. Adverse drug
reactions identified through post-marketing surveillance were considered to be rare or very
rare. The following convention has been used for the classification of frequency:
Very common 1/10
Common 1/100 to <1/10
Uncommon 1/1000 to <1/100
Rare 1/10,000 to <1/1000
Very rare <1/10,000
Adverse reactions in association with Zyloric are rare in the overall treated population and
mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic
disorder.
Table 1 Tabulated summary of adverse reactions
System Organ Class Frequency Adverse reaction
Infections and infestations Very rare Furuncle
Blood and lymphatic system disorders Very rare Agranulocytosis1
Aplastic anaemia1
Thrombocytopenia1
Immune system disorders Uncommon Hypersensitivity 2
Very rare Angioimmunoblastic T-cell lymphoma 3
Metabolism and nutrition disorders Very rare Diabetes mellitus
Hyperlipidaemia
Psychiatric disorders Very rare Depression
Nervous system disorders Very rare Coma
Paralysis
Ataxia
Neuropathy peripheral
Paraesthesia
Somnolence
HeadacheDysgeusia
Eye disorders Very rare Cataract
Visual impairment
Maculopathy
Ear and labyrinth disorders Very rare Vertigo
Cardiac disorders Very rare Angina pectoris
Bradycardia
Vascular disorders Very rare Hypertension
Gastrointestinal disorders Uncommon Vomiting4
Nausea4
Very rare Haematemesis
Steatorrhoea
Stomatitis
Change of bowel habit
Hepatobiliary disorders Uncommon Liver function test abnormal5
Rare Hepatitis (including hepatic necrosis a
granulomatous hepatitis) 5
Skin and subcutaneous tissue disorders Common Rash
Rare Stevens-Johnson syndrome/toxic epiderm
necrolysis 6
Very rare Angioedema7
Drug eruption
Alopecia
Hair colour changes
Renal and urinary disorders Very rare Haematuria
Azotaemia
Reproductive system and breast disorders Very rare Infertility male
Erectile dysfunction
Gynaecomastia
General disorders and administration site Very rare Oedema
conditions Malaise
Asthenia
Pyrexia 8
1 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.
2 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.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and
SJS/TEN. 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.
3 Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy
of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.
4 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 Zyloric after meals.
5 Hepatic dysfunction has been reported without overt evidence of more generalised
hypersensitivity.
6 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). The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is
within the first weeks of treatment. The best results in managing such reactions come from
early diagnosis and immediate discontinuation of any suspect drug. Zyloric should be
withdrawn immediately should such reactions occur. After recovery from mild reactions,
Zyloric may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually
increased. The HLA-B*5801 allele has been shown to be associated with the risk of
developing allopurinol related hypersensitivity syndrome and SJS/TEN. The use of
genotyping as a screening tool to make decisions about treatment with allopurinol has not
been established. If the rash recurs, Zyloric should be permanently withdrawn as more
severe hypersensitivity may occur (see section 4.8 Immune system disorders). If SJS/TEN,
or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce
allopurinol due to the potential for a severe or even fatal reaction. 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.
7 Angioedema has been reported to occur with and without signs and symptoms of a more
generalised hypersensitivity reaction.
8 Fever has been reported to occur with and without signs and symptoms of a more
generalised Zyloric hypersensitivity reaction (see section 4.8 Immune system disorders).
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:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms
and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a
patient who ingested 20 g allopurinol. Recovery followed general supportive measures.
Massive absorption of Zyloric may lead to considerable inhibition of xanthine oxidase
activity, which should have no untoward effects unless affecting concomitant medication,
especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain
optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered
necessary haemodialysis may be used.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Preparations inhibiting uric acid production, ATC code:
M04AA01.
Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol
lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the
enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In
addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients,
de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine
phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside
and oxipurinol-7-riboside.
5.2 Pharmacokinetic properties
Absorption
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 Zyloric, but
fall rapidly and are barely detectable after 6 hours. Peak plasma levels of oxipurinol
generally occur after 3-5 hours after oral administration of Zyloric and are much more
sustained.
Distribution
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 1.6 litre/kg which, suggests relatively extensive uptake by
tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is
likely that allopurinol and oxipurinol will be present in the highest concentrations in the
liver and intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of Zyloric is oxipurinol. Other metabolites of allopurinol include
allopurinol-riboside and oxipurinol-7-riboside.
Elimination
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 0.5 to 1.5 hours.
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 Zyloric. 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/litre.
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/litre 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 dose of Zyloric
is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients
The kinetics of the drug are not likely to be altered other than due to deterioration in renal
function (see section 5.2 Pharmacokinetics in patients with renal impairment).
5.3 Preclinical safety data
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 a mean period of 40 months.
Allopurinol does not produce nitroso 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.
Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for
up to 2 years.
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
Maize Starch
Povidone
Magnesium Stearate
Purified Water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Do not store above 25C. Store in the original packaging.
6.5 Nature and contents of container
Zyloric 100 mg Tablets
PVC/aluminium foil blister packs of 100 tablets.
Zyloric-300 Tablets
PVC/aluminium foil blister packs (2 strips of 14 tablets).
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Aspen Pharma Trading Limited
Absorbsi Oral : Alopurinol hampir 80% diabsorpsi setelah
pemberian peroral.
Biotransformasi : Mekanisme ( s ) tindakan tidak diketahui dengan
pasti ; muncul bronkodilatasi yang dimediasi oleh
penghambatan kompetitif dari 2 isozim dari
phosphodiesterase ( PDE III dan , pada tingkat lebih
rendah , PDE IV ) , sedangkan non - bronkodilator
tindakan profilaksis mungkin dimediasi melalui
mekanisme molekuler yang tidak melibatkan
penghambatan PDE III atau antagonisme reseptor
adenosin.
Waktu Paruh : 1 3 jam
Distribusi : Volume distribusinya 1,6 L/Kg.
Metabolisme :Alupurinol dimetabolisme sendiri oleh xantin
oksidase menjadi metabolit aktif oxypurinol ( 75%).
Eliminasi : Ekskresi alopurinol dalam urin sebesar 76% dalam
bentuk oxypurinol dan 12% dalam bentuk utuh.
Dosis : 100 mg.
Mekanisme kerja : Alopurinol adalah obat penyakit pirai (gout) yang
dapat menurunkan kadar asam urat dalam darah.
Alopurinol bekerja dengan menghambat xantin
oksidase yaitu enzim yang dapat mengubah
hipoxantin menjadi xantin, selanjutnya mengubah
xantin menjadi asam urat. Dalam tubuh Alopurinol
mengalami metabolisme menjadi oksipurinol
(alozantin) yang juga bekerja sebagai penghambat
enzim xantin oksidase. Mekanisme kerja senyawa
ini berdasarkan katabolisme purin dan mengurangi
produksi asam urat, tanpa mengganggu biosintesa
purin.
2
Efek samping :Ruam (hentikan terapi; jika ruam ringan, gunakan
kembali dengan hati-hati namun hentikan segera
apabila muncul kembali reaksi kulit dikaitkan
dengan pengelupasan kulit, demam, limfadenopati,
artralgia, dan eosinofilia, sindrom mirip sindrom
Stevens-Johnson atau Lyell, jarang terjadi);
gangguan saluran cerna; jarang malaise; sakit
kepala, vertigo, mengantuk, gangguan pengecapan,
hipertensi, deposit xantin di otot tanpa gejala,
alopesia, hepatotoksisitas, para-estasia, dan
neuropati.
(Iso Farmakoterapi 1)

Allopurinol : Zat aktif


Sorbitol : Bahan pengisi
Gelatin : Pengikat
Metil selulosa : Desintegran
Kalsium stearat : Lubrikan
Zinc stearat : Glidan
b. Metoda yang digunakan : Granulasi basah.
c. Alasan pemilihan metode : Karena zat aktif memiliki titik leleh yang
cukup tinggi sehingga dapat dilakukan
pemanasan.

Pembuatan tablet Allopurinol ini dilakukan dengan metode granulasi basah. Granulasi basah
merupakan suatu proses perubahan dari bentuk serbuk halus menjadi granul dengan bantuan
larutan bahan pengikat yang sesuai. Pada metode granulasi basah ini bahan pengikat yang
ditambahkan harus mempunyai jumlah yang relatif cukup, karena kekurangan atau kelebihan
sedikit saja bahan pengikat akan menyebabkan granul yang tidak sesuai dengan yang diinginkan
dan akan mempengaruhi hasil akhir tablet (Robert et al, 1990). (Anggraini)
Adapun cara dari metode granulasi basah adalah timbang semua bahan yang akan
dipakai dan lakukan pembuatan larutan pengikat. Larutan pengikat berfungsi memberikan
daya adhesi pada massa serbuk sewaktu granulasi serta menambah daya kohesi pada
bahan pengisinya. Pembuatan larutan pengikat yaitu siapkan air murni dan tambahkan
Povidone K30 masukkan ke dalam beaker glass aduk selama 5 menit.
Lalu dilakukan pembuatan tablet, yaitu masukkan Allopurinol sebagai zat aktif, tambahkan
Laktosa sebagai pengisi, Corn Starch sebagai penghancur, dan Kollidon CL sebagai
penghancur, aduk selama 5 menit lalu dicampurkan didalam lumpang, masukkan larutan
pengikat secara perlahan sambil digerus pelan selama 5 menit. Massa basah diayak
dengan pengayak mesh 20, pengayakan berfungsi untuk homogenitas ukuran partikel.
Setelah massa basah diayak masukkan massa basah ke dalam oven dengan suhu 40C
selama 3 jam.
Setelah dioven ayak massa kering dengan ayakan mesh 20. Lalu lakukan lubrikasi. Lubrikasi
mengurangi gesekan selama proses pengempaan tablet dan juga berguna untuk mencegah massa
tablet melekat pada cetakan (Depkes RI, 2014). Lalu masukkan granul kering ke dalam plastik
tambahkan talkum dan magnesium stearat sebagai pelincir dikocok 5 menit sampai homogen.
(anggaini)