Allopurinol
Allopurinol
Allopurinol
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.
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)