This information is intended for use by health professionals

1. Name of the medicinal product

ALLOPURINOL TABLETS BP 300mg

2. Qualitative and quantitative composition

Each tablet contains 300mg Allopurinol PhEur

Excipient with known effect: Each tablet contains 93.00 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 with the identifying letters “AG” and “C” 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-Nyhan 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).

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.

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, 8-15% in the Thai, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. Screening for HLA-B*5801 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high. Chronic kidney disease may increase the risk in these patients additionally In case that no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or Korean descent the benefits should be thoroughly assessed and considered outweigh the possible higher risks before starting therapy. The use of genotyping has not been established in other patient populations. If the patient is a known carrier of HLA-B*5801 (especially in those who are from Han Chinese, Thai or Korean descent, allopurinol should not be started unless there are no other reasonable therapeutic options and 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.

SJS/TEN can still occur in patients who are found to be negative for HLA-B*5801 irrespective of their ethnic origin.

Thyroid disorders

Increased TSH values (>5.5 μIU/mL) were observed in patients on long-term treatment with allopurinol (5.8%) in a long term open label extension study. Caution is required when allopurinol is used in patients with alteration of thyroid function.

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: Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. 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 Allopurinol, but the significance needs to be assessed in each case.

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.

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 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.

Cytostatics: 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.

With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halogenides), blood dyscrasias occur more frequently than when these active substances are administered alone. Blood count monitoring should therefore be performed at regular intervals.

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.

Aluminium hydroxide: If aluminium hydroxide is taken concomitantly, allopurinol may have an attenuated effect. There should be an interval of at least 3 hours between taking both medicines.

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 Fertility, 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.

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 risks for the mother or unborn child.

Breast-feeding

Allopurinol and its metabolite oxipurinol is excreted in the 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 Allopurinol 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

Allopurinol during breastfeeding is not recommended.

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

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.

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, dysgeusia

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

Rare: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN) have been reported (see section 4.4). The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the first weeks of treatment.

Very Rare: alopecia, angioedema, discoloured hair, fixed drug eruptions.

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, azotaemia

Frequency not known: nephrolithiasis

Reproductive system and breast disorders

Very rare: gynaecomastia, impotence, infertility, erectile dysfunction

Frequency not known: nocturnal emissions

General disorders and administration site conditions

Very rare: asthenia, general malaise, oedema, pyrexia*

Investigations

Common: blood thyroid stimulating hormone increased**

*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).

**The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did not report any impact on free T4 levels or had TSH levels indicative of subclinical hypothyroidism.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Ingestion of up to 22.5 g allopurinol without adverse effect has been reported.

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 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 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

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 25°C 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) 250µm white rigid PVC. (ii) Surface printed 20µm 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

Administrative Data

7. Marketing authorisation holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing authorisation number(s)

PL 0142/0147

9. Date of first authorisation/renewal of the authorisation

November 1980

(Renewed: November 1985; January 1992)

10. Date of revision of the text

24th August 2018