4.1. Therapeutic indications

Allopurinol oral suspension 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 oral suspension is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.

Allopurinol oral suspension 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 oral suspension 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.

Based on published articles higher baseline plasma urate will require a higher maintenance dose of allopurinol. A simple equation (UT = (1 –D/(ID50 + D)) ¥ (UP – UR) + UR,) can be used to estimate the continuing allopurinol dose likely to effectively lower the plasma urate concentrations to target.

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.

Elderly

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 oral suspension immediately after each dialysis with none in the interim. (See section 5.2)

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 oral suspension 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 oral suspension 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.

Due to high Cmax of allopurinol oral suspension, complete blood count, liver function tests, renal function, and serum uric acid levels shall be measured every 2 to 5 weeks while titrating the dose until achieving the target serum uric acid level and every 6 months thereafter (see section 5.2).

Patients need counselling about the signs and symptoms of allopurinol hypersensitivity Syndrome (AHS) with a recommendation to discontinue allopurinol promptly if they develop skin rash concerning AHS, especially early in therapy.

Method of administration

For oral administration.

Please shake the bottle thoroughly before use.

Allopurinol oral suspension 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. Take Allopurinol oral suspension with a glass of water.

Measuring your dose

The syringe in the pack delivers:

• 30mg for every 0.5 ml graduation mark

• 60mg for every 1 ml graduation mark

The dosing syringe provided has only been demonstrated to deliver doses accurately at 1.5 mL volume and above (equivalent to 90mg allopurinol and higher). Alternative measuring devices should be considered if low allopurinol doses are to be administered.

4.3. Contraindications

Allopurinol oral suspension 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.

Elevated concentrations of metabolite oxypurinol is reported to be linked to an increased risk of allopurinol hypersensitivity.

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, 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 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.

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 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.

Excipient Warnings

This product contains:

• Liquid Maltitol - Patients with rare hereditary problems of fructose intolerance should not take this medicine.

• Sodium Benzoate - may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

• This medicine contains less than 1 mmol sodium (23 mg) per 5 ml, that is to say essentially 'sodium-free'.

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 oral suspension, 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 Allopurinol oral suspension, but the significance needs to be assessed in each case.

Chlorpropamide

If Allopurinol oral suspension 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.

Cytostatics

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.

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 risks for the mother or unborn child.

Breast-feeding

Allopurinol and its metabolite oxipurinol are 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

Summary of the safety profile

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

Common

Uncommon

Rare

Very rare

≥1/10

≥1/100 to <1/10

≥1/1000 to <1/100

≥1/10,000 to <1/1000

<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.

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

Anaphylactic reaction

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

Headache

Dysgeusia

Not known

Aseptic meningitis

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

Diarrhoea

Very rare

Haematemesis

Steatorrhoea

Stomatitis

Change of bowel habit

Hepatobiliary disorders

Uncommon

Liver function test abnormal5

Rare

Hepatitis (including hepatic necrosis and granulomatous hepatitis) 5

Skin and subcutaneous tissue disorders

Common

Rash

Rare

Stevens-Johnson syndrome/toxic epidermal 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 conditions

Very rare

Oedema

Malaise

Asthenia

Pyrexia 8

Investigations

Common

Blood thyroid stimulating

hormone increased9

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.

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).

9 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. 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.