Allopurinol

Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.

Large doses of alcohol may reduce the activity of allopurinol.

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.

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.

An increased risk of hypersensitivity has been reported when allopurinol is given with ACE inhibitors especially in 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.

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.

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.

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.

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.

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.

In healthy volunteers and HIV patients receiving didanosine, plasma didanosine C_max and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half life. Coadministration 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.

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.

In concomitant administration with allopurinol, the toxicity of methotrexate is increased and its effect is prolonged, which requires a reduction in its administered dose.

Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

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.

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.

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.

Concomitant administration of allopurinol with high doses of ascorbic acid or other acidifying agents may increase the risk of kidney stones.

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.

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 risks for the mother or unborn child.

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.

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.

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 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.

Summary of adverse reactions:

Infections and infestations

Very rare: Furuncle

Blood and lymphatic system disorders

Very rare: Agranulocytosis¹, Aplastic anaemia¹, Thrombocytopenia¹

Immune system disorders

Uncommon Hypersensitivity²

Very rare: Angioimmunoblastic, T-cell lymphoma³

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

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 and granulomatous hepatitis)⁵

Skin and subcutaneous tissue disorders

Common: Rash

Rare: Stevens-Johnson syndrome/toxic epidermal necrolysis⁶

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, Pyrexia⁸

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 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 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.