Puricos 100 mg, 300 mg Tablets

PURICOS is indicated in adults:

• for the treatment of gout and hyperuricaemia associated with other conditions. It reduces the concentration of uric acid in plasma with gradual resolution of tophi and reduces the risk of the formation of uric acid calculi. It may be effective in patients with impaired renal function.
• in the treatment of hyperuricaemia associated with leukaemia or resulting from radiotherapy or the use of anti-neoplastic medicines such as mercaptopurine or during treatment with thiazides (e.g. hydrochlorothiazide).

Adults

In gout, it is usual to commence with 50 mg twice daily and to increase this dose as required up to 200 mg to 400 mg daily in divided doses. In severe conditions, daily doses of up to 900 mg may be necessary. In hyperuricaemia associated with leukaemia a suggested initial dose is 200 mg three times daily commencing, if possible, 2 or 3 days before radiotherapy or the commencement of treatment with anti-neoplastic medicines, and adjusted as requested to a maintenance dose, usually of 300 mg to 400 mg daily.

Instructions for use

Fluid intake should be sufficient to maintain daily urinary volume above 2 litres. PURICOS is well tolerated, especially after food. Patients on high doses (> 300 mg) may benefit from a divided dose regimen.

Special populations

Renal impairment

Since PURICOS and its metabolites are excreted by the kidney, impaired renal function may lead to retention PURICOS 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). PURICOS 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 mg to 400 mg PURICOS immediately after each dialysis with none in the interim.

Hepatic impairment

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

Paediatric population

For children the suggested initial dose is 8 mg per kg body mass daily.

Method of administration

For oral administration.

PURICOS is contraindicated in:

• Hypersensitivity to allopurinol or to any of the other ingredients of PURICOS (see section 2).
• Pregnancy and breastfeeding (see section 4.6).
• Children, except those with malignancy.

Hypersensitivity

PURICOS 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 sections 4.3 and 4.8). 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 (SJS) and toxic epidermal necrolysis (TEN). PURICOS should be withdrawn immediately should such reactions occur. After recovery from mild reactions, PURICOS may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually increased. If the rash recurs, PURICOS should be permanently withdrawn as more severe hypersensitivity may occur (see section 4.8). 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.

Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction. Fever has been reported to occur with and without signs and symptoms of a more generalised PURICOS hypersensitivity reaction (see section 4.8).

HLA-B*5801 allele

The HLA-B*5801 allele 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 % to 30 % of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1 % to 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 PURICOS has not been established.

Hepatic and renal impairment

Reduced doses should be used in patients with hepatic or renal impairment. PURICOS should be used with caution in patients with hypertension and cardiac insufficiency treated with diuretics and ACE inhibitors. Adverse reactions in association with PURICOS 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. Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.

Asymptomatic hyperuricaemia

Asymptomatic hyperuricaemia is generally not considered an indication for use of PURICOS. Fluid and dietary modification with management of the underlying cause may correct the condition.

Acute gout attacks:

PURICOS 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 PURICOS, an acute attack of gout arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory medicine or colchicine for at least one month. If acute attacks develop in patients receiving PURICOS, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory medicine.

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 PURICOS will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function have been reported rarely, reinforcing the need for particular care in this group of patients. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment. PURICOS should be withdrawn immediately and permanently. 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. Angioimmunoblastic lymphadenopathy has been described following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of PURICOS. Nausea and vomiting can be avoided by taking PURICOS after meals.

Excipients

PURICOS contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, total lactase deficiency or glucose-galactose malabsorption should not take PURICOS.

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 PURICOS, 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 these two products are used concomitantly caution is necessary, to recognise enhanced toxic effects.

Salicylates and uricosuric medicines:

Oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, medicines with uricosuric activity such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of PURICOS, but the significance of this needs to be assessed in each individual case.

Chlorpropamide:

If PURICOS 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 reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with PURICOS. Therefore, all patients receiving anticoagulants must be carefully monitored.

Phenytoin:

PURICOS 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 PURICOS therapy.

Ampicillin / amoxicillin:

An increase in frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with PURICOS, compared to patients who are not receiving both medicines. The cause of the reported association has not been established. However, it is recommended that in patients receiving PURICOS, an alternative to ampicillin or amoxicillin is used where available.

Cyclophosphamide, doxorubicin, bleomycin:

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic medicines has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol, as contained in PURICOS. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin and/or bleomycin, allopurinol, as contained in PURICOS, did not appear to increase the toxic reaction of these cytotoxic medicines.

Ciclosporin:

Plasma concentration of ciclosporin may be increased during concomitant treatment with PURICOS. Enhanced ciclosporin toxicity should be considered if these medicines are co-administered.

Didanosine:

In healthy volunteers and HIV patients receiving didanosine, plasma didanosine C max and AUC values were approximately doubled with concomitant allopurinol, as contained in PURICOS, treatment (300 mg daily) without affecting terminal half-life. Co-administration of these two medicines is not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.

Pregnancy

PURICOS is contraindicated in pregnancy (see section 4.3).

Breastfeeding

PURICOS is contraindicated in lactation (see section 4.3).

Fertility

No data available.

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving PURICOS, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that PURICOS does not adversely affect performance.

a) Tabulated list of adverse reactions

System organ class

Frequent

Less frequent

Infections and infestations

Furunculosis

Blood and the lymphatic system disorders

Leucopenia leucocytosis eosinophilia haemolytic anaemia agranulocytosis aplastic anaemia thrombocytopenia

Immune system disorders

Hypersensitivity reactions (including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia, eosinophilia, Stevens-Johnson syndrome and toxic epidermal necrolysis), vasculitis, angioimmunoblastic lymphadenopathy

Metabolism and nutrition disorders

Diabetes mellitus, hyperlipidaemia

Psychiatric disorders

Drowsiness, depression

Nervous system disorders

Headache, peripheral neuritis, seizures, paraesthesia, coma, paralysis, ataxia, somnolence

Eye disorders

Cataract, visual disturbances, macular changes

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Angina, bradycardia

Vascular disorders

Hypertension

Gastrointestinal disorders

Nausea, vomiting, abdominal pain, diarrhoea, gastric irritation, taste disturbances, recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit

Hepato-biliary disorders

Hepatic damage, hepatotoxicity, altered liver function, hepatitis (including hepatic necrosis and granulomatous hepatitis)

Skin and subcutaneous tissue disorders

Rash Stevens-Johnson syndrome, toxic epidermal necrolysis, skin eruptions, exfoliative rash, alopecia, angioedema, discoloured hair

Musculoskeletal and connective tissue disorders

Arthralgia

Renal and urinary disorders

Renal damage, haematuria, uraemia

Reproductive system and breast disorders

Gynaecomastia, male infertility, erectile dysfunction

General disorders and administrative site conditions

Fever, chills, malaise, oedema, asthenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms

Ingestion of up to 22,5 g allopurinol, as contained in PURICOS, 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.

Treatment

Treatment is symptomatic and supportive. Recovery followed general supportive measures. Massive absorption of PURICOS 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, as contained in PURICOS, and its metabolites. If considered necessary haemodialysis may be used.