Uripolt 100 , 300 100 mg, 300 mg Tablets

URIPOLT is used to reduce urate concentrations in body fluids and/or urine to prevent or reverse the deposition of urate/uric acid. URIPOLT is indicated in:

• the management of the main clinical manifestations of urate deposition which are: gouty arthritis, skin tophi, idiopathic gout, uric acid lithiasis and acute uric acid nephropathy.
• the management of patients with neoplastic and myeloproliferative disease with high cell turnover rates which cause elevations of serum and urinary levels. These include leukaemia, lymphomas, or other malignancies, especially when cytotoxic therapy has been initiated.
• the management of patients with recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria when fluid, dietary and similar measures have failed.

Posology

The dose should be titrated against the patient by monitoring serum urate/uric acid and/or urinary uric acid levels at appropriate intervals. Up to and including 300 mg URIPOLT may be taken once a day. Larger doses should be administered as divided doses of not more than 300 mg. It is recommended that URIPOLT be taken after meals for better tolerance.

Adults

Daily oral dose 100 to 900 mg depending on severity of the condition or 2 to 10 mg/kg body mass/day.

Special populations

Dose precautions in renal disorder

Since allopurinol and its metabolites are excreted by the kidney, renal failure may lead to the retention of the medicine and its metabolites with consequent prolongation of plasma half-lives. To reduce attendant risks, the amount and frequency of the dosage may require reduction. The following schedule is provided for guidance in adults: If creatinine clearance exceeds 20 mL/minute - give standard dose. If creatinine clearance is between 10 and 20 mL/minute - give 100 to 200 mg/day. If creatinine clearance is less than 10 mL/minute - give 100 mg/day or at longer intervals. If plasma monitoring facilities are available, plasma allopurinol levels should be maintained below 100 micromol/litre (15,2 micrograms/mL).

Dose precautions in renal dialysis

Allopurinol and its metabolites are removed by renal dialysis and dosages should be adjusted accordingly. Consideration should be given to an alternative dosage schedule of 300 to 400 mg URIPOLT immediately after each dialysis.

Paediatric population

Children under 15 years: Daily oral dose 100 to 400 mg or 10 to 20 mg/kg body mass/day.

Method of administration

For oral use.

• Hypersensitivity to allopurinol or to any of the other excipients of URIPOLT (see section 6.1).
• Severe hepatic or renal disorder.
• An acute gout attack.

Hypersensitivity syndrome, Stevens - Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (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 to 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.

Treatment of neoplasia

Before instituting cytotoxic therapy, it is advisable to assess existing serum urate and urinary acid levels. Hyperuricaemia and/or hyperuricosuria should be corrected prior to starting treatment. Adequate hydration to maintain maximum diuresis throughout is important. Renal disorder (see section 4.2).

Hepatic and renal impairment

Reduced doses should be used in patients with hepatic or renal impairment. URIPOLT should be used with caution in patients with hypertension and cardiac insufficiency treated with diuretics and ACE inhibitors. Patients with chronic renal impairment and concomitant diuretic use in particular thiazides may be at 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 dysfunction has been reported without overt evidence of more generalized hypersensitivity. Thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function have been reported, 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. URIPOLT should be withdrawn immediately and permanently.

Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalized 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 generalized lymphadenopathy. It appears to be reversible on withdrawal of URIPOLT.

Nausea and vomiting can be avoided by taking URIPOLT after meals.

Asymptomatic hyperuricaemia

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

Acute gouty attacks

URIPOLT 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 URIPOLT, as with uricosuric medicines, an acute attack of gouty arthritis may be precipitated. Therefore, it is advisable to give prophylaxis with a suitable anti-inflammatory medicine or colchicine for at least one month. The literature should be consulted for details of appropriate dosage, 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 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 URIPOLT 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 u03bcIU/mL) were observed in patients on long-term treatment with allopurinol. Caution is required when allopurinol is used in patients with alteration of thyroid function.

Lactose

URIPOLT contains lactose. Patients with the rare hereditary conditions of galactose intolerance total lactase deficiency or, glucose - galactose malabsorption should not take URIPOLT. Lactose may have an effect on the glycaemic control of patients with diabetes mellitus.

6 - Mercaptopurine and azathioprine

6 - Mercaptopurine and azathioprine are inactivated by the action of xanthine oxidase. Hence inhibition of xanthine oxidase may prolong the action of these medicines. Therefore, when either of these medicines is given by mouth concomitantly with URIPOLT, only one - quarter of the usual dosage of these medicines should be given.

Salicylates and uricosuric medicines

Oxypurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a very similar way to urate. Hence medicines causing uricosuria (e.g. probenecid, large doses of salicylate) may also accelerate the excretion of oxypurinol. This may lead to partial loss of therapeutic activity of URIPOLT, but the significance of this needs to be assessed in each case.

Chlorpropamide

In the presence of allopurinol, there may be competition in the renal tubule for excretion of chlorpropamide. When renal function is poor, the recognised risk of prolonged hypoglycaemic activity of chlorpropamide may be increased if URIPOLT is given concomitantly.

Coumarin anticoagulants

There is no evidence that interaction between allopurinol and the coumarins seen under experimental conditions has any clinical significance. However, all patients receiving anticoagulants must be carefully monitored. Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Vidarabine (Adenine arabinoside)

Evidence suggests that the plasma half-life of adenine arabinoside is increased in the presence of allopurinol. When the two medicines are used concomitantly, extra vigilance is necessary, to recognise enhanced toxic effects.

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 medicines. 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

The plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the 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 treatment (300 mg daily) without affecting terminal half-life. Co-administration of these 2 medicines 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.

Pregnancy

There is inadequate evidence of the safety of URIPOLT in human pregnancy.

Breastfeeding

URIPOLT should not be given to nursing mothers since it is excreted in breast milk.

Fertility

URIPOLT can cause infertility in male patients.

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.

a. Summary of the safety profile

The incidence of adverse effects is higher in the presence of renal and/or hepatic disorder and a dosage reduction should be considered in these cases. Skin reactions are the most common and may occur anytime during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative. As severe skin reactions may occur, URIPOLT should be withdrawn IMMEDIATELY should such reactions occur.

b. Tabulated summary of adverse reactions

The frequency of adverse reactions listed below is defined using the following convention: frequent; less frequent or frequency unknown (cannot be estimated from the available data).

System organ class Frequency Adverse reactions Infections and infestations Less frequent Furuncle

Massive absorption of URIPOLT may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless 6 - mercaptopurine and/or azathioprine is being taken concomitantly. In this case, the risk of increased activity of these medicines must be recognised. Adequate hydration to maintain maximum diuresis facilitates excretion of allopurinol and its metabolites. Haemodialysis may be resorted to if considered necessary.