Mirpolyz 100 & 300 100 mg, 300 mg Tablets

MIRPOLYZ is used to reduce urate concentrations in body fluids and/or urine to prevent or reverse the deposition of urate/uric acid. MIRPOLYZ 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 MIRPOLYZ may be taken once a day. Larger doses should be administered as divided doses of not more than 300 mg. It is recommended that MIRPOLYZ 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 bodymass/day.

Special populations
Renal impairment
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 oxypurinol 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 MIRPOLYZ immediately after each dialysis.

Paediatric population
Children under 15 years: Daily oral dose 100 to 400 mg or 10 to 20 mg/kg bodymass/day.

Method of administration
MIRPOLYZ is for oral administration

• Hypersensitivity to allopurinol and any of the excipients listed in section 6.1.
• Severe hepatic or renal disorder.
• An acute gout attack.
• Lactating mothers (see section 4.6)
• Children, except those with malignancy

• Serious allergic reactions may occur including exfoliative rashes, Stevens-Johnson syndrome and toxic epidermal necrolysis. Should a skin rash or other evidence of sensitivity occur, MIRPOLYZ should be withdrawn immediately (see section 4.8).
• Other hypersensitivity responses may occur e.g. skin eruptions, fever, chills, leukopenia or leucocytosis and eosinophilia, arthralgia and vasculitis leading to renal and hepatic damage. These reactions may be severe, even fatal and may occur at any time during treatment. Patients with renal impairment or taking thiazide diuretics are at special risk. These reactions usually subside a few days after administration is stopped (see section 4.8).
• Treatment with MIRPOLYZ should not be started until an acute attack of gout has completely subsided as this can exacerbate the attack. When starting treatment with MIRPOLYZ, mobilisation of urate deposition may result in exacerbation of attacks of acute gouty arthritis. It is hence advisable to give colchicine at prophylactic doses or an anti-inflammatory medicine for at least one month when starting therapy with MIRPOLYZ. This effect can also be minimised by using small initial doses (100 mg per day) of MIRPOLYZ and gradual increasing of the dose at intervals. If an acute attack of gout develops while the patient is receiving MIRPOLYZ, therapy should be continued at the same dosage and the acute attack treated separately.
• When MIRPOLYZ is used concurrently with azathioprine or mercaptopurine, the dosage of azathioprine or mercaptopurine must be reduced to one-fourth of the usual dose due to prolongation of activity of these medicines (see section 4.5).
• Treatment of neoplasia: Prior to 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 impairment: In patients with impaired renal function, reduced doses should be used (see section 5.1, Pharmacokinetics in patients with renal impairment; see section 4.2).
• Hepatic impairment: MIRPOLYZ should be used with caution. Reduced doses should be used.
• Fluid intake should be sufficient to maintain daily urinary volume above 2 litres. Taking allopurinol after food minimises gastric irritation.
• A possibility of xanthine stone formation exists in children with Lesch-Nyhan syndrome. This can be minimised by alkalinisation of the urine and increasing daily fluid intake.
• Adequate therapy with MIRPOLYZ will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.
• Increased TSH (thyroid stimulating hormone) values (> 5,5 u03bcIU /mL) were observed in patients on long-term treatment with allopurinol. Caution is required when MIRPOLYZ is used in patients with alteration of thyroid function. MIRPOLYZ contains lactose; thus, patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take MIRPOLYZ.

• 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.
• Azathioprine is metabolised to 6-mercaptopurine by xanthine oxidase. Inhibition of this enzyme by MIRPOLYZ results in prolongation of the activity of azathioprine and mercaptopurine and hence the dosage of azathioprine or mercaptopurine must be reduced to one-fourth of the usual dosage when these medicines are given concomitantly with MIRPOLYZ (see section 4.4).
• Concurrent usage of cyclophosphamide and other anti-neoplastic medicines such as doxorubicin, bleomycin, procarbazine and mechlorethamine with MIRPOLYZ, may cause an increase in the toxicity of these anti-neoplastic medicines. Allopurinol may reduce the clearance of theophylline and other xanthines and their dosage might have to be reduced to avoid toxicity.
• Administration of MIRPOLYZ concomitantly with chlorpropamide may lead to prolonged hypoglycaemic action since there may be competition in the renal tubule for the excretion of chlorpropamide. Poor renal function may exacerbate this further.
• Oxypurinol, the major active metabolite of allopurinol, is excreted by the kidney in a very similar way to urate. Medicines with uricosuric activity such as probenecid or large doses of salicylates may accelerate the excretion of oxypurinol. This may lead to partial loss of therapeutic activity of MIRPOLYZ, but the significance of this needs to be assessed in each case.
• An increase in hypersensitivity reactions, and possibly other side effects, may occur in patients taking MIRPOLYZ with an ACE inhibitor or a thiazide diuretic. Care is advised during concomitant use of an ACE inhibitor or a thiazide diuretic with MIRPOLYZ, particularly in patients with renal impairment.
• There is no evidence that an interaction between allopurinol and the coumarins (such as warfarin) seen under experimental conditions, has any clinical significance. However, all patients receiving anticoagulants concomitantly with MIRPOLYZ should be carefully monitored.
• There may be an increased incidence of skin rashes in patients receiving amoxicillin or ampicillin concomitantly with MIRPOLYZ. In patients receiving therapy with MIRPOLYZ, it is recommended that an alternative to amoxicillin or ampicillin is utilised.
• As evidence suggests that the plasma half-life of vidarabine (adenine arabinoside) is increased in the presence allopurinol, additional vigilance for increased toxic effects is recommended during concomitant use of MIRPOLYZ and vidarabine.
• Concomitant use of didanosine and MIRPOLYZ is not recommended due to possible increases in C max and AUC values of didanosine during concomitant therapy. If co-administration cannot be avoided, a dose reduction of didanosine may be required and close monitoring of the patient is advised.
• MIRPOLYZ may inhibit the hepatic oxidation of phenytoin, but the clinical significance has not been determined.
• Plasma concentrations of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered during co-administration of ciclosporin and MIRPOLYZ.

Pregnancy
The safety of MIRPOLYZ in human pregnancy has not been established.

Breastfeeding
Allopurinol and oxypurinol have been detected in human breast milk. Use of MIRPOLYZ in lactating mothers is contraindicated (see section 4.3).

Adverse effects such as headaches, drowsiness and vertigo have been reported in patients receiving allopurinol. Patients should exercise caution before driving and using machinery until they are certain that MIRPOLYZ does not adversely affect performance.

b) Tabulated list of adverse reactions
The table below shows all adverse drug reactions (ADRs) observed during clinical trials and post market spontaneous reports with Allopurinol.

System Organ Class Frequency Frequent Less Frequent Not known Infections and infestations Furuncle Blood and lymphatic system disorders Agranulocytosis Aplastic anaemia Thrombocytopenia Leukopenia, leucocytosis, eosinophilia Immune system disorders Hypersensitivity Angioimmunoblastic T-cell lymphoma Anaphylactic reaction Metabolism and nutrition disorders Diabetes mellitus, hyperlipidaemia, taste perversion Psychiatric disorders Depression Nervous system disorders Coma Paralysis Ataxia Neuropathy peripheral Paraesthesia Somnolence Headache Dysgeusia Peripheral neuritis, drowsiness, epilepsy Aseptic meningitis Eye disorders Cataract Visual impairment Maculopathy Ear and labyrinth disorders Vertigo Cardiac disorders Angina pectoris Bradycardia Vascular disorders Hypertension Gastrointestinal disorders Vomiting, Nausea, Diarrhoea Haematemesis Steatorrhoea Stomatitis Change of bowel habit Abdominal pain, gastric irritation, diarrhoea Hepatobiliary disorders Liver function test abnormal Hepatitis (including hepatic necrosis and granulomatous hepatitis) Skin and subcutaneous tissue disorders Rash Stevens-Johnson syndrome/toxic epidermal necrolysis Angioedema Drug eruption Alopecia Hair colour changes Exfoliative rashes Musculoskeletal and connective tissue disorders Arthralgia Renal and urinary disorders Haematuria, Azotaemia, Uraemia Reproductive system and breast disorders Infertility male Erectile dysfunction Gynaecomastia Impotence General disorders and administration site conditions Oedema Malaise Asthenia Pyrexia Investigations Blood thyroid stimulating hormone increased

Symptoms
The most likely reaction to allopurinol overdose would be gastro-intestinal intolerance. Nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20 g of allopurinol.

Management
Administer sufficient fluids to maintain maximum diuresis since this in turn facilitates excretion of allopurinol and its metabolites. Treatment is symptomatic and supportive. If considered necessary, haemodialysis may be used.