Aloric

Allopurinol.

A yellow color round tablet with the diameter of 9.1 mm, one side impressed with a "
Click on icon to see table/diagram/image
" mark.
Aloric Tablets 100 mg: Each tablet contains: Allopurinol 100 mg.

Pharmacology: Pharmacodynamics: Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
Pharmacokinetics: Absorption: Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of Allopurinol, but fall rapidly and are barely detectable after 6 hours. Peak plasma levels of oxipurinol generally occur after 3-5 hours after oral administration of Allopurinol and are much more sustained.
Distribution: Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 litre/kg which, suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.
Biotransformation: The main metabolite of Allopurinol is oxipurinol. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.
Elimination: Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine. Allopurinol has a plasma half-life of about 0.5 to 1.5 hours.

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

Adults: Allopurinol 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 Renal impairment as follows). 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.
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.
Older people: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice under Renal Impairment as follows and Precautions.
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.
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 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 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 Renal Impairment as previously mentioned should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation.
Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.
Method of Administration: Allopurinol may be taken orally once a day after a meal. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided regimen may be appropriate.

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.

This product should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation (Lactose Monohydrate, Potato Starch, Quinoline Yellow, Sunset Yellow Lake, Sodium Starch Glycolate, Magnesium Stearate, Talc, Hydroxypropyl Cellulose, Magnesium Aluminometasilicate, Isopropyl Alcohol).

Allopurinol should be discontinued at the first appearance of skin rash or other signs which may indicate an allergic reaction. In some instances, a skin rash may be followed by more severe reactions such as exfoliative, urticarial and purpuric lesions as well as Stevens-Johnson syndrome.
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 of 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 of 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.
Hepatic or renal impairment: Reduced doses should be used in patients with hepatic or renal impairment. 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 μlU/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.
Lactose: Allopurinol tablets contain lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

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. 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. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby. Allopurinol during breastfeeding is not recommended.

Infections and infestations: Furuncle.
Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, thrombocytopenia.
Immune system disorders: Hypersensitivity, angioimmunoblastic T-cell lymphoma, anaphylactic reaction.
Metabolism and nutrition disorders: Diabetes mellitus, hyperlipidaemia.
Psychiatric disorders: Depression.
Nervous system disorders: Coma, paralysis, ataxia, neuropathy peripheral, paraesthesia, somnolence, headache, dysgeusia.
Eye disorders: Cataract, visual impairment, maculopathy.
Ear and labyrinth disorders: Vertigo.
Cardiac disorders: Angina pectoris, bradycardia.
Vascular disorders: Hypertension.
Gastrointestinal disorders: Vomiting, nausea, haematemesis, steatorrhea, stomatitis, change of bowel habit, diarrhoea.
Hepatobiliary disorders: Liver function test abnormal, hepatitis.
Skin and subcutaneous tissue disorders: Rash, Stevens-Johnson syndrome/toxic epidermal necrolysis, angioedema, drug eruption, alopecia, hair colour changes.
Renal and urinary disorders: Haematuria, azotaemia.
Reproductive system and breast disorders: Infertility male, erectile dysfunction, gynaecomastia.
General disorders and administration site conditions: Oedema, malaise, asthenia, pyrexia.
Investigations: Blood thyroid stimulating hormone increased.

6-mercaptopurine and azathioprine: 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.
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, but the significance needs to be assessed in each case.
Chlorpropamide: 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.
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 the 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.

Keep in a tight container. Store below 30°C. Protect from light and moisture.
Shelf-life: 3 years from the date of manufacture.

Hyperuricemia & Gout Preparations

M04AA01 - allopurinol ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.

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