Allopurinol Tablets 300mg Taj Pharma USP

1. NAME OF THE MEDICINAL PRODUCT
Allopurinol Tablets USP 100mg Taj Pharma
Allopurinol Tablets USP 300mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each tablet contains:
Allopurinol USP 100mg
Excipients q.s.
b) Each tablet contains:
Allopurinol USP 300mg
Excipients q.s.
For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM
White to off white, round, biconvex uncoated tablet

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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 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.

4.2 Posology and method of administration
Posology
Adults: Allopurinol should be introduced at low dosage e.g. 100mg/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 Patients with renal impairment). 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 in patients with renal impairment and section 4.4.

Patients with 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 100mg 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.

Patients with 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 Patients with renal impairment should be followed.

These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. See also sections 4.5 and 4.8.

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. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.

4.3 Contraindications
Allopurinol should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation listed in section 6.1.

4.4 Special Warnings and precautions for use
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 with Han Chinese, Thai or Korean descent the benefits should be thoroughly assessed and considered 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.

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 (see section 4.8).

Hepatic or renal impairment
Reduced doses should be used in patients with hepatic or renal impairment (See Section 4.2). 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 µIU/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.

4.5 Interaction with other medicinal products and other forms of interaction
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.

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.

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.

Azathioprine and 6-mercaptopurine: 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.

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 active metabolite of allopurinol, is excreted by the kidney in a similar way to urate. Hence drugs with uricosuric activity such as probenecid or large doses of salicylates 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.

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 the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared with 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.

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.

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

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 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.

4.6 Fertility, Pregnancy and lactation
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 risk for the mother or unborn child.

Breast-feeding:
Allopurinol and its metabolite oxipurinol is excreted in human breast milk. Allopurinol during breastfeeding is not recommended.

Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from woman taking Allopurinol 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

4.7 Effects on ability to drive and use machines
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.

4.8 Undesirable Effects
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 and <1/10
Uncommon	≥1/1000 and <1/100
Rare	≥1/10,000 and <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.

Table 1 Undesirable effects
System Organ Class	Frequency	Adverse reaction
Infections and infestations	Very rare	Furuncle
Blood and lymphatic system disorders	Very rare	Agranulocytosis1 Aplastic anaemia1 Thrombocytopenia1
Immune system disorders	Uncommon	Hypersensitivity 2
Immune system disorders	Very rare	Angioimmunoblastic T-cell lymphoma 3, Anaphylactic reaction
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 HeadacheDysgeusia
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
Gastrointestinal disorders	Very rare	Haematemesis Steatorrhoea Stomatitis Change of bowel habit
Hepatobiliary disorders	Uncommon	Liver function test abnormal5
Hepatobiliary disorders	Rare	Hepatitis (including hepatic necrosis and granulomatous hepatitis) 5
Skin and subcutaneous tissue disorders	Common	Rash
	Rare	Stevens-Johnson syndrome/toxic epidermal necrolysis 6
	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 Pyrexia 8
Investigations	common	blood thyroid stimulating hormone increased ⁹

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 tablets.

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 tablets 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 tablets should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Allopurinol tablets may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually increased. If the rash recurs, Allopurinol tablets 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 tablets hypersensitivity reaction (see Immune system disorders).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antigout preparations inhibiting uric acid production
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.

5.2 Pharmacokinetic properties
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 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 tablets 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 1 to 2 hours.

Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half-life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of Allopurinol. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10 mg/litre.

Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.

Pharmacokinetics in patients with renal impairment.
Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20ml/min, showed plasma oxipurinol concentrations of approximately 30mg/litre after prolonged treatment with 300 mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of Allopurinol is therefore required in patients with renal impairment.

Pharmacokinetics in elderly patients.
The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see Pharmocokinetics in patients with renal impairment).

5.3 Preclinical safety data
A. Mutagenicity
Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600 mg/day for mean period of 40 months.

Allopurinol does not produce nitraso compounds in vitro or affect lymphocyte transformation in vitro.

Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.

Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.

Teratogenicity
One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.

An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Lactose
Maize starch
Povidone K-30
Crospovidone
Magnesium stearate

6.2 Incompatibilities
None known.

6.3 Shelf life
3 years.

6.4 Special precautions for storage
Container pack: Do not store above 25°C. Store in the original container. Keep the container tightly closed.
Blister pack: Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container
Polypropylene tablet containers fitted with low density polyethylene caps.
Pack sizes: 28,100,500 and 1000 tablets.
Blister pack (clear PVC 250 micron and plain aluminium foil 20 micron)
Pack size: 28 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
Not applicable.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the patient

a) Taj Pharma Allopurinol 100 mg Tablets USP.
b) Taj Pharma Allopurinol 300 mg Tablets USP.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4).

What is in this leaflet
1. What Allopurinol Tablets Taj Pharma is and what it is used for
2. What you need to know before you take Allopurinol Tablets Taj Pharma
3. How to take Allopurinol Tablets Taj Pharma
4. Possible side effects
5. How to store Allopurinol Tablets Taj Pharma
6. Contents of the pack and other information

1. WHAT ALLOPURINOL TABLETS TAJ PHARMA IS AND WHAT IT IS USED FOR
Allopurinol belongs to a group of medicines called enzyme inhibitors. These medicines inhibit the amount of uric acid production in your body.

Allopurinol works by slowing down the speed of certain chemical reactions in your body to lower the level of uric acid in the blood and urine.

Allopurinol Tablets Taj Pharma are used to treat the following conditions:
· Gout (increased uric acid quantity in the body). The uric acid builds up in your joints and tendons as crystals causing an inflammatory reaction. The inflammation causes the skin around certain joints to become swollen, tender and sore when only slightly touched. You may also get severe pain when the joint is moved.
· Kidney stones formation and certain other types of kidney diseases due to increase in the amount of uric acid in the body
· Some types of Cancer due to increase in the amount of uric acid in the body
· Enzyme disorders due to increase in the amount of uric acid in the body

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE ALLOPURINOL TABLETS TAJ PHARMA
Do not take Allopurinol Tablets Taj Pharma:
· if you are allergic (hypersensitive) to Allopurinol or any of the other ingredients of Allopurinol Tablets Taj Pharma (see section 6)
Do not take Allopurinol Tablets Taj Pharma if the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Allopurinol Tablets Taj Pharma.

Warnings and precautions:
Talk to your doctor or pharmacist before taking your medicine if:
· you are of Han Chinese, African or Indian origin
· you have problems with your kidneys or liver. Your doctor may give you a lower dose or ask you to take it less often than each day. They will monitor you more closely.
· you suffer from high blood pressure or have heart problems and you take diuretics and/or a medicine called ACE-inhibitors.
· you are currently having an attack of gout
· you have thyroid problems
· you suffer from rare inherited forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactase malabsorption. Allopurinol Tablets Taj Pharma contain a small amount of lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Take special care with Allopurinol Tablets Taj Pharma:
· Serious skin rashes (Hypersensitivity syndrome, Stevens- Johnson syndrome, toxic epidermal necrolysis) have been reported with the use of allopurinol. Frequently, the rash can involve ulcers of the mouth, throat, nose, genitals and conjunctivitis (red and swollen eyes). These serious skin rashes are often preceded by influenza-like symptoms fever, headache, body ache (flu-like symptoms). The rash may progress to widespread blistering and peeling of the skin. If you develop a rash or these skin symptoms, stop taking allopurinol and contact your doctor immediately.
· These serious skin reactions can be more common in people of Han Chinese, Thai or Korean origin. Chronic kidney disease may increase the risk in these patients additionally.
· If you have cancer or Lesch-Nyhan syndrome the amount of uric acid may increase in your urine. To prevent this, you need to assure to drink sufficiently to dilute your urine.
· In case you have kidney stones, the kidney stones will become smaller and may enter your urinary tract.

Children
Use in children is rarely indicated, except in some types of cancer (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.

Other medicines and Allopurinol Tablets Taj Pharma
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Allopurinol Tablets Taj Pharma can affect the way some medicines work. Also some other medicines can affect the way Allopurinol Tablets Taj Pharma works.

Tell your doctor or pharmacist if you are taking any of the following:
· Aspirin
• medicines used to treat high blood pressure (ACE inhibitors e.g. captopril).
• medicines used to treat bacterial infections (antibiotics e.g. ampicillin and amoxicillin).
• medicines used to thin the blood (anticoagulants e.g. dicoumarol, phenprocoumon, warfarin).
• medicines used to treat diabetes (e.g. chlorpropamide and tolbutamide).
• medicines used to treat epilepsy (e.g. phenytoin, carbamazepine).
• medicines used for chemotherapy (e.g. azathioprine, mercaptopurine, cyclophosphamide).
• ciclosporin – a medicine used to suppress the immune system following organ transplant and in immune related disorders.
• theophylline – a medicine used in asthma and breathing disorders.
• thiazide diuretics – medicines used to get rid of excess fluid from the body and in high blood pressure such as ACE inhibitors or water tablets (diuretics).
• uricosurics – medicines that are used to reduce uric acid levels (e.g. probenecid, salicylate).
• vidarabine (adenine arabinoside) is an anti-viral drug which is used to treat herpes simplex or chicken pox.
• any other medicine to treat gout.
• didanosine used to treat HIV infection.
• 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.
• 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.

Taking Allopurinol Tablets Taj Pharma with food and drink
Allopurinol Tablets Taj Pharma should be taken with food and water.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Allopurinol is excreted in the human breast milk.
Allopurinol during breastfeeding is not recommended.

Driving and using machines
Allopurinol Tablets Taj Pharma may make some people feel drowsy, giddy or have problems with coordination. Do not drive or operate dangerous machinery if you are affected.

Allopurinol Tablets Taj Pharma contains lactose:
Allopurinol Tablets Taj Pharma contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. HOW TO TAKE ALLOPURINOL TABLETS TAJ PHARMA
Always take Allopurinol Tablets Taj Pharma exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
Swallow the tablet with a glass of water after meal.

Adults (Over 18 years)
The initial dose is usually 100mg daily, after food, but this can be gradually increased over one to three weeks according to the levels of uric acid in your blood and urine. The following dosages are administered depending on the severity of the disease.
100mg to 200mg average daily dose for mild gout
300 to 600mg daily for moderately severe gout
700 to 900mg daily for severe gout.
Up to 300mg can be taken as a single dose; larger doses should be divided throughout the day.

Patients with liver disease:
Your dose may need to be reduced ; this is determined by monitoring the levels of uric acid in your body.

Patients with kidney disease:

You may be asked to take less than 100 mg each day
• or you may be asked to take single dose of 100 mg at longer intervals than one day.
If you are receiving frequent dialysis for kidney disease then your dose may need to be adjusted or else a single dose of 300 to 400mg following dialysis may be given.

Elderly (Over 65 years):
Your doctor will prescribe a lower dose of Allopurinol Tablets Taj Pharma that best controls your symptoms.

Children under 15 years (for use in enzyme disorders and with chemotherapy)
The daily dose is calculated based on body weight and is usually 10 to 20 mg/Kg body weight.
The usual dose ranges from 100 to 400mg daily.

Treatment of high uric acid levels in chemotherapy:
Treatment commences from one to two days before chemotherapy and take 600 to 800mg daily in divided doses for 2 to 3 days.

The maintenance dose is then decided depending on your response to treatment.

While taking this medicine the dose of your chemotherapy may be reduced as this medicine can increase its effects.

Note: While you are taking Allopurinol Tablets Taj Pharma your doctor may ask you to undergo regular blood tests to check your levels of uric acid and in some cases monitor your liver and kidneys function.

If you take more Allopurinol Tablets Taj Pharma than you should
If you or someone else swallows several of these tablets all together, or if you think a child has swallowed any of these tablets, contact your doctor or pharmacist or hospital emergency department immediately. Always take any tablets left over with you, also the box and leaflet as this will allow easier identification of the tablets. Signs of an overdose may include nausea, vomiting, diarrhoea and dizziness.

If you forget to take Allopurinol Tablets Taj Pharma
If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose and just carry on as before. Do not take a double dose to make up for a forgotten dose.

If you stop taking Allopurinol Tablets Taj Pharma
Keep taking the medicine for as long as your doctor has told you, even if you are feeling better. If you stop the medicine too soon, your condition may become worse again.

Do not stop taking your tablets without consulting your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS
Like all medicines, Allopurinol can cause side effects, although not everybody gets them. If you experience the following side effects seek immediate medical attention.

Hypersensitivity
Uncommon (may affect less than 1 in 100 people)
If you have a hypersensitivity (allergic) reaction, stop taking Allopurinol Tablets Taj Pharma and see a doctor straight way.
The signs may include:
· flaking skin, boils or sore lips and mouth
· very rarely signs may include sudden wheeziness, fluttering or tightness in the chest and collapse.

Rare (may affect less than 1 in 1000 people)
· fever and chills, headache, aching muscles (flu-like symptoms) and generally feeling unwell
· serious hypersensitivity reactions involving fever, skin rash, joint pain, and abnormalities in blood and liver function tests (these may be signs of a multi-organ sensitivity disorder).
· bleeding in the lips, eyes, mouth, nose or genitals.
· any changes to your skin, for example; ulcers of the mouth, throat, nose, genitals, conjunctivitis (red and swollen eyes), widespread blisters or peeling.
· Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction such as red welts that suddenly appear, especially near the eyes and lips, but also on the hands, feet, and the inside of the throat, burning, painful, swollen, sometimes itchy areas, discoloured patches or rash on the hands, feet, face, or genitals
· vomiting blood (haematemesis)
· liver problems such as liver inflammation

Very rare (may affect up to 1 in 10,000 people)
· occasionally Allopurinol Tablets Taj Pharma may affect your blood, which can manifest as bruising more easily than usual, or you may develop a sore throat or other signs of an infection. These effects usually occur in people with liver or kidney problems. Tell your doctor as soon as possible.
· Allopurinol may affect the lymph nodes (T cell lymphoma) with signs of red, rash like pactches, raised patches (plagues), lumps
· loss of consciousness
· abnormal glucose metabolism (diabetes). Your doctor may wish to measure the level of sugar in your blood to check if this is happening.
· serious allergic reaction which causes swelling of the face or throat
· serious potentially life-threatening allergic reaction

Do not take any more tablets unless your doctor tells you to do so.

Other side effects
Common (may affect up to 1 in 10 people)
· skin rash
· Increased level of thyroid stimulating hormone in the blood.

Uncommon (may affect up to 1 in 100 people)
· feeling sick (nausea) or being sick (vomiting)
· abnormal liver tests.

Very rare (may affect up to 1 in 10,000 people)
· furuncle/pimples
· high temperature
· blood in your urine (haematuria)
· high levels of cholesterol in your blood (hyperlipidaemia)
· a general feeling of being unwell or feeling weak
· weakness, numbness, unsteadiness on your feet, feeling unable to move muscles (paralysis)
· headache, dizziness, drowsiness or disturbance of your vision
· chest pain (angina), high blood pressure or a slow pulse
· male infertility or erectile dysfunction
· enlargement of the breasts, in men as well as women
· a change in your normal bowel habit
· a change in taste
· cataracts
· hair loss or discolouration
· depression
· lack of voluntary coordination of muscle movements (ataxia)
· sensation of tingling, tickling, pricking or burning of skin (paraesthesia)
· build up of fluid leading to swelling (oedema) particularly of your ankles
· oily stools
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine.

5.HOW TO STORE ALLOPURINOL TABLETS TAJ PHARMA
Do not store above 25C. Store in the original package. Keep the container tightly closed. Keep out of the sight and reach of children.
Do not use your tablets after the expiry date stated on the carton or label. The expiry date refers to the last day of that month
Medicines should not be disposed of via waste
water or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. CONTENTS OF THE PACK AND FURTHER INFORMATION

What Allopurinol Tablets Taj Pharma contain
The active substance is Allopurinol.
a) Each tablet contains: Allopurinol USP 100mg
b) Each tablet contains: Allopurinol USP 300mg
The other ingredients are Lactose monohydrate, crospovidone, maize starch, povidone K-30 and magnesium stearate (see section 2 for Important information about some of the ingredients of Allopurinol Tablets Taj Pharma).

What Allopurinol Tablets Taj Pharma look like and contents of the pack
Allopurinol 100 mg Tablets are white to off white, round, biconvex, uncoated.
Allopurinol 300 mg Tablets are white to off white, round, biconvex, uncoated.
Allopurinol Tablets Taj Pharma are available in container packs of 28, 100, 500 and 1000 tablets.
They are also available in blister pack of 28 tablets (Not all pack sizes may be marketed).

Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com