Consumer medicine information

Allopurinol APOTEX Tablets

Allopurinol

BRAND INFORMATION

Brand name

Allopurinol APOTEX Tablets

Active ingredient

Allopurinol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Allopurinol APOTEX Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about allopurinol. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What this medicine is used for

Allopurinol APOTEX Tablets is used to treat:

  • gouty arthritis or gout
  • kidney stones
  • rare conditions where high levels of uric acid occur in the blood (for example, Lesch-Nyhan syndrome).

It belongs to a group of medicines called anti-uricaemic agents.

This medicine works by reducing the production of uric acid in the body. High levels of uric acid may cause gout attacks or kidney stones. Allopurinol is used to prevent gout attacks, not to treat them once they occur.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Use in children

There is not enough information to recommend the use of this medicine for children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • any medicine containing allopurinol
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • muscle pain or tenderness or joint pain

If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.

Do not take this medicine if you have or have had any of the following:

  • You or a member of your immediate family has been diagnosed with haemochromatosis (a disease involving too much iron in the body) and you are taking iron salts.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems, including kidney stones
  • liver problems
  • high blood pressure
  • heart problems
  • conditions where the levels of uric acid are abnormally high
  • cancer or tumours.

Tell your doctor if you are currently having an attack of gout.

Treatment with allopurinol should not be started until the attack has stopped, otherwise more attacks may occur.

(However, if an attack of gout occurs when a person is already taking allopurinol, it can be continued).

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Allopurinol passes into breast milk and may affect your baby. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop

Some medicines and allopurinol may interact with each other. These include:

  • some medicines used to treat high blood pressure or heart problems
  • thiazide diuretics (a certain type of water tablet)
  • mercaptopurine, azathioprine or cyclosporin - medicines used to suppress the immune system
  • aspirin and other medicines known as salicylates
  • probenicid, a medicine used to treat gout
  • warfarin, used to help prevent blood clots
  • chlorpropamide, a medicine used to treat diabetes
  • phenytoin, a medicine used to treat epilepsy
  • certain antibiotics such as ampicillin and amoxycillin
  • theophylline, a medicine used to treat asthma
  • adenine arabinoside ('Vidarabine'), an anti-viral medicine.

These medicines may be affected by allopurinol or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Other medicines not listed above may also interact with allopurinol.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

The usual adult dose range is:

  • 100 - 200 mg per day for mild conditions
  • 300 - 600 mg per day for moderately severe conditions
  • 700 - 900 mg per day for severe conditions.

People over 65 years of age, and those with kidney and/or liver problems should be started on the lowest dose possible to control uric acid production.

Children under 15 years of age usually take 100 - 400 mg per day.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

Take your medicine immediately after food, as this will lessen the chance of a stomach upset.

Take your medicine at the same time each day.

Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

Allopurinol is usually taken once daily. However, if your dose is more than 300 mg, your doctor may advise you to take your medicine twice a day. Then, it should be taken morning and night, after breakfast and dinner.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is less than 4 hours to your next dose, skip the missed dose and take your next dose at the usual time.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include:

  • nausea
  • vomiting
  • diarrhoea
  • dizziness.

While you are taking this medicine

Things you must do

You should drink at least two litres (8 - 10 glasses) of fluid each day.

This will assist in reducing the uric acid levels in your body and prevent kidney stones from forming.

Tell your doctor if you have an acute attack of gout while you are taking allopurinol.

Your doctor may prescribe a medicine to relieve the acute attack. You can continue taking allopurinol.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this one.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant or plan to breastfeed while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Do not take this medicine to treat an acute attack of gout.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you.

This medicine may cause (dizziness, drowsiness, lack of co-ordination etc.) in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine.

Allopurinol helps most people but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious but most of the time they are not. You may need medical attention if you get some of the side effects. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • stomach upsets, including nausea, vomiting or diarrhoea
  • dizziness, drowsiness or unsteadiness when walking
  • change in bowel habits
  • headache
  • change in taste sensation
  • sleeplessness
  • hair loss or change in hair colour

Tell your doctor as soon as possible if you notice any of the following:

  • changes in vision
  • tingling or numbness of the hands or feet
  • a change in the amount of urine passed, going to the toilet more often or a burning feeling while passing urine
  • blood in your urine
  • yellowing of the skin and eyes (jaundice)
  • generally feeling of being unwell or depressed
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily
  • angina or palpitations
  • swelling of the hands, ankles or legs.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • asthma, wheezing or shortness of breath
  • swelling of the face, lips, tongue or throat which may cause difficulty in breathing
  • sudden or severe itching, skin
  • rash or hives, other skin problems
  • fainting, seizures or fits
  • pain or tightness in the chest.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may occur in some patients.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take the tablets out of their original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Allopurinol APOTEX Tablets looks like

Allopurinol 100 mg tablets:
White, to off-white, colored round, biconvex uncoated tablets with 'AL' & '100' separated by breakline on one side and plain on the other side.

Bottle (HDPE white opaque bottle with screw cap) of 200's tablets.

Blister Pack (Clear PVDC/PVC/ Aluminium silver foil) of 60's tablets.

Allopurinol 300 mg tablets:
Peach colored, round, biconvex uncoated tablets coded with 'AL' & '300' separated by breakline on one side and plain on other side.

Blister Pack (Clear PVDC/PVC/ Aluminium silver foil) of 60's tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each allopurinol tablet contains allopurinol as the active ingredient. In addition, each tablet contains the following inactive ingredients: It also contains the following inactive ingredients:

  • lactose monohydrate
  • maize starch
  • povidone
  • sodium starch gylcollate type A
  • sunset yellow FCF
  • stearic acid

This medicine contains lactose but is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Allopurinol APOTEX 100mg bottle: AUST R 269652

Allopurinol APOTEX 300mg blister: AUST R 269638

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
November 2017

BRAND INFORMATION

Brand name

Allopurinol APOTEX Tablets

Active ingredient

Allopurinol

Schedule

S4

 

1 Name of Medicine

Allopurinol.

6.7 Physicochemical Properties

Chemical Name: 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. Molecular Formula: C5H4N4O. Molecular Weight: 136.1.

Chemical structure.


CAS number.

315-30-0.

2 Qualitative and Quantitative Composition

Allopurinol is a white or off-white, almost odourless powder. It is very slightly soluble in water and in alcohol, and is practically insoluble in chloroform and in ether. It dissolves in dilute solutions of alkali hydroxides.
Each allopurinol tablet contains allopurinol as the active ingredient.
In addition, each tablet contains the following inactive ingredients: lactose monohydrate, maize starch, povidone, sodium starch glycollate type A, sunset yellow FCF and stearic acid.

3 Pharmaceutical Form

Allopurinol APOTEX 100 mg tablets.

White to off white, colored round biconvex, uncoated tablets with 'AL' and '100' separated by breakline on one side and plain on other side.

Allopurinol APOTEX 300 mg tablets.

Peach colored, round, biconvex, uncoated tablets with 'AL' and '300' separated by breakline on one side and plain on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Allopurinol inhibits xanthine oxidase, the enzyme which catalyses the conversion of hypoxanthine to xanthine, and of xanthine to urate/uric acid. See Figure 1.
Allopurinol decreases urate formation in two ways:
1. The inhibition of xanthine oxidase reduces the amount of hypoxanthine and xanthine converted to urate/uric acid.
2. This action makes more hypoxanthine and xanthine available for reutilisation in the purine metabolic cycle, which in turn, by a feedback mechanism, decreases overall de novo purine formation.
Since allopurinol decreases urate formation, it reduces urate/uric acid concentrations in both body fluids and urine. In contrast, the uricosuric agents which increase urate/uric acid excretion via the kidney will reduce the urate concentration in body fluids, but increase urate/uric acid concentration in urine. Reduction of the urate concentrations in body fluids by allopurinol permits mobilisation and dissolution of urate deposits anywhere in the body, the commonest sites being those in the skin, bones, joints and kidney interstitial tissue. Therapeutic effects therefore include: the resolution of skin tophi and the healing of urate sinuses; eventual reduction in the frequency of attacks of acute gouty arthritis, improvement in joint mobility; reduction of the urate load to be excreted via the kidney; prevention and treatment of acute uric acid nephropathy; and, in the long-term, reduced risk of renal impairment by urate/uric acid and prevention and dissolution of uric acid renal stones.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Allopurinol is approximately 90% absorbed from the gastrointestinal tract.

Distribution.

Allopurinol is uniformly distributed in total tissue water with the exclusion of the brain, where concentrations of the drugs are approximately 50% those of other tissues. Within muscle, small amounts of allopurinol and oxypurinol crystals have been found. Allopurinol and oxypurinol are not bound to plasma proteins. Allopurinol and oxypurinol are distributed into breast milk.

Metabolism.

Allopurinol is rapidly converted in the body to the pharmacologically active principal metabolite oxypurinol and other metabolites including allopurinol riboside and oxypurinol-7- riboside. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for allopurinol and oxypurinol respectively. Oxypurinol is also an inhibitor of xanthine oxidase.

Excretion.

The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid. The increased xanthine and hypoxanthine in the urine have not been accompanied by problems of nephrolithiasis.
Approximately 20% of the ingested allopurinol is excreted in the faeces. Because of its rapid oxidation to oxypurinol and a renal clearance rate approximately that of glomerular filtration rate, allopurinol has a plasma half-life of about 1 to 2 hours. Little allopurinol is found in the urine 6 hours after administration. Allopurinol and oxypurinol are mainly excreted in the urine. Oxypurinol, however, has a longer plasma half-life (approximately 15.0 hours) and therefore effective xanthine oxidase inhibition is maintained over a 24 hour period with single daily doses of allopurinol. Whereas allopurinol is cleared essentially by glomerular filtration, oxypurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid.

5.3 Preclinical Safety Data

Genotoxicity/ carcinogenicity.

No data is available on whether or not allopurinol has mutagenic or carcinogenic effects within humans or animals. Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 microgram/mL and in vivo at doses up to 600 mg/day for mean period of 40 months.

4 Clinical Particulars

4.1 Therapeutic Indications

Main clinical manifestations of urate/uric acid deposition. These are gouty arthritis, skin tophi and/or renal involvement through crystal deposition or stone formation. Such clinical manifestations may occur in: 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 and involve:
hypoxanthine guanine phosphoribosyltransferase including Lesch-Nyhan syndrome,
glucose 6-phosphatase including glycogen storage disease,
phosphoribosylpyrophosphate synthetase,
phosphoribosylpyrophosphate amidotransferase.
Allopurinol is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyl transferase.
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.

4.3 Contraindications

Allopurinol should not be administered to individuals known to be hypersensitive to allopurinol or to any other components of the formulation (see Section 2 Qualitative and Quantitative Composition).
Allopurinol should not be given concomitantly with iron salts to patients with idiopathic haemochromatosis, nor should it be given to the immediate relatives of such patients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs.
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 these patients.
Asymptomatic hyperuricaemia per se is not an indication for the use of allopurinol. Fluid and dietary modifications with management of the underlying cause may correct the condition. If other clinical conditions suggest a need for allopurinol it must be introduced at low dosage (50 to 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 Section 4.2 Dose and Method of Administration).
Allopurinol must be withdrawn immediately and permanently at the first signs of intolerance.

Dermatological effects.

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 hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum), drug rash with eosinophilia and systemic symptoms (DRESS), Lyell's disease, generalised vasculitis, irreversible hepatotoxicity, and on rare occasions death. DRESS is also referred to as drug-induced hypersensitivity syndrome (DIHS) and Lyell's disease is also referred to as toxic epidermal necrolysis.

Hypersensitivity effects.

The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

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 (0.5 mg three times a day) for at least one month.

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.

Haematological effects.

Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as six weeks to as long as six years after the initiation of therapy of allopurinol. Rarely a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone.

Haemochromatosis.

Allopurinol's primary action in treating gout is to inhibit the enzyme, xanthine oxidase. Xanthine oxidase may be involved in the reduction and clearance of hepatically stored iron. Some rodent studies have found increased iron storage in animals treated with allopurinol, whilst others have not. A study in 28 healthy volunteers found no change in hepatic iron storage with allopurinol treatment. There are no human studies which have investigated the safety of administering allopurinol to patients with haemochromatosis. Administration of allopurinol to patients with abnormal iron storage, including haemochromatosis, should be undertaken with caution.

Instructions to patients.

Wherever possible a high fluid intake sufficient to yield a daily urinary output of 2 L and the maintenance of a neutral or alkaline urine are desirable in hyperuricaemic patients whether or not they are on allopurinol therapy. Allopurinol is better tolerated if taken after meals.

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 population, 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 the 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.

Use in hepatic impairment.

A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol, and in some patients asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.
Reduced doses should be used in patients with hepatic impairment.

Use in renal impairment.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in serum urea during administration of allopurinol. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of allopurinol administration and dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. 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 these patients.
Renal failure in association with administration of allopurinol has been observed among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with allopurinol. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. A dose reduction will be required in patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

Adenine arabinoside.

Evidence suggests that the plasma half-life of adenine arabinoside 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.

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.

Phenytoin.

Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Theophylline.

Experimental studies of the effect of allopurinol on theophylline metabolism have produced contradictory findings. Inhibition of the metabolism of theophylline has been reported. 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 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.

Cyclosporin.

Reports suggest that the plasma concentration of cyclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced cyclosporin toxicity should be considered if the drugs are co-administered.

Antacids.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction studies in rabbits and rats using dosages up to 20 times the usual human dosage have not revealed any evidence of impaired fertility. Only rarely has infertility in human males and impotence occurred during allopurinol therapy, however a casual relationship to the drug has not been established.
(Category B2)
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.
One study in mice receiving a high intraperitoneal dose on days 10 to 13 of pregnancy resulted in foetal abnormalities but extensive studies of high oral doses in mice, rats and rabbits during days 8 to 16 produced none.
Use in pregnancy only when there is no safe alternative and when the disease itself carries risks for the mother or child.
Reports indicate that allopurinol and its metabolite, oxipurinol are excreted in human breast milk. Concentrations of 1.5 mg/L allopurinol and 53.7 mg/L oxipurinol have been demonstrated in breast milk from a woman taking allopurinol 300 mg/day. There are, however, no data concerning the effects of allopurinol, or its metabolism, on the breast-fed child. Allopurinol during breastfeeding is not recommended.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions are usually reversed by the reduction of dosage or complete withdrawal of allopurinol. Taking allopurinol after meals may minimise gastrointestinal disturbances. Where hypersensitivity reactions occur, allopurinol should be withdrawn immediately. Corticosteroids may be beneficial in overcoming such reactions.
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.

Dermatological.

These 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. Allopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions, allopurinol may, if desired, be reintroduced at a small dose (e.g. 50 mg/day) and gradually increased. If the rash recurs, allopurinol should be permanently withdrawn as more severe hypersensitivity reactions may occur.

Generalised hypersensitivity.

Skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-Johnson and/or Lyell's disease (toxic epidermal necrolysis) occur rarely. Drug rash with eosinophilia and systemic symptoms (DRESS) (drug-induced hypersensitivity syndrome (DIHS)) also occurs rarely.
Associated vasculitis and tissue response may be manifested in various ways including hepatitis, interstitial nephritis and, very rarely, epilepsy. If such reactions do occur, it may be at any time during treatment, Allopurinol 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.
Very rarely acute anaphylactic shock has been reported.

Angioimmunoblastic lymphadenopathy.

Angioimmunoblastic lymphadenopathy has been described rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.

Hepatic function.

Rare reports of hepatic dysfunction ranging from asymptomatic rises in liver function tests to hepatitis (including hepatic necrosis and granulomatous hepatitis) have been reported without overt evidence of more generalised hypersensitivity. Granulomatous hepatitis appears to be reversible on withdrawal of allopurinol.

Gastrointestinal.

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 after meals. Recurrent haematemesis has been reported as an extremely rare event as has steatorrhoea.

Haematological.

Bone marrow depression has been reported in patients receiving additional medications during allopurinol therapy. However rarely has a patient receiving allopurinol alone, acquired one or more of their cell lines to be affected by bone marrow depression. There have been occasional reports of transient reduction in the numbers of circulating formed elements of the blood, usually in association with renal and/or hepatic disorder. Adverse effects such as leukocytosis, leukopenia, eosinophilia, thrombocytopenia, aplastic anaemia, agranulocytosis and granulocytopenia, have occurred very rarely. The clinical significance has yet to be demonstrated.

Other.

The following complaints have been reported occasionally: fever, general malaise, asthenia, headache, vertigo, ataxia, somnolence, coma, depression, paralysis, paraesthesia, neuropathy, visual disorder, cataract, macular changes, taste perversion, stomatitis, changed bowel habit, infertility, impotence, nocturnal emission, diabetes mellitus, hyperlipidaemia, furunculosis, alopecia, discoloured hair, angina, hypertension, bradycardia, oedema, uraemia, haematuria, angioedema and gynaecomastia.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.

Dose frequency.

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 dose regimen may be appropriate.

Adults.

2 to 10 mg/kg bodyweight/day or 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.

Children under 15 years.

10 to 20 mg/kg bodyweight/day or 100 to 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.

Use in the elderly.

In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to the dosage advice in renal disorder 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 the presence of impaired renal function, serious consideration should be given to initiating treatment with a maximum dose of 100 mg/day and increasing it only if the serum and/or urinary urate response is unsatisfactory. In severe renal insufficiency, it may be advisable to use less than 100 mg/day or to use single doses of 100 mg at longer intervals than one day. Alternative schedules based on creatinine clearances are unsatisfactory because of the imprecision of low clearance values.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels below 100 micromol/L (15.2 microgram/mL).

Renal dialysis.

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 allopurinol 300 to 400 mg immediately after each dialysis with none in the interim.

Dosage in 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 in the lower range.
If urate nephropathy or other pathology has compromised renal function, the advice given in Renal impairment (above) should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions and Section 4.8 Adverse Effects (Undesirable Effects)).

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 where alertness is mandatory until they are reasonably certain that allopurinol does not adversely affect performance.

4.9 Overdose

Accidental or deliberate ingestion of up to 5 g of allopurinol or very rarely 20 g has been reported.

Symptoms.

These include nausea, vomiting, diarrhoea and dizziness.

Treatment.

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 6-mercaptopurine and/or azathioprine is being taken concomitantly. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary, haemodialysis may be used.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Allopurinol APOTEX 100 mg tablet.

Bottle (HDPE white opaque bottle with screw cap) of 200 tablets (AUST R 269652).

Allopurinol APOTEX 300 mg tablet.

Blister Pack (Clear PVDC/PVC/Aluminium silver foil) of 60 tablets (AUST R 269638).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes