Consumer medicine information

Allopurinol Sandoz

Allopurinol

BRAND INFORMATION

Brand name

Allopurinol Sandoz

Active ingredient

Allopurinol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Allopurinol Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Allopurinol Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor 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 ALLOPURINOL SANDOZ IS USED FOR

This medicine is used to treat or prevent medical problems that may occur if too much uric acid is present in the body.

These include gout, gouty arthritis, certain kidney problems or enzyme disorders where the body produces too much uric acid.

It contains the active ingredient allopurinol.

Allopurinol belongs to a group of medicines called xanthine oxidase inhibitors.

It works by reducing the production of uric acid in the body, therefore helping to prevent the formation of deposits of uric acid crystals.

Deposits of uric acid crystals in the body can cause a variety of medical problems.

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 not addictive.

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

BEFORE YOU TAKE ALLOPURINOL SANDOZ

When you must not take it

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

  • allopurinol, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • hay fever
  • 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 your nearest hospital.

Do not take this medicine if you or a member of your immediate family has haemochromatosis, a condition where there is too much iron in the body, and you are also taking iron salts at the same time.

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 disease
  • liver disease
  • heart disease or high blood pressure
  • conditions where the levels of uric acid are abnormally high
  • cancers or tumours
  • thyroid problems
  • diabetes
  • epilepsy
  • haemochromatosis, a condition where there is too much iron in the body
  • any other medical conditions.

Tell your doctor if you are currently having an acute 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 taking medicines to treat cancer. Your doctor may need to do regular blood tests if you are being treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine or alkyl halogenides.

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 him/her before you start taking Allopurinol Sandoz.

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 Sandoz may interfere with each other. These include:

  • some medicines used to treat high blood pressure or heart problems
  • medicines used for cancer (e.g. cyclophosphamide, doxorubicin)
  • didanosine, used to treat HIV infection
  • adenine arabinoside, a medicine used to treat viral infections
  • azathioprine, mercaptopurine and cyclosporin, medicines used to suppress the immune system
  • chlorpropamide, a medicine used to treat diabetes
  • aspirin (a drug which is used to treat headache, pain, inflammation, clotting or high temperatures) and other salicylates
  • other medicines used to treat gout or hyperuricaemia (high levels of uric acid in the blood), such as probenecid
  • ampicillin or amoxycillin, antibiotic medicines used to treat bacterial infections
  • warfarin and other coumarin type anticoagulant medicines used to prevent blood clots
  • thiazide diuretics (a certain type of water tablet)
  • phenytoin, a medicine used to treat epilepsy
  • theophylline, a medicine used to treat asthma.
  • medicines containing aluminium hydroxide, used to treat heartburn, upset stomach or indigestion.

These medicines may be affected by Allopurinol Sandoz 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 ALLOPURINOL SANDOZ

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, ask your doctor or pharmacist for help.

How much to take

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Allopurinol Sandoz may not work as well and your problem may not improve.

The recommended daily doses are:

Adults:
100mg to 600mg daily.

If the dose is more than 300mg each day, it is recommended that half the dose is taken in the morning and half is taken at night (divided doses).

The dose may be as much as 900mg a day to treat very high levels of uric acid.

Children under 15 years:
100mg to 400mg daily in divided doses.

Elderly patients:
Elderly patients usually receive the lowest dose possible to control uric acid production.

How to take it

Swallow the tablets whole with a full glass of water.

When to take Allopurinol Sandoz

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

Take your medicine during or immediately after a meal. If you take it on an empty stomach, it may increase the possibility of feeling sick or causing a stomach upset.

How long to take Allopurinol Sandoz

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.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Allopurinol Sandoz. 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 ALLOPURINOL SANDOZ

Things you must do

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

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

If you become pregnant while taking this medicine, tell your doctor immediately.

If you develop a skin rash or any other allergic reaction, stop taking Allopurinol Sandoz and seek medical attention immediately.

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.

Drink plenty of water (at least 8-10 glasses of fluid per day) while you are taking Allopurinol Sandoz. This will assist in reducing the uric acid levels in your body and prevent kidney stones from forming.

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

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

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

Things you must not do

Do not take Allopurinol Sandoz 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, unless a skin rash or allergic reaction occurs. 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 Allopurinol Sandoz affects you. This medicine may cause drowsiness, dizziness and lack of co-ordination in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, drowsiness, dizziness and blurred vision may be worse.

SIDE EFFECTS

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. 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.

The most common side effect is skin rash. Stop treatment with Allopurinol Sandoz immediately and contact your doctor if a rash does occur.

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

  • nausea (feeling sick) or vomiting or diarrhoea
  • dizziness, drowsiness or unsteadiness when walking
  • headache
  • taste changes
  • 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 burning feeling when passing urine
  • blood in your urine
  • yellow 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
  • swelling of the hands, ankles or legs
  • angina or palpitations.

If any of the following happen, tell your doctor immediately:

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

The above are very serious side effects. You may need urgent medical attention or hospitalisation. Serious side effects are rare, although skin rash and itching are more common side effects.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, high blood pressure) can only be found when your doctor does tests from time to time to check your progress.

AFTER TAKING ALLOPURINOL SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Allopurinol Sandoz 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 the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Allopurinol Sandoz comes in two types of tablets:

Allopurinol Sandoz 100mg - white, round tablets with a score notch on one side.

Available in bottles of 200 tablets.

Allopurinol Sandoz 300mg - white, oblong tablets, scored on both sides.

Available in bottles of 60 tablets.

Ingredients

Active ingredients:

  • Allopurinol Sandoz 100mg - 100mg allopurinol.
  • Allopurinol Sandoz 300mg - 300mg allopurinol.

Inactive ingredients:

  • powdered cellulose
  • povidone
  • macrogol 4000
  • crospovidone
  • purified talc
  • magnesium stearate
  • microcrystalline cellulose.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in May 2023.

Australian Register Numbers

100mg tablets: AUST R 65905

300mg tablets: AUST R 65906

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Allopurinol Sandoz

Active ingredient

Allopurinol

Schedule

S4

 

1 Name of Medicine

Allopurinol.

2 Qualitative and Quantitative Composition

Each Allopurinol Sandoz 100 mg tablet contains 100 mg allopurinol.
Each Allopurinol Sandoz 300 mg tablet contains 300 mg allopurinol.
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.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Allopurinol Sandoz allopurinol 100 mg tablet - round, white, scored tablet.
Allopurinol Sandoz allopurinol 300 mg tablet - oblong, white, scored tablet.

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.
Management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyl transferase.
Management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

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 dosage advice in renal disorders and precautions.

Use in 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 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.

(For example 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 Use in patients with renal impairment (above) should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. (Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).

4.3 Contraindications

Allopurinol should not be administered in individuals known to be hypersensitive to allopurinol or to any other ingredients of the product (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients).
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.

Warnings.

Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs.

Use with caution in the following circumstances.

Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics or angiotensin converting enzyme (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 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 effects, and increased only if the serum urate response is unsatisfactory. Extra caution should be exercised if renal function is poor (also see Section 4.2 Dose and Method of Administration).
Allopurinol must be withdrawn immediately and permanently at the first signs of intolerance.

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.

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 (SJS; erythema multiforme exudativum), drug rash with eosinophilia and systemic symptoms (DRESS), Lyell's syndrome, generalised vasculitis, irreversible hepatotoxicity, and on rare occasions death. DRESS is also referred to as a drug-induced hypersensitivity syndrome (DIHS) and Lyell's syndrome is also referred to as toxic epidermal necrolysis (TEN).

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.

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. When generalized hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.

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 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 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 the 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.

Haematological effects.

Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant medicines 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, while 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.

Thyroid disorders.

Increased thyroid stimulating hormone (TSH) values were observed in patients on long-term treatment with allopurinol in a long term open label extension study. Caution is required when allopurinol is used in patients with alteration of thyroid function.

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. Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due precautions when engaging in activities where alertness is mandatory.

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 medicine 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 with 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).
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.

Use in the elderly.

In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Paediatric use.

Allopurinol is contraindicated in children with the exception of those with hyperuricemia secondary to malignancy or with Lesch-Nyhan syndrome, because safety and efficacy have not been established in other conditions.

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, medicines 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.

Didanosine.

Plasma didanosine levels were increased with concomitant allopurinol treatment. Therefore co-administration is not recommended. If concomitant use is unavoidable a dose reduction of didanosine may be required and patients should be closely monitored.

Chlorpropamide and other cytotoxic agents.

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. 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 and other xanthines.

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 medicines. The cause of the reported association has not been established, however, it is recommended that in patients receiving allopurinol, an alternative to ampicillin or amoxicillin is used where available.

Cytostatics.

With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halogenides), blood dyscrasias occur more frequently than when these active substances are administered alone.
Blood count monitoring should therefore be performed at regular intervals.

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 medicine are co-administered.

Diuretics.

An interaction between allopurinol and furosemide that results in increased serum urate and plasma oxipurinol concentrations has been reported.
Thiazide diuretics may increase the risk of serious allopurinol toxicity, including hypersensitivity reactions and the combination should be monitored, especially if renal function is compromised.

Angiotensin-converting-enzyme (ACE) inhibitors.

An increased risk of hypersensitivity has been reported when allopurinol is given with ACE inhibitors especially in renal impairment.

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 causal relationship to the drug has not been established.
(Category B2)
Category B2: 'Drugs which have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.'
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 or 13 of pregnancy resulted in fetal 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 safer alternative and when the disease itself carries risks for the mother or child.
 Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Allopurinol during breastfeeding is not recommended. 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 breastfed child.

4.7 Effects on Ability to Drive and Use Machines

Since adverse effects 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.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects 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. Corticosteroid may be beneficial in overcoming such reactions.
Adverse effects 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.

Immune system disorders.

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.

Dermatological.

These are the most common effects 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 hypersensitivity reactions may occur.

Generalised hypersensitivity.

Skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-Johnson and/or Lyell's syndrome (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. Very rarely acute anaphylactic shock has been reported. 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, dysgeusia, 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, pyrexia, uraemia, haematuria, azotaemia, 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://tga/gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
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.

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.
Allopurinol decreases urate formation in two ways: the inhibition of xanthine oxidase reduces the amount of hypoxanthine and xanthine converted to urate/ uric acid; 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% of those of other tissues. Within muscles, 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-ribose. 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 ten 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 one to two hours. Little allopurinol is found in the urine six 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.

No data are available on whether or not allopurinol has mutagenic 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 a mean period of 40 months.

Carcinogenicity.

No data are available on whether or not allopurinol has carcinogenic effects within humans or animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Allopurinol Sandoz 100 mg and 300 mg tablets contain powdered cellulose, povidone, macrogol 4000, crospovidone, purified talc, magnesium stearate and microcrystalline cellulose.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

100 mg.

HDPE bottle of 200 tablets.

200 mg.

HDPE bottle of 60 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one.
C5H4N4O.
MW: 136.1.

CAS number.

315-30-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes