Consumer medicine information

APO-Allopurinol Tablets

Allopurinol

BRAND INFORMATION

Brand name

APO-Allopurinol Tablets

Active ingredient

Allopurinol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about APO-ALLOPURINOL (Allopurinol tablets).

It does not contain all of the available information about APO-ALLOPURINOL tablets.

It does not replace talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child taking APO-ALLOPURINOL against the benefits he or she expects it will have.

Ask your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with the medicine.

You may need to read it again.

What this medicine is used for

The name of your medicine is APO-ALLOPURINOL and is available in tablets of two different strengths.

The active ingredient is called allopurinol.

Allopurinol belongs to a group of medicines called anti-uricaemic agents and is used to reduce the amount of uric acid in the body. Most commonly, high levels of uric acid in the body are related to gout.

APO-ALLOPURINOL is available as a 100 mg and 300 mg tablet.

APO-ALLOPURINOL is used to treat high levels of uric acid in the blood (hyperuricaemia) associated with gout or some other conditions. Your doctor will identify these other conditions if necessary, as they are very uncommon (e.g. Lesch-Nyhan Syndrome).

Your doctor however, may have prescribed APO-ALLOPURINOL for another purpose not listed above.

Ask your doctor if you have any questions about why APO-ALLOPURINOL has been prescribed for you.

If you have any concerns, you should discuss this with your doctor.

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

Before you take this medicine

When you must not take it

Do not take APO-ALLOPURINOL if you are allergic to:

  • Allopurinol or any of the ingredients listed at the end of this leaflet including lactose.

Some of the symptoms of an allergic reaction to APO-ALLOPURINOL may include hives and other skin rashes, difficulty breathing, hay fever, swelling of the face or throat or faintness.

Do not take APO-ALLOPURINOL after the expiry date (EXP.) printed on the pack.

If you take it after the expiry date has passed, it may have no effect at all, or worse, there may be an entirely unexpected effect.

Do not purchase or take APO-ALLOPURINOL if the packaging is torn or shows signs of tampering.

Do not take the tablets if they do not look quite right.

If you are not sure whether you should start taking APO-ALLOPURINOL, contact your doctor or pharmacist.

Do not give your medicine to children unless your doctor has prescribed it.

Before you start to take it

You must tell your doctor if you are:

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Some of the symptoms of an allergic reaction to APO-ALLOPURINOL 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.

  1. You have or have had any medical conditions, especially the following:
  • kidney disease
  • liver disease
  • high blood pressure
  • diabetes
  • epilepsy
  • heart disease
  • haemochromatosis (a disease involving excessive deposits of iron in the body).
  1. You are currently pregnant or you plan to become pregnant.
    APO-ALLOPURINOL like all medicines should not be used during pregnancy, unless your doctor tells you to.
  2. You are currently breastfeeding or you plan to breast-feed.
  3. Having an attack of gout
    If you are having an attack of gout before starting APO-ALLOPURINOL, you should tell your doctor and wait for the attack to subside before starting APO-ALLOPURINOL. If an acute attack of gout does occur when you are already taking APO-ALLOPURINOL, it should be continued. Do not stop taking this medicine during an attack of gout unless advised by your doctor.
    When you first start taking APO-ALLOPURINOL, it may make the symptoms of gout attack temporarily worse. During an acute gout attack, it is important to continue taking the medicines prescribed for gout attack relief while you are taking APO-ALLOPURINOL.

If you have not told your doctor about any of the above, tell him or her before you start to take APO-ALLOPURINOL.

Taking other medicines

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

Some medicines may interfere with APO-ALLOPURINOL.

These include:

  • Aspirin (a drug which is used to treat headache, pain, inflammation, clotting or high temperatures). Other salicylate type drugs are also included. Ask your pharmacist.
  • Coumarin type anticoagulant drugs, medicine used to prevent blood clots (e.g. warfarin)
  • Other medicines used to treat gout or hyperuricaemia such as probenecid (Benemid)
  • Some medicines used to suppress the immune system such as azothioprine (Imuran), 6-mercaptopurine and cyclosporin
  • Some medicines used to treat epilepsy such as phenytoin (Dilantin)
  • Theophylline (a drug used to treat asthma)
  • Ampicillin or amoxycillin, which are two commonly used antibiotics used to treat bacterial infections
  • Chlorpropamide (Diabinese) used to treat diabetes
  • Medicines containing thiazide diuretics, used to decrease blood pressure and fluid retention (e.g. Chlorothiazide, hydrochlorothiaide, bendrofluazide)

The above medicines may reduce the effectiveness of APO-ALLOPURINOL, reduce its own effectiveness and/or react with APO-ALLOPURINOL resulting in untoward or sometimes dangerous side effects.

This list is not exhaustive. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking APO-ALLOPURINOL.

How to take this medicine

How to take it

Swallow the tablets with plenty of water and after food to reduce the possibility of gastric upset.

When to take it

Take APO-ALLOPURINOL immediately after meals at the frequency directed by your doctor. For example, morning and night, after breakfast and dinner for a twice daily dosage.

If you forget to take it

If your dosing schedule is one dose a day, take the missed dose as soon as possible, but not later than 4 hours before your next dose.

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

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

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

Speak to your doctor or pharmacist if you are unsure about whether to take your next dose.

Do not try to make up for missed doses by taking more than one dose at a time. This may increase the chance of you getting an unwanted side effect.

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much APO-ALLOPURINOL. Do this even if there are no signs of discomfort or poisoning. Also, report any other medicines or alcohol which has been taken. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you take too much APO-ALLOPURINOL you may have the following symptoms: nausea, vomiting, diarrhoea and dizziness.

While you are taking this medicine

Things you must do

Immediately stop taking APO-ALLOPURINOL and check with your doctor if a skin rash or other allergic reaction occurs.

Take your medicine exactly as your doctor has prescribed.

It is important to drink at least 2 litres of fluid per day. This will help prevent kidney stones.

APO-ALLOPURINOL helps prevent, but does not relieve gout attacks. It is important that you continue taking APO-ALLOPURINOL with the medication prescribed for gout attacks.

Tell all doctors, dentists and pharmacists who are treating you that you are taking this medicine.

Tell your doctor (immediately) if you become pregnant while you are taking it.

Visit your doctor regularly. Your doctor needs to check your progress and see whether you need to keep taking APO-ALLOPURINOL.

Always discuss with your doctor any problems or difficulties during or after taking APO-ALLOPURINOL.

Tell your doctor if for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Keep enough APO-ALLOPURINOL to last weekends and holidays.

Things you must not do

Do not take any other medicine while you are taking APO-ALLOPURINOL without first telling your doctor.

Do not drive, operate machinery, or participate in any dangerous activities where alertness is required, until you know how APO-ALLOPURINOL affects you.

APO-ALLOPURINOL may cause dizziness and affect co-ordination in some people. Therefore, it may affect alertness or concentration. it can also affect your eyesight.

Make sure you know how you react to this medicine before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or have affected vision.

Do not take APO-ALLOPURINOL for a longer time than your doctor has prescribed.

Do not change your dose without first checking with your doctor.

Do not stop taking it or lower the dose without checking first with your doctor.

Stopping this medicine suddenly on your own accord may cause some unwanted and dangerous effects, or your condition may reappear.

Your doctor will advise you when you can stop taking APO-ALLOPURINOL completely.

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

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking APO-ALLOPURINOL.

APO-ALLOPURINOL helps most people with the medical conditions listed in the beginning of this leaflet, but it may have unwanted side effects in some people.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist any questions you may have.

Common side effects:
The most common side effect is skin rash. Stop treatment with APO-ALLOPURINOL immediately and contact your doctor if a rash does occur.

Tell your doctor if you notice any of the following:

  • nausea (feeling sick)
  • oedema (swelling)
  • high blood pressure
  • abdominal pain
  • headache
  • dizziness
  • skin rash
  • vomiting
  • blurred vision
  • unexplained nosebleeds

There are other side effects that occur less often.

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

  • fatty stools
  • going to the toilet often
  • blood in the urine
  • hair loss
  • general malaise or depression
  • sleepiness
  • confusion or vision problems
  • numbness in the limbs
  • angina (chest pain involving the heart)
  • severe palpitations
  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue or other parts of the body
  • wheezing, shortness of breath, or trouble breathing
  • pain or tightness in the chest
  • if chills, fever, joint pain or swollen glands occur, especially if they occur together with or shortly after a skin rash

These are serious side effects.

You may need urgent medical attention.

Serious side effects are rare.

Some people may get other side effects when taking APO-ALLOPURINOL.

Your doctor may lower the dose to help control any serious side effects and decide on the necessary tests to monitor any of the above problems.

Check with your doctor as soon as possible if you have any problems while taking APO-ALLOPURINOL, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Storage and disposal

Storage

Keep it where children cannot reach it.

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

Keep APO-ALLOPURINOL in a cool dry place where the temperature stays below 30°C and protect from light. Do not store it or any other medicines in a bathroom or near a sink.

Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep your tablets in the packs or bottles they were provided in until it is time to take them.

Disposal

If your doctor tells you to stop taking this medication OR it has passed the expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like

APO-ALLOPURINOL 100 mg tablets are white to off-white, biconvex, round tablets coded with “U4A” and scored on the upper face, bottom face plain; in bottles of 200.

APO-ALLOPURINOL 300 mg tablets are white, biconvex, round tablets coded with “C9B” and scored on the upper face, bottom face plain; in blister packs of 60.

Ingredients

Each APO-ALLOPURINOL 100 mg and 300 mg tablet contains the active ingredient allopurinol.

The non-active ingredients in each APO-ALLOPURINOL tablet are:

  • povidone
  • maize starch
  • lactose monohydrate
  • magnesium stearate

APO-ALLOPURINOL tablets contain lactose but do not contain gluten or sucrose.

Sponsor or Supplier

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Australian Registration Numbers

APO-ALLOPURINOL 100 mg AUST R 218874

APO-ALLOPURINOL 300 mg AUST R 218875

This leaflet was last updated in: February 2017

BRAND INFORMATION

Brand name

APO-Allopurinol Tablets

Active ingredient

Allopurinol

Schedule

S4

 

Name of the medicine

Allopurinol.

Excipients.

Povidone, maize starch, lactose monohydrate and magnesium stearate.

Description

Chemical name: 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. Molecular formula: C5H4N4O. MW: 136.1. CAS: 315-30-0. 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.

Pharmacology

Actions.

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.

Pharmacokinetics.

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.

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

Contraindications

APO-Allopurinol should not be administered to individuals known to be hypersensitive to allopurinol or to any other components of the formulation (see Excipients).
APO-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.

Warnings

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

Precautions

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 APO-Allopurinol. Fluid and dietary modifications with management of the underlying cause may correct the condition. If other clinical conditions suggest a need for APO-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 Dosage and Administration).
APO-Allopurinol must be withdrawn immediately and permanently at the first signs of intolerance.

Dermatological effects.

APO-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 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.

Hepatic effects.

A few cases of reversible clinical hepatotoxicity have been noted in patients taking APO-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 APO-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.

Hypersensitivity effects.

The occurrence of hypersensitivity reactions to APO-Allopurinol may be increased in patients with decreased renal function receiving thiazides and APO-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 APO-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 APO-Allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Renal effects.

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 Dosage and Administration).

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.

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 micrograms/mL and in vivo at doses up to 600 mg/day for mean period of 40 months.

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.

Use in pregnancy.

(Category B2)
There is inadequate evidence of safety of APO-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.

Use in lactation.

Reports indicate that allopurinol and 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 breastfed child.

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 APO-Allopurinol therapy. APO-Allopurinol is better tolerated if taken after meals.

Effects on ability to drive and use machinery.

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.

Interactions

6-Mercaptopurine and azathioprine.

When 6-mercaptopurine or azathioprine is given concurrently with APO-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 APO-Allopurinol, but the significance needs to be assessed in each case.

Chlorpropamide.

If APO-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 coadministered.

Adverse Effects

Adverse reactions are usually reversed by the reduction of dosage or complete withdrawal of APO-Allopurinol. Taking APO-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 APO-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. APO-Allopurinol should be withdrawn immediately should such reactions occur. After recovery from mild reactions, APO-Allopurinol may, if desired, be reintroduced at a small dose (e.g. 50 mg/day) and gradually increased. If the rash recurs, APO-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. APO-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 APO-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 APO-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 APO-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, 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.

Dosage and Administration

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

Dose frequency.

APO-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 APO-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 APO-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 APO-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 Interactions with Other Medicines and Adverse Effects).

Overdosage

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 APO-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.

Presentation

Tablets (biconvex, round, plain on one side), 100 mg (white to off white, marked U4A and scoreline on reverse): 200's (glass or HDPE bottle); 300 mg (white, marked C9B and scoreline on reverse): 60's (PVC/Al blister pack).

Storage

Store below 30°C. Protect from moisture.

Poison Schedule

S4.