Consumer medicine information

Progout

Allopurinol

BRAND INFORMATION

Brand name

Progout

Active ingredient

Allopurinol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Progout.

What is in this leaflet

This leaflet answers some common questions about PROGOUT.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking PROGOUT against the benefits expected for you.or your child.

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

Keep this leaflet with your medicine. You may need to read it again.

What PROGOUT is used for

PROGOUT is used in the treatment of:

  • gouty arthritis or gout, a condition of painful swollen joints caused by uric acid crystals
  • kidney stones
  • other rare conditions where high levels of uric acid occur in the blood, for example Lesch-Nyhan syndrome.

PROGOUT helps to treat the symptoms of these conditions but will not cure them. It will not help treat the pain that occurs in an acute attack of gout.

PROGOUT belongs to a group of medicines called anti-uricaemic agents. These medicines reduce the amount of uric acid in the body. Most commonly, high levels of uric acid in the body are related to gout. Excess amounts of uric acid in the blood may lead to the development of crystals which deposit in the joints, causing pain, swelling and tenderness.

Ask your doctor if you have any questions about why PROGOUT has been prescribed for you. Your doctor may have prescribed PROGOUT for another reason.

PROGOUT is available only with a doctor's prescription.

There is no evidence that PROGOUT is addictive.

Use in children

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

Before you take PROGOUT

When you must not take it

Do not take PROGOUT if you are allergic to medicines containing allopurinol (e.g. Zyloprim) or any of the ingredients listed at the end of this leaflet, including lactose monohydrate. Some of the symptoms of an allergic reaction may include skin rash, itching or hives; swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing; or other parts of the body; wheezing or difficulty breathing; shortness of breath; muscle pain or tenderness of joint pain.

Do not take PROGOUT if:

  • you or a member of your immediate family have haemochromatosis, a condition where there is too much iron in the body, and you are also taking iron salts at the same time.
  • you are having an acute attack of gout.
    If a person first starts taking PROGOUT when they are having an attack of gout it can make the symptoms of this condition temporarily worse. However, if an acute attack of gout does occur when a person is already taking PROGOUT, it can be continued. Do not stop taking this medicine during an attack of gout unless advised by your doctor.

Do not take PROGOUT if the expiry date (EXP.) printed on the pack has passed. If you take this medicine after the expiry date, it may not work as well.

Do not take PROGOUT if the packaging shows signs of tampering or the tablets do not look like the tablets described at the end of this leaflet.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor will discuss the risks and benefits of taking PROGOUT during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed. PROGOUT passes into breast milk and may affect your baby. Your doctor will discuss the risks and benefits of taking PROGOUT when breastfeeding.

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

  • liver problems
  • kidney problems, including kidney stones
  • high blood pressure
  • heart failure or other heart problems
  • diabetes mellitus
  • epilepsy
  • cancers or tumours
  • conditions where the levels of uric acid are abnormally high
  • haemochromatosis (a disease involving excessive deposits of iron in the body)
  • thyroid problems.

Your doctor may want to take special care if you have any of these conditions.

Tell your doctor if you plan to have surgery.

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

Taking other medicines

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

Some medicines may be affected by PROGOUT, or may affect how well it works. These include:

  • some medicines used to treat high blood pressure or heart problems
  • aspirin and other salicylates
  • probenecid, a medicine used to treat gout
  • warfarin (Coumadin, Marevan), a medicine used to prevent blood clots
  • azathioprine (e.g. Imuran) and ciclosporin (Neoral, Sandimmun), medicines used to prevent organ transplant rejection or to treat certain immune system problems
  • mercaptopurine monohydrate (Puri-Nethol), a medicine used in the treatment of leukaemia
  • chlorpropamide, a medicine for diabetes
  • phenytoin (Dilantin), a medicine for epilepsy
  • theophylline (Nuelin), a medicine used in asthma
  • antibiotics called amoxicillin (e.g. Amoxil, Moxacin) and ampicillin (Alphacin)
  • thiazide diuretics or fluid tablets (e.g.Dithiazide).
  • aluminium hydroxide, a medicine used to treat the symptoms of too much stomach acid
  • adenine arabinoside ('Vidarabine'), an anti-viral medicine
  • medicines used for cancer (e.g. cyclophosphamide, doxorubicin)
  • didanosine, used to treat HIV infection.

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

The above list is not exhaustive.Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

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

How to take PROGOUT

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to take

The dose varies from person to person. Your doctor will tell you how much to take.

The usual dose is 100 mg to 600 mg daily in divided doses (that is one 100mg tablet daily up to one 300mg tablet twice daily) but the dose may be as much as 900mg daily to treat very high blood levels of uric acid.

Elderly people over 65 years of age and those with kidney and/or liver problems usually receive the lowest dose possible to control uric acid production.

Children under 15 years of age usually take 100 mg to 400 mg daily in divided doses.

Your doctor may advise you to take a different dose. This depends on your condition and whether or not you are taking any other medicines.

How to take PROGOUT

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

When to take PROGOUT

Take PROGOUT during or immediately after food at the frequency directed by your doctor.

Take your medicine at the same time each day.

PROGOUT is usually taken once a day. However, if your dose is higher than 300 mg a day, your doctor may advise you to take it morning and night.

If you forget to take PROGOUT

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

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

If you have any questions about this, check with your doctor or pharmacist.

How long to take PROGOUT for

To properly control your condition, PROGOUT must be taken every day.

PROGOUT will not cure your condition but will help control pain, stiffness and other symptoms.

Keep taking PROGOUT for as long as your doctor recommends.

If you take too much PROGOUT (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much PROGOUT. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much PROGOUT, you may feel dizzy, nauseous, and experience vomiting and diarrhoea.

While you are taking PROGOUT

Things you must do

Drink at least 2 litres (8 to 10 glasses) of fluid each day. This will help to reduce the levels of uric acid in your body and prevent the formation of kidney stones.

Stop taking PROGOUT immediately if you develop a skin rash or any other sign of an allergic reaction. Before starting any new medicine, tell your doctor or pharmacist that you are taking PROGOUT.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking PROGOUT.

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

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

Visit your doctor regularly so they can check on your progress. You may need to have blood or urine tests.

Tell your doctor if you feel PROGOUT is not helping your condition. If you continue to have painful attacks of gout your doctor may need to adjust your treatment.

Tell your doctor if, for any reason, you have not taken PROGOUT exactly as prescribed. Otherwise, your doctor may adjust your treatment unnecessarily.

Things you must not do

Do not take PROGOUT to treat an acute attack of gout. Your doctor will prescribe another medicine such as colchicine or a non-steroidal anti-inflammatory drug (NSAID) to relieve an acute attack of gout.

Do not use PROGOUT to treat any other conditions unless your doctor tells you to.

Do not give PROGOUT 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.

Things to be careful of

Be careful driving or operating machinery until you know how PROGOUT affects you. PROGOUT may cause drowsiness, dizziness or lack of co-ordination in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Avoid drinking alcohol while taking PROGOUT. Combining PROGOUT and alcohol can make you more sleepy, dizzy or lightheaded. Alcohol may also increase the formation of uric acid.

Certain foods are best avoided when you have gout. Food such as organ meats, anchovies and yeast extracts (includes Vegemite®) can increase the levels of uric acid in your body. Ask your doctor or pharmacist for more advice about which foods to avoid.

Side effects

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

PROGOUT helps most people with gouty arthritis and kidney stones, but it may have unwanted side effects in some people.

Side effects only occur rarely in people taking PROGOUT. Most of the time they are minor. You may need medical treatment if you get some of the side effects.

People with liver and kidney problems have an increased chance of experiencing side effects.

Do not be alarmed by this list of possible 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 PROGOUT immediately and contact your doctor if a rash does occur.

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

  • nausea, vomiting, diarrhoea
  • headache
  • oedema (swelling)
  • drowsiness, dizziness, unsteadiness when walking
  • high blood pressure
  • abdominal pain
  • skin rash
  • blurred vision, vision problems
  • confusion
  • unexplained nosebleeds
  • change in bowel habits
  • change in taste sensation
  • sleeplessness
  • change in hair colour

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

  • fatty stools
  • going to the toilet often
  • blood in the urine
  • burning feeling while passing urine
  • change in the amount of urine
  • yellowing of the skin and eyes (jaundice)
  • bleeding or bruising more easily
  • swelling of the hands, ankles or legs
  • hair loss
  • general malaise or depression
  • sleepiness
  • confusion or vision problems
  • numbness in the limbs
  • angina (chest pain involving the heart)
  • severe palpitations
  • severe itching, skin flaking, skin rash or hives
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing or shortness of breath
  • 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.
  • fainting, seizures or fits

These are very serious yet rare side effects. You may need urgent medical attention or hospitalisation.

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

Other side effects not listed above may also occur in some patients. Some of these side effects (e.g. high blood pressure) can only be found when your doctor does tests from time to time to check your progress.

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

After taking PROGOUT

Storage

Keep PROGOUT 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.

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

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

Do not store PROGOUT or any other medicine in the bathroom or near a sink.

Do not leave PROGOUT in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking PROGOUT, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

PROGOUT tablets are available 2 strengths:

  • PROGOUT 100 - 9.5mm white normal convex, tablet marked "AL/100" on one side and "G" on the other
  • PROGOUT 300 - 11mm white normal convex tablet marked "AL/300 " on one side and "G" on the other.

PROGOUT 100 is available in bottles of 200 tablets. PROGOUT 300 is available in bottles of 60 tablets.

Ingredients

The active ingredient in PROGOUT is allopurinol.

PROGOUT 100
Each PROGOUT 100 tablet contains 100 mg of allopurinol.

The tablets also contain:

  • Lactose monohydrate
  • maize starch
  • povidone
  • macrogol 8000
  • sodium lauryl sulfate
  • purified talc
  • magnesium stearate.

PROGOUT 100 tablet contains galactose, sulfites and sugars (as lactose).

PROGOUT 300
Each tablet PROGOUT 300 contains 300 mg of allopurinol.

The tablets also contain:

  • maize starch
  • povidone
  • maltodextrin
  • sodium starch glycollate
  • microcrystalline cellulose
  • magnesium stearate.

PROGOUT 300 tablet contains sulfites.

Manufacturer

PROGOUT is made in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Australian registration numbers:

PROGOUT 100 - AUST R 27969

PROGOUT 300 - AUST R 17708

This leaflet was prepared in May 2023.

PROGOUT® is a Viatris company trade mark

PROGOUT_cmi\May23/00

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Progout

Active ingredient

Allopurinol

Schedule

S4

 

1 Name of Medicine

Allopurinol.

2 Qualitative and Quantitative Composition

Each Progout tablet contains 100 mg or 300 mg of allopurinol as the active ingredient.

Excipients with known effect.

Progout 100.

Galactose, sulfites and sugars as lactose.

Progout 300.

Sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Progout 100.

100 mg tablet: 9.5 mm white normal convex tablet marked AL/100 on one side, G on the reverse.

Progout 300.

300 mg tablet: 11 mm white normal convex tablet marked AL/300 on one side, G on the reverse.

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.
Progout is indicated for the management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.
Progout is indicated for the management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

4.2 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.

Progout may be taken orally after a meal and may be taken once a day. 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.
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 Progout therapy.

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 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 impression of low clearance values.
If facilities are available to monitor plasma oxypurinol concentrations, the dose should be adjusted to maintain plasma oxypurinol 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 Progout 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 Progout 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 Progout 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 oxypurinol 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 to individuals known to be hypersensitive to allopurinol or any other components of the formulation (see 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

Warnings.

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 a drug-induced hypersensitivity syndrome (DIHS) and Lyell's disease is also referred to as toxic epidermal necrolysis.

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 or 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 (see Section 4.2 Dose and Method of Administration).

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.

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.

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 hyperuricaemia 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.

Haematological effects.

Bone marrow depression has been reported in patients receiving allopurinol, most of whom receive concomitant drugs with 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.

Hemochromatosis.

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 at least two litres and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to help prevent renal precipitation of urates in hyperuricemic 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 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 monohydrate and azathioprine.

Allopurinol inhibits the enzymatic oxidation of 6-mercaptopurine monohydrate and azathioprine. Therefore, when 6-mercaptopurine monohydrate or azathioprine is given concurrently with allopurinol, only one-quarter of the usual dose of 6-mercaptopurine monohydrate or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity. Subsequent adjustment of doses of mercaptopurine monohydrate or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects.

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.

Oxypurinol, 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 oxypurinol. 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. 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 and other xanthines.

Inhibition of the metabolism of theophylline has been reported in normal subjects given relatively high doses of allopurinol (300 mg twice daily) under experimental conditions. Although there have been no clinical reports of interaction, 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.

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.

Ciclosporin.

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

Angiotensin-converting-enzyme (ACE) inhibitors.

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

Diuretics.

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.

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 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 oxypurinol are excreted in human breast milk. Concentrations of 1.5 mg/L allopurinol and 53.7 mg/L oxypurinol have been demonstrated in breast milk from a woman taking allopurinol 300 mg/day. However, there is no data concerning the effects of allopurinol, or its metabolism, on the breastfed child. Allopurinol during breastfeeding is not recommended.

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.

4.8 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. When 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 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 them. 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 effects.

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 www.tga.gov.au/reporting-problems.

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 monohydrate and/or azathioprine are 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 Poisons Information Centre on 13 11 26 (Australia).

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 re-utilisation 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. Due to 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. Allopurinol and oxypurinol are mainly excreted in the urine and little allopurinol is found in the urine 6 hours after administration. 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. 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 available.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Progout 100 tablet contains 100 mg of allopurinol. The tablets also contain the following inactive ingredients: lactose monohydrate, maize starch, povidone, macrogol 8000, sodium lauryl sulfate, purified talc and magnesium stearate. The tablets are gluten free.
Each Progout 300 tablet contains 300 mg of allopurinol. The tablets also contain the following inactive ingredients: maize starch, povidone, maltodextrin, sodium starch glycollate, microcrystalline cellulose and magnesium stearate.

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

Progout 100.

Available in HDPE bottles with PP screw cap or PP child-resistant cap of 200 tablets.

Progout 300.

Available in HDPE bottles with a PP child resistant closure of 60 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 27969 - Progout 100 allopurinol 100 mg tablet bottle.
AUST R 17708 - Progout 300 allopurinol 300 mg tablet bottle.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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.

Chemical structure.

Active ingredient: Allopurinol.
Chemical name: 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one.
Structural formula:
Molecular formula: C5H4N4O. Molecular weight: 136.1.

CAS number.

315-30-0.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes