Consumer medicine information

Allosig

Allopurinol

BRAND INFORMATION

Brand name

Allosig Tablets

Active ingredient

Allopurinol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Allosig.

What is in this leaflet

This leaflet answers some common questions about ALLOSIG.

It does not contain all of the available information about this medicine.

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 ALLOSIG 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 ALLOSIG is used for

The name of your medicine is ALLOSIG 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.

ALLOSIG 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 may have prescribed ALLOSIG for another purpose not listed above.

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

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

Before you take it

When you must not take it

Do not take ALLOSIG 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 may include urticaria and other skin rashes, difficulty breathing, hay fever, swelling of the face or throat or faintness.

Do not take this medicine 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 take this medicine if the packaging is torn or shows signs of tampering.

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

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

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

Before you start to take it

You must tell your doctor if you are:

  1. Allergic to any other medicines or any other foods, dyes or preservatives
    Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  2. You have or have had any medical/ health problems, including:
  • 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 pregnant or plan to become pregnant
    ALLOSIG like all medicines should not be used during pregnancy, unless your doctor tells you to.
  2. You are breast-feeding or plan to breastfeed
  3. Having an attack of gout
    If a person first starts taking ALLOSIG 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 ALLOSIG it can be continued. Do not stop taking your medicine during an attack of gout unless advised by your doctor.

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

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 ALLOSIG.

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 either reduce the effectiveness of ALLOSIG, reduce its own effectiveness and/or react with ALLOSIG 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 ALLOSIG.

How to take it

How much to take

The dose of ALLOSIG may be different for each person and their medical condition. Your doctor will decide the right dose for you.

The recommended doses are for:

  • Adults: Usually 100 mg to 600 mg daily in divided doses (that is one 100 mg tablet daily up to one 300 mg tablet twice daily), but the dose may be as much a 900 mg daily to treat very high blood levels of uric acid.
  • Children under 15 years: 100 mg to 400 mg daily in divided doses.
  • Elderly patients usually receive the lowest dose possible to control uric acid production.

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 your tablets immediately after meals at the frequency directed by your doctor.
For example: morning and night after breakfast and dinner twice daily.

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.

If you are unsure about whether to take your next dose, speak to your doctor or pharmacist.

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 ALLOSIG. 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 ALLOSIG you may have the following symptoms: nausea, vomiting and diarrhoea.

While you are taking it

Things you must do

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

Take this 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.

This medicine helps prevent, but does not relieve gout attacks. It is important that you continue taking it with the medication prescribed for gout attacks.

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

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 this medicine.

Always discuss with your doctor any problems or difficulties during or after taking ALLOSIG.

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 medicine to last weekends and holidays.

Things you must not do

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

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

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

Make sure you know how you react to the 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 it for a longer time than your doctor has prescribed.

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

Do not stop taking ALLOSIG 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 ALLOSIG 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.

Side effects

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

This medicine 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 ALLOSIG 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 ALLOSIG 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 ALLOSIG.

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 ALLOSIG, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

After taking it

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 it 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

ALLOSIG 100 mg tablets are white, biconvex round tablets, one side embossed with ‘AP’ and ‘100’ separated by a break line and plain on the other side; in bottles of 200.

ALLOSIG 300 mg tablets are white, biconvex round tablets, one side embossed with ‘AP’ and ‘300’ separated by a break line and plain on the other side; in blister packs of 60.

Ingredients

Each ALLOSIG 100 mg and 300 mg tablet contains the active ingredient allopurinol.

The non-active ingredients in each ALLOSIG tablet are:

  • povidone
  • maize starch
  • lactose monohydrate
  • stearic acid
  • sodium starch glycollate (300mg strength only)

ALLOSIG tablets contain lactose but do not contain gluten or sucrose.

BRAND INFORMATION

Brand name

Allosig Tablets

Active ingredient

Allopurinol

Schedule

S4

 

1 Name of Medicine

Allopurinol.

6.7 Physicochemical Properties

Allopurinol has the molecular formula: C5H4N4O with a molecular weight of 136.1. 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 Name: 1,5-dihydro-4H- pyrazolo(3,4- d)pyrimidin-4-one.

Chemical structure.


CAS number.

315-30-0.

2 Qualitative and Quantitative Composition

Allosig tablets contain 100 mg or 300 mg allopurinol.
Excipients with known effect: lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Allosig 100 mg tablets are white, biconvex round tablets, one side embossed with 'AP' and '100' separated by a break line and plain on the other side.
Allosig 300 mg tablets are white, biconvex round tablets, one side embossed with 'AP' and '300' separated by a break line and plain on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Allopurinol is approximately 90% absorbed from the gastrointestinal tract.

Distribution.

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

Metabolism.

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

Excretion.

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

5.3 Preclinical Safety Data

Genotoxicity.

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

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

4.3 Contraindications

Allosig should not be administered to individuals known to be hypersensitive to allopurinol or to any other components of the formulation (see Section 6.1 List of Excipients).
Allosig 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.

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

4.4 Special Warnings and Precautions for Use

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

Dermatological effects.

Allosig should be discontinued at the first appearance of skin rash or other signs which may indicate an allergic reaction. In some instances a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum), drug rash with eosinophilia and systemic symptoms (DRESS), Lyell's disease, generalised vasculitis, irreversible hepatotoxicity, and on rare occasions death. DRESS is also referred to as drug-induced hypersensitivity syndrome (DIHS) and Lyell's disease is also referred to as toxic epidermal necrolysis.

Hepatic effects.

A few cases of reversible clinical hepatotoxicity have been noted in patients taking Allosig, 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 Allosig, 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.

Hypersensitivity effects.

The occurrence of hypersensitivity reactions to Allosig may be increased in patients with decreased renal function receiving thiazides and Allosig 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 Allosig, 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 Allosig 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.

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.

Use in hepatic impairment.

Reduced doses should be used in patients with hepatic impairment.

Use in renal impairment.

A dose reduction will be required in patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

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 Allosig 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 Allosig, but the significance needs to be assessed in each case.

Chlorpropamide.

If Allosig 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.

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)
There is inadequate evidence of safety of Allosig in human pregnancy, although it has been in wide use for many years without apparent ill consequence.
One study in mice receiving a high intraperitoneal dose on days 10 to 13 of pregnancy resulted in foetal abnormalities but extensive studies of high oral doses in mice, rats and rabbits during days 8 to 16 produced none.
Use in pregnancy only when there is no safe alternative and when the disease itself carries risks for the mother or child.
Reports indicate that allopurinol and 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.

4.8 Adverse Effects (Undesirable Effects)

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

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 Allosig.

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 Allosig 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.

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.

4.2 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.

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

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 Allosig therapy. Allosig is better tolerated if taken after meals.

4.7 Effects on Ability to Drive and Use Machines

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol, patients should exercise caution before driving, using machinery or participating in dangerous activities where alertness is mandatory until they are reasonably certain that allopurinol does not adversely affect performance.

4.9 Overdose

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

Symptoms.

These include nausea, vomiting, diarrhoea and dizziness.

Treatment.

Recovery followed general supportive measures.
Massive absorption of Allosig 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Allosig tablet contains the excipients povidone, maize starch, lactose monohydrate, stearic acid and sodium starch glycollate (300 mg strength only).

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 30°C. Protect from moisture.

6.5 Nature and Contents of Container

Allosig 100 mg tablets are available in 200's, glass or HDPE bottle.
Allosig 300 mg tablets are available in 60's, PVC/Al blister pack.

6.6 Special Precautions for Disposal

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

Summary Table of Changes