Zyloric 100 mg Tablets

Text in red = new text

Text strikethrough = deleted text

 

 

4.4     Special warnings and precautions for use

 

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, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin.   The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established 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 case that no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or Korean descent   the use of allopurinol may be considered  the benefits should be thoroughly assessed and considered 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.

 

 

4.5      Interaction with other medicinal products and other forms of interaction

 

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.

 

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine

 

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol. However in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (mustine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.

 

 

Aluminium hydroxide

 

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

 

 

Allopurinol and its metabolite oxipurinol is excreted in the human breast milk.  Reports indicate that allopurinol and oxipurinol are excreted in human breast milk Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from a woman taking Zyloric 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby. . A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from allopurinol therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman Allopurinol during breastfeeding is not recommended.

 

4.8    Undesirable effects

 

Investigations

Common

Blood thyroid stimulating hormone increased9

 

 

8.9   The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did not report any impact on free T4 levels or had TSH levels indicative of subclinical hypothyroidism.

 

 

10.     DATE OF REVISION OF THE TEXT

 

April 2017  January 2018

 

Text in red = new text
Text strikethrough = deleted text

 

 

4.2     Posology and method of administration

 

Posology

 

Adults

 

Zyloric should be introduced at low dosage e.g. 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 Patients with renal impairment). The following dosage schedules are suggested:

 

 

Dosage higher than 300 mg should be given in divided doses not exceeding 300 mg at any time. If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be used. Where available, Zyloric granules should be used in preference to the halving of tablets.

 

Older people

 

In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice in “section 4.2  Patients with renal impairment” and section 4.4.

 

 

Patients with renal impairment

 

Patients with hepatic impairment

 

section 4.2 Patients with renal impairment

 

 

4.4    Special warnings and precautions for use

 

See section 4.8

 

Asymptomatic hyperuricaemia

 

Thyroid disorders

 

Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with allopurinol (5.8%) in a long term open label extension study. Caution is required when Zyloric is used in patients with alteration of thyroid function.

 

Lactose intolerance

 

 

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

There is inadequate evidence of safety of Zyloric in human pregnancy, although it has been in wide use for many years without apparent ill consequence (see section 5.3).

 

4.8       Undesirable effects

 

Very Common	≥1/10
Common	≥1/100 to <1/10
Uncommon	≥1/1,000 to <1/100
Rare	≥1/10,000 to <1/1000
Very Rare	<1/10,000

 

Tabulated summary of adverse reactions Undesirable effects

 

 

1.           Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.

2.      A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or DRESS) with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia hepato‑splenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas

 

6. Skin reactions 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, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Allopurinol should be withdrawn IMMEDIATELY should such reactions occur. The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the first weeks of treatment. The best results in managing such reactions come from early diagnosis and immediate discontinuation of any suspect drug.  After recovery from mild reactions, allopurinol may, if desired, be re‑introduced at a small dose (e.g. 50 mg/day) and gradually increased. The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established.  If the rash reoccurs, allopurinol should be PERMANENTLY withdrawn as more severe hypersensitivity reactions may occur (see section 4.8 Immune system disorders). If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce allopurinol due to the potential for a severe or even fatal reaction. The clinical diagnosis of SJS/TEN, or other serious hypersensitivity reactions remain the basis for decision making

 

 

5.2    Pharmacokinetic properties

Pharmacokinetics in elderly patients

 

The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see section 5.2 Pharmacokinetics in patients with renal impairment).

 

10.     DATE OF REVISION OF THE TEXT

 

April 2017  Oct 2015

 

 

Text in red = new text
Text strikethrough = deleted text

2.           QUALITATIVE AND QUANTITATIVE COMPOSITION

  

Excipient(s) with known effect:

4.2     Posology and method of administration

 

Posology

 

Adults

 

Zyloric should be introduced at low dosage e.g. 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 Patients with renal impairment). The following dosage schedules are suggested:

Paediatric population

 

Older people

 

In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice in Patients with renal impairment and section 4.4.

 

Patients with renal impairment

If urate nephropathy or other pathology has compromised renal function, the advice given in Patients with renal impairment should be followed.

 

These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. See also section 4.5 and section 4.8

 

 

4.3    Contraindications

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

 

4.4 Special warnings and precautions for use
Allopurinol should be withdrawn IMMEDIATELY when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions, (including Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)) and hypersensitivity syndrome (also known as Drug Rash with Eosinophilia and Systemic Symptoms, DRESS) (see section 4.8).

HLA-B*5801 allele
The HLA-B*58:01 allele has been identified as a genetic risk factor for allopurinol associated SJS/TEN (and possibly other serious hypersensitivity reactions) in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Thai, Korean, Japanese and European descent.
Up to 20-30% of people of Han Chinese, African and Indian ancestry carry the HLA-B*58:01 allele whereas only 1-2% of Northern European, US European and Japanese are estimated to be HLA-B*58:01 carriers.
Screening for HLA-B*58:01 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high. If these individuals test positive, allopurinol should not be started unless there are no other reasonable therapeutic options and the benefits of use outweigh the potential associated risks. Patients who are found to be negative for HLA-B*58:01 still have a low risk of SJS/TEN. The clinical diagnosis of SJS/TEN, and other hypersensitivity reactions, remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. (see section 4.8).

Chronic renal insufficiency and concomitant diuretic use, in particular thiazides, has been associated with an increased risk of allopurinol induced SJS/TEN, and other serious hypersensitivity reactions.

Diuretics

An interaction between allopurinol and furosemide that results in increased serum urate and plasma oxipurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with diuretics, in particular thiazides, especially in renal impairment.

Angiotensin-converting-enzyme (ACE) inhibitors.

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

Breast feeding 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from allopurinol therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

2. Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia and/or eosinophilia (DRESS) and Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), occur rarely (see Skin and subcutaneous tissue disorders). Associated vasculitis and tissue response may be manifested in various ways including hepato splenomegaly, hepatitis, vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), renal impairment and, very rarely, seizures. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, and colon). Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment. Allopurinol should be withdrawn IMMEDIATELY and PERMANENTLY.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. 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.
3. Angioimmunoblastic T cell lymphoma has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
4. 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.
5. Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.
6. Skin reactions 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, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Allopurinol should be withdrawn IMMEDIATELY should such reactions occur. The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the first weeks of treatment. The best results in managing such reactions come from early diagnosis and immediate discontinuation of any suspect drug. After recovery from mild reactions, allopurinol may, if desired, be re introduced at a small dose (e.g. 50 mg/day) and gradually increased. Consideration should be given to screening for the presence of the HLA-B*58:01 allele before allopurinol is reintroduced. If the rash reoccurs, allopurinol should be PERMANENTLY withdrawn as more severe hypersensitivity reactions may occur (see Immune system disorders). If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce allopurinol due to the potential for a severe or even fatal reaction. The clinical diagnosis of SJS/TEN, or other serious hypersensitivity reactions remain the basis for decision making.


5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Preparations inhibiting uric acid production



The main metabolite of Zyloric is oxipurinol. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7-riboside.

 

 Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine. Allopurinol has a plasma half-life of about 0.5 to 1.5 hours.

6.1 List of excipients

Lactose Monohydrate

10. DATE OF REVISION OF THE TEXT

October 2015

 

Text in red = new text
Text strikethrough = deleted text

3 PHARMACEUTICAL FORM

 

Tablet.

 

Round, white to off-white biconvex, bisected tablets, debossed with Z1 on one side

10 DATE OF REVISION OF THE TEXT

     April May2014

Text in red = new text
Text strikethrough = deleted text

4.6 Fertility, pregnancy and lactation

Lactation

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zyloric therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.8 Undesirable effects

 

 Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are as ked to report any suspected adverse reactions via the national reporting system  at www.imb.ie/EN/Safety--Quality/Online-Forms/Human-Medicine-Adverse-Drug-Reaction.aspx

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

 

7 MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited
12/13 Exchange Place

I.F.S.C Dublin 1
Ireland
Asepn Pharma Trading Limited

3016 Lake Drive,

Citywest Business Campus

Dublin 24

10 DATE OF REVISION OF THE TEXT

December 2013
February 2013
April 2014

Text in red = new text
Text strikethrough = deleted text

 

7 MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited

 

 

 

3016 Lake Drive,

Citywest Business Campus

12/13 Exchange Place

I.F.S.C Dublin 124

 

 

 

 

 

10 DATE OF REVISION OF THE TEXT

 

February April 2014

 

 

 

Text in red = new text
Text strikethrough = deleted text

 

4.4 Special warnings and precautions for use

 Zyloric should be withdrawn immediately if a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see Adverse Reactions- Immune system disorders and Skin and subcutaneous tissue disorders).

Hypersensitivity syndrome, SJS and TEN

Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and Steven Johnson Syndrome (SJS) /toxic epidermal necrolysis (TEN). These reactions are clinical diagnoses, and their clinical presentations remain the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately. Rechallenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. (see Adverse Reactions- Immune system disorders and Skin and subcutaneous tissue disorders).

 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, about 12% in the Korean population and 1-2% in individuals of Japanese or European origin. The use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. If the patient is a known carrier of HLA-B*5801, the use of allopurinol may be considered if 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.

 

 

 

 

 

 

 

 

 

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

If the rash reoccurs, Allopurinol should be PERMANENTLY withdrawn as more severe hypersensitivity reactions may occur (see Immune system disorders).

The HLA-B* 5801 allele has been identified as a genetic risk factor for allopurinol associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent.  Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern Europeans, US European and Japanese patients are estimated to be HLA-

B* 5801 carriers.  However, the use of genotyping as a screening tool to make decisions about treatment and Allopurinol has not been established.

 

The clinical diagnosis of SJS/TEN remains the basis for decision making.  If such eactions occur at any time during treatment, allopurinol should be withdrawn IMMEDIATELY  AND PERMANENTLY.

 

Change from

3 PHARMACEUTICAL FORM

Tablet.

White to off-white, biconvex, scored tablets coded ‘GXCM2’.

Change To

 

3 PHARMACEUTICAL FORM

 

 

 

Tablet.

Round, white biconvex, bisected tablets, debossed with Z1 on one side

Product ownership changed from GSK to Aspen

change to Marketing Authorisation Holder

SUMMARY OF PRODUCT CHARACTERISTICS CHANGES

(highlighted in red)

 

4.4     Special Warnings and Precautions for Use

 

Zyloric should be withdrawn immediately if a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see Adverse Reactions – Immune system disorders and Skin and subcutaneous tissue disorders).

 

Reduced doses should be used in patients with hepatic or renal impairment.  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 this group.

 

Asymptomatic hyperuricaemia per se is generally not considered an indication for use of Zyloric.  Fluid and dietary modification with management of the underlying cause may correct the condition.

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

 

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 Zyloric, 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 for at least one month.  The literature should be consulted for details of appropriate dosage and precautions and warnings.

 

If acute attacks develop in patients receiving allopurinol, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.

 

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 Zyloric will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

 

4.8     Undesirable Effects

 

Adverse reactions in association with Zyloric 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.

 

Skin and hypersensitivity reactions

 

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

 

Skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson syndrome and toxic epidermal necrolysis occur rarely.  Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and, very rarely, seizures.  If such reactions do occur, it may be at any time during treatment.   Zyloric 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 Zyloric.

 

Hepatic function

 

Rare cases 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.

 

Gastrointestinal disorder

 

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

 

Blood and lymphatic system

 

Occasional reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.

 

Miscellaneous

 

The following complaints, have been reported occasionally; fever, general malaise, asthenia, headache, vertigo, ataxia, somnolence, coma, depression, paralysis, paraesthesiae, neuropathy, visual disorder, cataract, macular changes, taste perversion, stomatitis, changed bowel habit, infertility, impotence, diabetes mellitus, hyperlipaemia, furunculosis, alopecia, discoloured hair, angina, hypertension, bradycardia, oedema, uraemia, haematuria, angioedema and gynaecomastia.

 

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

 

The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare.  The following convention has been used for the classification of frequency:

 

Very common	=1/10 (= 10%)
Common	=1/100 and < 1/10 (= 1% and <10%)
Uncommon	=1/1000 and <1/100 (=0.1% and <1%)
Rare	=1/10,000 and <1/1000 (=0.01% and < 0.1%)
Very rare	<1/10,000 (< 0.01%)

 

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.

 

Infections and infestations
Very rare	Furunculosis
Blood and lymphatic system disorders
Very rare	Agranulocytosis, aplastic anaemia, thrombocytopenia
Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.
Immune system disorders
Uncommon	Hypersensitivity reactions
Very rare	Angioimmunoblastic lymphadenopathy
Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis, occur rarely (see Skin and subcutaneous tissue disorders). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and, very rarely, seizures. Very rarely acute anaphylactic shock has been reported.  If such reactions do occur, it may be at any time during treatment. Allopurinol should be withdrawn IMMEDIATELY AND PERMANENTLY.
Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.
Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of allopurinol.
Metabolism and nutrition disorders
Very rare	Diabetes mellitus, hyperlipidaemia
Psychiatric disorders
Very rare	Depression
Nervous system disorders
Very rare	Coma, paralysis, ataxia, neuropathy, paraesthesiae, somnolence, headache, taste perversion
Eye disorders
Very rare	Cataract, visual disorder, macular changes
Ear and labyrinth disorders
Very rare	Vertigo
Cardiac disorders
Very rare	Angina, bradycardia
Vascular disorders
Very rare	Hypertension
Gastrointestinal disorders
Uncommon	Vomiting, nausea
Very rare	Recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit
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.
Hepatobiliary disorders
Uncommon	Asymptomatic increases in liver function tests
Rare	Hepatitis (including hepatic necrosis and granulomatous hepatitis)
Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.
Skin and subcutaneous tissue disorders
Common	Rash
Rare	Stevens-Johnson syndrome/toxic epidermal necrolysis
Very rare	Angioedema, fixed drug eruption, alopecia, discoloured hair
Skin reactions 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, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Allopurinol should be withdrawn IMMEDIATELY should such reactions occur. After recovery from mild reactions, allopurinol may, if desired, be re-introduced 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 (see Immune system disorders). The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent.  Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers.  However, the use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established. The clinical diagnosis of SJS/TEN remains the basis for decision making.  If such reactions occur at any time during treatment, allopurinol should be withdrawn IMMEDIATELY AND PERMANENTLY.
Angioedema has been reported to occur with and without signs and symptoms of a more generalised allopurinol hypersensitivity reaction.
Renal and urinary disorders
Very rare	Haematuria, uraemia
Reproductive system and breast disorders
Very rare	Male infertility, erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Very rare	Oedema, general malaise, asthenia, fever
Fever has been reported to occur with and without signs and symptoms of a more generalised allopurinol hypersensitivity reaction (see Immune system disorders).

 

 

New Individual SPC wsa previously a combined SPC

6.4 Special Precautions for Storage

Do not store above 25°C.

Store in the original package