Adverse reactions : תופעות לוואי

4.8 Undesirable effects

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

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.

Table 1 Tabulated summary of adverse reactions
System Organ Class              Frequency              Adverse reaction Infections and infestations     Very rare              Furuncle
Blood and lymphatic system      Very rare              Agranulocytosis1 disorders                                              Aplastic anaemia1 Thrombocytopenia1
Immune system disorders               Uncommon         Hypersensitivity 2 Very rare        Angioimmunoblastic T-cell lymphoma 3
Anaphylactic reaction

Metabolism and nutrition disorders    Very rare        Diabetes mellitus Hyperlipidaemia
Psychiatric disorders                 Very rare        Depression
Nervous system disorders              Very rare        Coma
Paralysis
Ataxia
Neuropathy peripheral
Paraesthesia
Somnolence
Headache
Dysgeusia
Not known        Aseptic meningitis
Eye disorders                         Very rare        Cataract
Visual impairment
Maculopathy
Ear and labyrinth disorders           Very rare        Vertigo
Cardiac disorders                     Very rare        Angina pectoris Bradycardia
Vascular disorders                    Very rare        Hypertension
Gastrointestinal disorders            Uncommon         Vomiting4
Nausea4
Diarrhoea
Very rare        Haematemesis
Steatorrhoea
Stomatitis
Change of bowel habit
Hepatobiliary disorders               Uncommon         Liver function test abnormal5 Rare             Hepatitis (including hepatic necrosis and granulomatous hepatitis) 5
Common           Rash
Rare              Stevens-Johnson syndrome/toxic epidermal necrolysis 6
Skin and subcutaneous tissue            Very rare        Angioedema7 disorders                                                Drug eruption Alopecia
Hair colour changes
Renal and urinary disorders             Very rare        Haematuria
Azotaemia
Reproductive system and breast          Very rare        Infertility male disorders                                                Erectile dysfunction Gynaecomastia
General disorders and                   Very rare        Oedema administration site conditions                           Malaise
Asthenia
Pyrexia 8
Investigations                          Common           Blood thyroid stimulating hormone increased9
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, myocardium, and colon). 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). 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. Alloril should be withdrawn immediately should such reactions occur. 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 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 remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.
7
Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.
8
Fever has been reported to occur with and without signs and symptoms of a more generalised Alloril hypersensitivity reaction (see section 4.8 Immune system disorders).
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.


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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://sideeffects.health.gov.il