Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
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 indication.

The most important adverse reactions include bone marrow depression, most frequently expressed as leukopenia, thrombocytopenia or anaemia; viral, fungal and bacterial infections; life-threatening liver injury; hypersensitivity, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Tabulated list of adverse reactions

The following convention has been utilised for the classification of frequency: 
Very common ≥ 1/10
Common ≥1/100 and <1/10
Uncommon ≥ 1/1000 and <1/100
Rare ≥1/10,000 and <1/1000
Very rare <1/10,000
Not known (cannot be estimated from the available data)

Body System                  Frequency                           Side effects Infections and infestations          Very common      Viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants
Uncommon         Viral, fungal and bacterial infections in other patient populations
Very Rare        Cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants (see
Section 4.4).
Neoplasms benign, malignant          Rare             Neoplasms including lymphoproliferative and unspecified (including cysts                      disorders, skin cancers (melanomas and and polyps)                                           non-melanomas), sarcomas (Kaposi’s and non- Kaposi’s) and uterine cervical cancer in situ,
acute myeloid leukaemia and myelodysplastic syndrome (see Section 4.4).
Not known        Hepatosplenic T-cell lymphoma (see Section
4.4).
Blood and lymphatic system           Very common      Bone marrow depression, leukopenia disorders                            Common           Thrombocytopenia Uncommon         Anaemia
Rare             Agranulocytosis, pancytopenia, aplastic anemia,
megaloblastic anaemia, erythroid hypoplasia
Immune system disorders              Uncommon         Hypersensitivity Very rare        Stevens-Johnson syndrome and toxic epidermal necrolysis
Metabolism and nutrition             Not known        Pellagra (Refer to section 4.4) Disorders
Respiratory, thoracic and            Very rare        Reversible pneumonitis mediastinal disorders
Gastrointestinal disorders           Common           Nausea
Uncommon         Pancreatitis
Very rare        Colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population
Hepatobiliary disorders              Uncommon         Cholestasis and cholestasis of pregnancy Rare             Life-threatening liver injury
Investigations                       Uncommon         Liver function test abnormal Skin and subcutaneous tissue         Rare             Alopecia disorders                            Not known        Acute febrile neutrophilic dermatosis (Sweet’s syndrome), photosensitivity

Description of selected adverse reactions
Infections and infestations

Patients receiving azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection and reactivation with VZV, hepatitis B and other infectious agents. (see Section 4.4).

Neoplasms benign, malignant and unspecified (including cysts and polyps) 
The risk of developing non-Hodgkin’s lymphomas and other malignancies, notably skin cancers (melanoma and non-melanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ, is increased in patients who receive immunosuppressants, particularly in transplant recipients receiving aggressive treatment and such therapy should be maintained at the lowest effective levels. The increased risk of developing non-Hodgkin’s lymphomas in immunosuppressed rheumatoid arthritis patients compared with the general population appears to be related at least in part to the disease itself.

There have been rare reports of acute myeloid leukaemia and myelodysplasia (some in association with chromosomal abnormalities).

Blood and lymphatic system disorders

Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leukopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the dose of azathioprine when receiving concurrent allopurinol therapy.

Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with azathioprine therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia are rare.

Immune system disorders

Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of azathioprine tablets. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, erythema nodosum, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis. (see Hepatobiliary disorders).

In many cases, rechallenge has confirmed an association with azathioprine.
Immediate withdrawal of azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases.
Other marked underlying pathology has contributed to the very rare deaths reported.
Following a hypersensitivity reaction to azathioprine tablets, the necessity for continued administration should be carefully considered on an individual basis.

Gastrointestinal disorders

Some patients experience nausea when first given azathioprine. With oral administration, nausea appears to be relieved by administering the tablets after meals. However, administration of azathioprine tablets after meals may reduce oral absorption, therefore monitoring for therapeutic efficacy should be considered after administration in this way (see Section 4.2, 4.5 and 5.2).

Serious complications, including colitis, diverticulitis and bowel perforation, have been described in transplant recipients receiving immunosuppressive therapy. However, the aetiology is not clearly established and high-dose corticosteroids may be implicated. Severe diarrhoea, recurring on rechallenge, has been reported in patients treated with azathioprine for inflammatory bowel disease. The possibility that exacerbation of symptoms might be related to the medicinal product should be borne in mind when treating such patients.

Pancreatitis has been reported in a small percentage of patients on azathioprine therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease.

Hepatobiliary disorders
Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Immune system disorders).

Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine has been described primarily in transplant patients. Histological findings include sinusoidal dilatation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms.

Skin and subcutaneous tissue disorders

Hair loss has been described on a number of occasions in patients receiving azathioprine and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 https://sideeffects.health.gov.il

In addition, you can report via the following address: Padagis.co.il