Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Nova Laboratories Ireland Limited, 3rd Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
Therapy with Jayempi in pre-existing, severe infections, in severe disorders of the liver and bone marrow function and in the presence of pancreatitis should only be initiated subject to a careful benefit/risk analysis and the precautions specified below.
Special attention should be given to monitoring the blood count. If necessary, the maintenance dose should be reduced as much as possible, provided there is clinical response.
Azathioprine should only be prescribed if the patient can be adequately monitored for haematological and hepatic effects throughout the duration of therapy.
During the first 8 weeks of treatment, a complete blood count, including platelet count must be performed at least once weekly. It should be controlled more frequently:
In particular, patients with impaired liver function require special monitoring when using azathioprine, as life-threatening liver damages have been reported (see section 4.8). This is particularly important in patients with severe impaired liver function and azathioprine should only be used after a careful benefit/risk analysis.
Azathioprine is hepatotoxic, thus regular liver function tests should be repeated during the treatment. More frequent tests are recommended in patients with liver disease and in those who may be undergoing therapy with a possible hepatotoxic adverse reaction. The patients should be advised to discontinue azathioprine immediately if jaundice occurs.
The frequency of blood counts may be reduced after 8 weeks and be repeated monthly or at least at intervals of no longer than 3 months (maximum quarterly).
At the first sign of an abnormal change in the blood count, treatment should be discontinued immediately because the number of leucocytes and platelets may continue to decrease after the end of treatment.
Patients receiving azathioprine must be advised to inform their doctor immediately about any evidence of infection, unexpected bruising or bleeding or other signs of myelosuppression. Myelosuppression is reversible if azathioprine is discontinued promptly.
About 10% of patients have decreased activity of the enzyme thiopurine methyltransferase (TPMT) as a result of genetic polymorphism. Especially in homozygous individuals, the degradation of azathioprine is impaired, so there is a higher risk of myelotoxic effects.
This effect can be enhanced by co-administration with medicinal products which inhibit the enzyme TPMT, e.g. olsalazine, mesalazine and sulfasalazine (see section 4.5). Also a possible link between decreased TPMT activity and secondary leukaemia and myelodysplasia has been reported in individual patients receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see section 4.8). Testing for TMPT deficiency is recommended before treatment, in particular for azathioprine therapy in high doses as well as with rapid deterioration of the blood count.
Patients with inherited mutated NUDT15 gene are at increased risk of severe azathioprine toxicity, such as early leucopenia and alopecia, with conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being homozygous carriers of NUDT15 variants (see section 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10% in East Asians, 4% in Hispanics, 0.2% in Europeans and 0% in Africans. In any case, close monitoring of blood counts is necessary.
Limited data indicate that azathioprine is not effective in patients with hereditary hypoxanthineguanine-phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome). Therefore, azathioprine should not be used in these patients.
Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants (see section 4.8).
Before starting the administration of immunosuppressants, the prescriber should check to see if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure.
Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. If the patient is exposed to VZV, special care must be taken to prevent patients from developing chickenpox or herpes zoster, and passive immunisation with varicella-zoster immunoglobulin (VZIG) may be considered.
If the patient is infected with VZV, appropriate measures should be taken, which may include antiviral therapy, discontinuation of treatment with azathioprine and supportive care.
PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents (see section 4.8). Immunosuppressive therapy should be withheld at the first signs or symptoms indicating PML and appropriate evaluation should be undertaken to establish a diagnosis.
Chromosomal abnormalities have been demonstrated in both male and female patients treated with azathioprine. It is difficult to assess the role of azathioprine in the development of these abnormalities.
Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the offspring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine.
Azathioprine and long-wave ultraviolet (UV) light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders.
Patients receiving immunosuppressive therapy, including azathioprine, are at increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancers in situ (see section 4.8). The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.
A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants given concomitantly increases the risk of EpsteinBarr virus (EBV)-associated lymphoproliferative disorders.
There are reports of hepatosplenic T-cell lymphoma in IBD patients who use azathioprine concomitantly with anti-TNF medicinal products.
Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression. Therefore, such therapy should be maintained at the lowest effective dose level.
The same as for patients with a high risk of developing skin cancers, exposure to sunlight and UV light should be limited and patients should wear protective clothing and use a sunscreen with a high protection factor to minimise the risk of skin cancer and photosensitivity (see also section 4.8).
Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there is potentially increased susceptibility for developing the condition with the use of azathioprine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
In preclinical studies azathioprine was mutagenic and teratogenic (see section 5.3). Since there are conflicting findings on the teratogenic potential of azathioprine in humans, contraceptive measures must be taken by both male and female patients of reproductive age during azathioprine therapy for at least six months after the end of azathioprine therapy. This applies also to patients with impaired fertility due to chronic uraemia, since fertility usually returns to normal after transplantation. Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices (coil or T-shaped ‘copper coil’). Therefore, it is recommended to use other or additional contraceptive measures (see also section 4.6).
Special caution is required when azathioprine is given concomitantly with neuromuscular blocking agents such as atracurium, rocuronium, cisatracurium or suxamethonium (also known as succinylcholine) (see section 4.5). Anaesthesiologists should check whether their patients are administered azathioprine prior to surgery.
Vaccination with live vaccines can cause infections in immunocompromised patients. Therefore, it is recommended that patients are not administered with any live vaccine until at least 3 months after the end of treatment with azathioprine (see section 4.5).
Concomitant use of ribavirin and azathioprine is not recommended. Ribavirin can reduce the efficacy of azathioprine and increase the toxicity levels of azathioprine (see section 4.5).
The dose should be reduced with concomitant use of azathioprine and myelosuppressive agents.
This medicinal product contains 1.5 mg sodium benzoate in each 1 ml which is equivalent to 300 mg/200 ml.
This medicinal product contains less than 1 mmol (23mg) sodium per dose, that is to say essentially ‘sodium-free’.
The immunosuppressive activity of azathioprine can lead to an atypical and possibly harmful response to live vaccines. Therefore, it is recommended that patients do not receive live vaccines until at least 3 months after the end of treatment with azathioprine (see section 4.4).
Immunosuppressed patients must not be vaccinated with live vaccines, since they are at risk of infection from the live vaccine (see section 4.4).
A decreased immune response to inactivated or toxoid vaccines is likely. This has been observed with hepatitis B vaccine among patients treated with a combination of azathioprine and corticosteroids. Therefore, the vaccination success should always be checked with a titre determination.
A small clinical study has indicated that standard therapeutic doses of azathioprine do not deleteriously affect the immune response to a polyvalent pneumococcal vaccine (as assessed on the basis of mean anti-capsular specific antibody concentration).
Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to lower production of active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore, co-administration is not advised (see sections 4.4 and 5.2).
Where possible, concomitant administration of cytostatic medicinal products, or medicinal products which may have a myelosuppressive effect, such as penicillamine, should be avoided (see section 4.4). There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and trimethoprim/sulfamethoxazole.
There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and ACE Inhibitors.
It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of azathioprine.
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol are given concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine should be reduced to one quarter of the original dose (see section 4.2).
Based on non-clinical data, other xanthine oxidase inhibitors, such as febuxostat, may prolong the activity of azathioprine possibly resulting in enhanced bone marrow suppression. Concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction of azathioprine.
There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine and sulfasalazine) inhibit the TPMT enzyme. Therefore, lower doses of azathioprine should be considered when administered concomitantly with aminosalicylate derivatives (see also section 4.4).
20 mg/m² oral methotrexate increased the AUC of 6-mercaptopurine by approximately 31% and 2 or 5 g/m² intravenous methotrexate increased the AUC of 6-mercaptopurine by 69% and 93% respectively. Therefore, when azathioprine is administered concomitantly with high-dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.
A reduction of the anticoagulant effect of warfarin was described following the simultaneous use of azathioprine.
There is clinical evidence that azathioprine antagonises the effect of non-depolarising muscle relaxants. Experimental data confirm that azathioprine reverses the neuromuscular blockade produced by non-depolarising agents, and show that azathioprine potentiates the neuromuscular blockade produced by depolarising agents (see section 4.4).
Malformations occurred in animal experiments due to azathioprine. In animal studies azathioprine was teratogenic and embryotoxic (see section 5.3). There are conflicting findings on the teratogenic potential of azathioprine in humans. Azathioprine must only be used during pregnancy after a careful benefit/risk analysis.
Both male and female patients of reproductive age should use contraceptive methods while using azathioprine. Men should not father children during and up to 6 months after the end of treatment. This also applies to patients with reduced fertility due to chronic uraemia, as fertility generally returns to normal after a transplant.
Case reports indicate that intrauterine devices (IUD) (coil or T-shaped ‘copper coil’) can fail under azathioprine therapy. Therefore, other or additional contraceptive methods should be recommended.
It is known that considerable amounts of azathioprine and its metabolites pass through the placenta and amniotic sac, and are thereby transferred from the mother to the foetus.
Blood count changes (leucopenia and/or thrombocytopenia) have been reported in a number of neonates whose mothers received azathioprine during pregnancy. Extra care in haematological monitoring of the mother is advised during pregnancy.
Temporary impairment of the immune response was detected in neonates from intrauterine exposure to a combination of azathioprine with prednisone. There have been reports of intrauterine growth retardation, premature births and low birth weights vis-à-vis azathioprine, in particular in combination with corticosteroids. Moreover, data is available on spontaneous abortions after both maternal and paternal exposure.
Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes of the offspring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine.
6-Mercaptopurine, the active metabolite of azathioprine, has been identified in the colostrum and breast milk of women receiving azathioprine treatment. Breast-feeding and concomitant use of azathioprine are contra-indicated (see section 4.3). If treatment with azathioprine is unavoidable, breast-feeding should be discontinued.
No preclinical or clinical data is available on the possible influence of azathioprine on male and female fertility (see section 4.4).
Jayempi has no or negligible influence on the ability to drive and use machines.
The most important adverse reactions include bone marrow depression, most frequently expressed as leukopenia and thrombocytopenia; viral, fungal and bacterial infections; life-threatening liver injury; hypersensitivity, Stevens-Johnson syndrome and toxic epidermal necrolysis.
The adverse reactions are listed below according to system organ class and frequency. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) (including isolated cases), not known (cannot be estimated from the available data).
| System organ class | Frequency | Adverse reactions |
|---|---|---|
| Infections and infestations | Very common | Viral, fungal and bacterial infections (in transplant recipients who are treated with azathioprine in combination with other immune-suppressants) |
| Uncommon | Viral, fungal and bacterial infections (in other patients) | |
| Very rare | Cases of progressive multifocal leukoencephalopathy (PML) caused by the JC virus have been reported after using azathioprine in combination with other immunosuppressants (see section 4.4) | |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | Rare | Neoplasms including lymphoproliferative disorders, skin cancers (malignant melanomas and nonmelanomas), sarcomas (Kaposi’s and non-Kaposi’s), uterine cancer, cervix carcinoma, acute myeloid leukaemia and myelodysplastic syndrome (see also section 4.4) |
| Very rare | Hepatosplenic T-cell lymphoma (in IBD patients using other anti- TNF drugs concomitantly) | |
| Blood and lymphatic system disorders | Very common | Leukopenia |
| Common | Thrombocytopenia | |
| Uncommon | Anaemia | |
| Rare | Agranulocytosis, pancytopenia, aplastic anaemia, anaemia megaloblastic and bone marrow failure | |
| Very rare | Haemolytic anaemia | |
| Immune system disorders | Uncommon | Hypersensitivity |
| Very rare | Stevens-Johnson syndrome and toxic epidermal necrolysis | |
| Respiratory, thoracic and mediastinal disorders | Very rare | Pneumonitis (reversible) |
| Gastrointestinal disorders | Common | Nausea, vomiting |
| Uncommon | Pancreatitis | |
| Very rare | Colitis, diverticulitis and intestinal perforation in transplant recipients, diarrhoea (severe) in patients with inflammatory bowel disease | |
| Hepatobiliary disorders | Uncommon | Cholestasis |
| Rare | Liver injury | |
| Skin and subcutaneous tissue disorders | Rare | Alopecia |
| Not known | Acute febrile neutrophilic dermatosis (Sweet’s syndrome), photosensitivity reaction | |
| Investigations | Uncommon | Liver function test abnormal |
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 infections with varicella, herpes zoster and other infectious pathogens (see section 4.4).
The risk of developing non-Hodgkin’s lymphoma and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ, is increased in patients who receive immunosuppressants, particularly in transplant patients receiving aggressive treatment, and such therapy should be maintained at the lowest effective levels (see section 4.4). 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 leucaemia and myelodysplasia (some in association with chromosomal abnormalities).
The most common adverse reaction of azathioprine is a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as thrombocytopenia and anaemia, and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelosuppression, such as those with TPMT deficiency and renal or hepatic impairment and in patients failing to reduce the dose of azathioprine when receiving concurrent allopurinol therapy.
Reversible, dose-related macrocytosis and increase in 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.
Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of azathioprine. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, erythema nodosum, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis. In many cases, re-challenge has confirmed an association with azathioprine.
Hypersensitivity reactions and other marked underlying pathology may have contributed to the very rare deaths reported.
Immediate withdrawal of azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases. Following a hypersensitivity reaction to azathioprine, the necessity for continued administration of azathioprine should be carefully considered on an individual basis.
Gastrointestinal disorders occur primarily in the form of nausea after taking oral azathioprine. A small number of patients experience nausea when first given azathioprine. To reduce nausea, the dose should be taken after a meal.
Pancreatitis has been reported in patients on azathioprine therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease. It is difficult to attribute pancreatitis to the administration of one particular medicinal product, although re-challenge has confirmed an association with azathioprine in some instances.
Serious complications, including colitis, diverticulitis and bowel perforation, have been reported in transplant patients receiving immunosuppressive therapy. However, the causal relationship is not clearly established and high-dose corticosteroids may be implicated.
Severe diarrhoea, recurring on re-exposure, has been reported in patients with inflammatory bowel disease treated with azathioprine. If there is any exacerbation of symptoms in these patients, a possible causal relationship with the azathioprine treatment should be taken into consideration.
Dose-dependent cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on discontinuation of therapy. This may be associated with features of a hypersensitivity reaction.
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 temporary or permanent improvement in liver histology and the symptoms.
Alopecia has been described for both monotherapy and combined therapy with azathioprine. In many instances, the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and azathioprine treatment is still unclear
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 the national reporting system listed in Appendix V.
Not applicable.
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