4.1. Therapeutic indications

Azathioprine is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.

Azathioprine, in combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated to enhance the survival of organ transplants, such as renal transplants, cardiac transplants, and hepatic transplants. It also reduces the corticosteroid requirements of renal transplant recipients.

Azathioprine is indicated for the treatment of moderate to severe inflammatory bowel disease (IBD) (Crohn's disease or ulcerative colitis) in patients in whom corticosteroid therapy is required, in patients who cannot tolerate corticosteroid therapy, or in patients whose disease is refractory to other standard first line therapy.

Azathioprine, either alone or more usually in combination with corticosteroids and/or other medicinal products and procedures, has been used with clinical benefit (which may include reduction of dosage or discontinuation of corticosteroids) in a proportion of patients suffering from the following:

- Severe active rheumatoid arthritis;

- Systemic lupus erythematosus;

- Dermatomyositis and polymyositis;

- Auto-immune chronic active hepatitis;

- Pemphigus vulgaris

- Polyarteritis nodosa;

- Auto-immune haemolytic anaemia;

- Chronic refractory idiopathic thrombocytopenic purpura

4.2. Posology and method of administration

Posology

When the oral route is impractical, azathioprine injection may be administered by the IV route only, however, this route should be discontinued as soon as oral therapy can be tolerated once more.

Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.

Adults

Transplants

Depending on the immunosuppressive regimen employed, a dosage of up to 5mg/kg bodyweight/day may be given orally or intravenously on the first day of therapy.

Maintenance dosage should range from 1 to 4mg/kg bodyweight/day and must be adjusted according to clinical requirements and haematological tolerance.

Evidence indicates that azathioprine therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.

Other indications

In general, the starting dosage is from 1 to 3mg/kg bodyweight/day, and should be adjusted, within these limits, depending on the clinical response (which may not be evident for weeks or months) and haematological tolerance.

When therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement occurs in the patient's condition within three months, consideration should be given to withdrawing azathioprine. However, for patients with IBD, a treatment duration of at least twelve months should be considered and a response to treatment may not be clinically apparent until after three to four months of treatment.

The maintenance dosage required may range from less than 1mg/kg bodyweight/day to 3mg/kg bodyweight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Paediatric population

Transplants

The posology in children is the same as in adults (see section 4.2 Adults – Transplants).

Other indications:

The posology in children is the same as in adults (see section 4.2 Adults - Other Indications).

Overweight children

Children considered to be overweight may require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended (see section 5.2).

Elderly population

There is limited experience of the administration of azathioprine to elderly patients. Although the available data do not provide evidence that the incidence of side effects among elderly patients is higher than that among other patients treated with azathioprine, it is advisable to monitor renal and hepatic function, and to consider dosage reduction if there is impairment (see section 4.2).

Renal impairment

Since azathioprine pharmacokinetics has not been formally studied in renal impairment, no specific dose recommendations can be given. Since impaired renal function may result in slower elimination of azathioprine and its metabolites, consideration should be given to reducing the starting doses in patients with impaired renal function. Patients should be monitored for dose related adverse effects (see sections 4.4 and 5.2).

Hepatic impairment

Since azathioprine pharmacokinetics has not been formally studied in hepatic impairment, no specific dose recommendations can be given. Since impaired hepatic function may result in reduced elimination of azathioprine and its metabolites, consideration should be given to reducing the starting doses in patients with impaired hepatic function. Patients should be monitored for dose related adverse effects (see sections 4.4 and 5.2).

TPMT-deficient patients

Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe azathioprine toxicity from conventional doses of azathioprine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see sections 4.4 and 5.2).

Most patients with heterozygous TPMT deficiency can tolerate recommended azathioprine doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see sections 4.4 and 5.2).

Interactions with other medicinal products

When xanthine oxidase inhibitors such as allopurinol and azathioprine are administered concomitantly it is essential that only 25% of the usual dose of azathioprine is given since allopurinol decreases the rate of catabolism of azathioprine (see section 4.5).

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity (see 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating azathioprine therapy. In any case, close monitoring of blood counts is necessary.

Method of administration

For oral use.

Azathioprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. 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 4.8).

The dose should not be taken with milk or dairy products (see section 4.5). Azathioprine should be taken at least 1 hour before or 2 hours after milk or dairy products (see section 5.2).

4.3. Contraindications

Hypersensitivity to azathioprine or to any of the excipients listed in section 6.1.

Hypersensitivity to 6-mercaptopurine should alert the prescriber to probable hypersensitivity to azathioprine.

4.4. Special warnings and precautions for use

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, it is recommended that patients do not receive live organism vaccines until at least 3 months after the end of their treatment with azathioprine (see section 4.5).

Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine (see section 4.5).

Monitoring

There are potential hazards in the use of azathioprine. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy.

Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.

It is suggested that during the first eight weeks of therapy, complete blood counts, including platelets, should be performed weekly or more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly, or at least at intervals of not longer than 3 months.

At the first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped.

Patients receiving azathioprine should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression. Bone marrow suppression is reversible if azathioprine is withdrawn early enough.

Azathioprine is hepatotoxic and liver function tests should be routinely monitored during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. Cases of non-cirrhotic portal hypertension/portosinusoidal vascular disease have been reported. Early clinical signs include liver enzyme abnormalities, mild jaundice, thrombocytopenia, and splenomegaly (see section 4.8). The patient should be informed about the symptoms of liver injury and advised to contact their doctor immediately if these occur.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co-administration with medicinal products that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also, a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see section 4.8). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary. The dosage of azathioprine may need to be reduced when this agent is combined with other medicinal products whose primary or secondary toxicity is myelosuppression (see section 4.5).

Hypersensitivity

Patients suspected to have previously presented a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, and vice-versa, unless the patient has been confirmed as hypersensitive to the culprit drug with allergological tests, and tested negative for the other.

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see 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.

Renal and/or hepatic impairment

Caution is advised during the administration of azathioprine in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the starting dosage in these patients and haematological response should be carefully monitored (see sections 4.2 and 5.2).

Lesch-Nyhan syndrome

Limited evidence suggests that azathioprine is not beneficial to patients with hypoxanthine- guanine- phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive azathioprine.

Neuromuscular blocking agents

Special care is necessary when azathioprine is given concomitantly with neuromuscular blocking agents such 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.

Mutagenicity

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 off-spring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the off-spring of patients treated with azathioprine (see section 4.6).

Azathioprine and long-wave ultraviolet light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders.

Carcinogenicity (see section 4.8)

Patients receiving immunosuppressive therapy, including azathioprine, are at an 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 cancer in situ. 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 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 Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.

As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited, and patients should wear protective clothing and use a sunscreen with a high protection factor.

Reports of hepatosplenic T-cell lymphoma have been received when azathioprine is used alone or in combination with anti-TNF agents or other immunosuppressants. Although most reported cases occurred in the IBD population, there have also been cases reported outside of this population (see section 4.8).

Macrophage activation syndrome

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 could potentially be an 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.

Metabolism and nutrition disorders

Purine analogues, azathioprine and mercaptopurine, may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency (pellagra). Few cases have been reported with the use of azathioprine, especially in patients with IBD (Crohn's disease, colitis ulcerative). Diagnosis of pellagra should be considered in a patient presenting with localised pigmented rash (dermatitis); gastroenteritis (diarrhoea); or neurologic deficits, including cognitive decline (dementia). Appropriate medical care with niacin/nicotinamide supplementation must be initiated, and dose reduction or discontinuation of azathioprine must be considered.

Varicella Zoster Virus Infection (see section 4.8)

Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised especially with respect to the following:

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 avoid patients 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 and supportive care.

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis (see section 4.8).

Posterior reversible encephalopathy syndrome (PRES)

Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients using azathioprine. If patients taking azathioprine present with symptoms indicating PRES such as headache, altered mental status, seizures, hypertension, and visual disturbances, a diagnostic imaging should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of azathioprine is advised. Most cases reported resolved following discontinuation of azathioprine and appropriate treatment.

Hepatitis B (see section 4.8)

Hepatitis B carriers (defined as patients positive for hepatitis B surface antigen [HBsAg] for more than six months), or patients with documented past HBV infection, who receive immunosuppressants are at risk of reactivation of HBV replication, with asymptomatic increases in serum HBV DNA and ALT levels. Local guidelines may be considered including prophylactic therapy with oral anti-HBV agents.

Xanthine oxidase inhibitors

If allopurinol, oxipurinol and/or thiopurinol are given concomitantly with azathioprine, the dosage of azathioprine must be reduced to a quarter of the original dose (see section 4.2).

Neuromuscular agents

Special care is necessary when azathioprine is given concomitantly with neuromuscular acting agents like tubocurarine or succinylcholine (see section 4.5). It can also potentiate the neuromuscular block that is produced by depolarising agents such as succinylcholine (see section 4.5). Patients should be advised to inform their anaesthesiologists of their treatment with azathioprine prior to surgery.

Excipient(s) with known effect

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Food, milk and dairy products

The administration of azathioprine with food may decrease systemic exposure slightly but this is unlikely to be of clinical significance (see section 4.8). Therefore, azathioprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises 6–mercaptopurine and might therefore lead to reduced plasma concentrations of 6–mercaptopurine (see sections 4.2 and 5.2).

Vaccines

The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines. It is therefore recommended that patients do not receive live vaccines until at least 3 months after the end of their treatment with azathioprine (see section 4.4).

A diminished response to killed vaccines is likely and such a response to hepatitis B vaccine has been observed among patients treated with a combination of azathioprine and corticosteroids.

A small clinical study has indicated that standard therapeutic doses of azathioprine do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific antibody concentration.

Effects of concomitant medicinal products on azathioprine

Ribavirin

Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the 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).

Cytostatic/myelosuppressive agents (see section 4.4)

Where possible, concomitant administration of cytostatic agents, or medicinal products which may have a myelosuppressive effect, such as penicillamine, should be avoided. There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and trimethoprim/sulfamethoxazole (co-trimoxazole).

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.

Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors

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). Fatal cases have been reported in patients treated concomitantly with azathioprine and allopurinol.

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.

Aminosalicylate

There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme. Therefore, lower doses of azathioprine may need to be considered when administered concomitantly with aminosalicylate derivatives (see section 4.4).

Methotrexate

Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased 6-mercaptopurine AUC by 69 and 93%, respectively.

Infliximab

An interaction has been observed between azathioprine and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and a decrease in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months.

Neuromuscular agents

There is clinical evidence that azathioprine antagonises the effect of non-depolarising muscle relaxants such as curare, d-tubocurarine and pancuronium. Experimental data confirm that azathioprine reverses the neuromuscular blockade produced by d- tubocurarine and show that azathioprine potentiates the neuromuscular blockade produced by succinylcholine (see section 4.4). There is considerable variation in the potency of this interaction.

Effect of azathioprine on other medicinal products

Anticoagulants

Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with azathioprine; therefore, higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with azathioprine.

4.6. Pregnancy and lactation

Fertility

The specific effect of azathioprine therapy on human fertility is unknown.

Pregnancy

Substantial transplacental and transamniotic transmission of azathioprine and its metabolites from the mother to the foetus have been shown to occur.

Azathioprine should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefits.

Evidence of the teratogenicity of azathioprine in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving azathioprine.

Women of childbearing potential/contraception in men and women

Due to the genotoxic potential of azathioprine (see section 5.3), women of childbearing potential should use effective contraceptive measures while being treated with azathioprine and for one month following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child while receiving azathioprine and for three months following completion of treatment.

Cholestasis of pregnancy has occasionally been reported in association with azathioprine therapy. Early diagnosis and discontinuation of azathioprine may minimise impact on the foetus. However, a careful assessment of benefit to the mother and impact on the foetus should be performed, if cholestasis of pregnancy is confirmed.

Mutagenicity

Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the off-spring 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 light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders (see section 4.4).

There have been reports of intra-uterine growth retardation, premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure.

Leukopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. Extra care in haematological monitoring is advised during pregnancy.

Breast-feeding

6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment. Available data has shown that the excreted levels in breast-milk are low. From the limited available data, the risk to newborns/infants is considered to be unlikely but cannot be excluded.

It is recommended that women receiving azathioprine should avoid breast-feeding unless the benefits outweighs the potential risks.

If a decision is made to breastfeed, because 6-mercaptopurine is a strong immunosuppressant, the breastfed infant should be closely monitored for signs of immunosuppression, leukopenia, thrombocytopenia, hepatotoxicity, pancreatitis or other symptoms of 6-mercaptopurine exposure.

4.7. Effects on ability to drive and use machines

There are no data on the effect of azathioprine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of azathioprine.

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, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

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 and unspecified (including cysts and polyps)

Rare

Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and 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 disorders

Very common

Bone marrow depression, leukopenia.

Common

Thrombocytopenia

Uncommon

Anaemia

Rare

Agranulocytosis, pancytopenia, aplastic anaemia, megaloblastic anaemia, erythroid hypoplasia

Immune system disorders

Uncommon

Hypersensitivity

Very rare

Stevens-Johnson syndrome and toxic epidermal necrolysis

Metabolism and nutrition disorders

Not known

Pellagra (refer to section 4.4)

Nervous system disorders

Not known

Posterior reversible encephalopathy syndrome (PRES)

Tremor

Respiratory, thoracic and mediastinal disorders

Very rare

Reversible pneumonitis

Gastrointestinal disorders

Common

Nausea

Uncommon

Pancreatitis

Very rare

Colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population

Not known

Sialoadenitis

Hepatobiliary disorders

Uncommon

Cholestasis and cholestasis of pregnancy

Rare

Life-threatening liver injury

Not known

Non-cirrhotic portal hypertension, portosinusoidal vascular disease

Investigations

Uncommon

Liver function test abnormal

Skin and subcutaneous tissue disorders

Rare

Alopecia

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 (see sections 4.2 and 4.5).

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 and injection. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, erythema nodosum, vasculitis, myalgia, arthralgia, hypotension, cardiac dysfunction, renal dysfunction, hepatic dysfunction and cholestasis (see section 4.8 - 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 and injection, 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 sections 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. 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 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with azathioprine and result from bone marrow depression which may be maximal after 9 to 14 days. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose. There has been a report of a patient who ingested a single overdose of 7.5 g of azathioprine. The immediate toxic effects of this overdose were nausea, vomiting and diarrhoea, followed by mild leukopenia and mild abnormalities in liver function. Recovery was uneventful.

Treatment

As there is no specific antidote, blood counts should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of azathioprine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

The value of dialysis in patients who have taken an overdose of azathioprine is not known, though azathioprine is partially dialysable.