IMURAN 50 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Imuran 50mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Azathioprine

Each tablet contains 50 mg of the active substance azathioprine.

Excipient(s) with known effect

Each 50 mg tablet contains 74 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Yellow, round, biconvex, scored, film-coated tablets, branded ‘IM 5’

The score line is not for breaking the tablet.

4 CLINICAL PARTICULARS

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 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.

Populations

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 1to 4 mg/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, starting dosage is from 1 to 3 mg/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 1 mg/kg bodyweight/day to 3 mg/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 Section 4.4 and section 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 Section 4.4 and section 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 Section 4.4 and Section 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 Section 4.4 and Section 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).

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 three 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. The patient should be instructed to discontinue azathioprine immediately if jaundice becomes apparent.

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 sulphasalazine. 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 Section 4.2 and Section 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 as atracurium, rocuronium, cisatracurium or suxamethonium (also known as succinylcholine) (see section 4.5).

Anesthesiologists 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 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 Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

Patients receiving multiple immunosuppressive agents may be at risk of overimmunosup­pression, 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.

Varicella Zoster Virus Infection (see Section4.8)

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).

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.

Neuromuscular agents

Special care is necessary when azathioprine is given concomitantly with neuromuscular acting agents like tubocurarine or succinylcholine. 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 anaesthesiologist of their treatment with azathioprine prior to surgery.

Lactose

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

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 Section 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.

Effect 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 coadministration is not advised (see Section 4.4. and Section 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 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 25% 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.

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 blocking agents

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 (such as tubocurarine), and show that azathioprine potentiates the neuromuscular blockade produced by depolarising agents, such as 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 Fertility, 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 benefit.

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.

Mutagenicity

Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the off-spring of patients treated with Imuran. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with Imuran. 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 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 breastfeeding 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 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)

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 and injection. 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 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 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.

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.

Website: 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 to14 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 7.5g 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS, IMMUNOSUPPRESSANTS, Other immunosuppressants, ATC code: L04AX01

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and a methylnitroimi­dazole moiety. The 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The rate of conversion varies from one person to another. Nucleotides do not traverse cell membranes and therefore do not circulate in body fluids. Irrespective of whether it is given directly or is derived in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid. This oxidation is brought about by xanthine oxidase, an enzyme that is inhibited by allopurinol. The activity of the methylnitroimi­dazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP. Determination of plasma concentrations of azathioprine or 6-MP have no prognostic values as regards effectiveness or toxicity of these compounds.

While the precise modes of action remain to be elucidated, some suggested mechanisms include:

1. the release of 6-MP which acts as a purine antimetabolite.

2. the possible blockade of -SH groups by alkylation.

3. the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.

4. damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues.

Because of these mechanisms, the therapeutic effect of Imuran may be evident only after several weeks or months of treatment.

Imuran appears to be well absorbed from the upper gastro-intestinal tract.

Studies in mice with [35S]-azathioprine showed no unusually large concentration in any particular tissue, and there was very little [35S]-label found in brain.

Plasma levels of azathioprine and 6-MP do not correlate well with the therapeutic efficacy or toxicity of Imuran.

5.2 Pharmacokinetic properties

Absorption

Azathioprine is well absorbed following oral administration. Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-mercaptopurine have been conducted that are relevant to azathioprine. The mean relative

bioavailability of 6-mercaptopurine was approximately 27% lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see Section 4.2). 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 (see Section 4.2).

After oral administration of [35S]-azathioprine, the maximum plasma radioactivity occurs at 12 hours and decays with a half-life of 4–6 hours. This is not an estimate of the half-life of azathioprine itself, but reflects the elimination from plasma of azathioprine and the [35S]-containing metabolites of the drug. As a consequence of the rapid and extensive metabolism of azathioprine, only a fraction of the radioactivity measured in plasma is comprised of unmetabolised drug. Studies in which the plasma concentration of azathioprine and 6-mercaptopurine have been determined following intravenous administration of azathioprine have estimated the mean plasma T1/2 for azathioprine to be in the range of 6–28 minutes and the mean plasma T1/2 for 6-mercaptopurine to be in the range 38–114 minutes after i.v. administration of the drug.

Azathioprine is principally excreted as 6-thiouric uric acid in the urine. 1-methyl-4-nitro-5-thioimidazole has also been detected in urine as a minor excretory product. This would indicate that, rather than azathioprine being exclusive cleaved by nucleophilic attack at the 5-position of the nitroimidazole ring to generate 6-mercaptopurine and 1-methyl-4-nitro-5-(S-glutathionyl)i­midazole. A small proportion of the drug may be cleaved between the S atom and the purine ring. Only a small amount of the dose of azathioprine administered is excreted unmetabolised in the urine.

Biotransformation

Thiopurine S-Methyl Transferase (TPMT)

TPMT activity is inversely related to red blood cell 6-mercaptopurine derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations.

Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles — TPMT*2, TPMT*3A and TPMT*3C — account for about 95% of individuals with reduced levels of TPMT activity. Approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. There may also be a group of approximately 2% who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative (see section 4.4).

Special Patient Populations

Paediatric population – Overweight children

In a US clinical study, 18 children (aged 3 to 14 years) were evenly divided into two groups; either a weight to height ratio above or below the 75th percentile. Each child was on maintenance treatment of 6-mercaptopurine and the dosage was calculated based on their body surface area. The mean AUC (0-oo) of 6-mercaptopurine in the group above the 75th percentile was 2.4 times lower than that for the group below the 75th percentile. Therefore, children considered to be overweight may require azathioprine doses at the higher end of the dose range and close monitoring of response to treatment is recommended (see section 4.2).

Patients with renal impairment

Studies with azathioprine have shown no difference in 6-mercaptopurine pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of azathioprine in renal impairment, consideration should be given to reducing the dosage in patients with impaired renal function (see section 4.2).

Azathioprine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.

Patients with hepatic impairment

A study with azathioprine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease. Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see section 4.2).

5.3 Preclinical safety data

Teratogenicity

Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5 to 15 mg/kg body weight/day over the period of organogenesis have shown varying degrees of foetal abnormalities. Teratogenicity was evident in rabbits at 10 mg/kg body weight/day.

6.1

Lactose

Pregelatinised starch

Maize starch

Stearic acid,

Magnesium sterate,

Methylhydroxyl­propyl cellulose

Polyethylene glycol 400

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Store below 25°C. Protect from light.

6.5 Nature and contents of container

Blister strips in a pack.

Pack sizes: 28, 30, 56, 60, 100 and 1000 tablets.

6.6 Special precautions for disposal

Safe handling

Health professionals who handle uncoated azathioprine tablets should follow guidelines for the handling of cytotoxic medicinal products according to prevailing local recommendations and/or regulations.

Provided that the film-coating is intact, there is no risk in handling film-coated azathioprine tablets.

Film-coated azathioprine tablets should not be divided and, provided the coating is intact, no additional precautions are required when handling them.

Disposal

Azathioprine tablets should be disposed of in a manner appropriate to the prevailing local regulatory requirements for the destruction of dangerous substances.

7. Marketing Authorisation Holder

Aspen Pharma Trading Limited

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland.