SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Imuran Injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Azathioprine EP 50 mg/vial.

3 PHARMACEUTICAL FORM

Injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Imuran 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.

Imuran, 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, and to reduce the corticosteroid requirement of renal transplant recipients.

Imuran, either alone or more usually in combination with corticosteroids and/or other drugs 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

Imuran Injection should be used ONLY when the oral route is impractical, and should be discontinued as soon as oral therapy is tolerated. It must be administered only by the intravenous route.

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

Dosage in transplantation - adults and children

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

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

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

Dosage in other conditions - adults and children

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 3 months, consideration should be given to withdrawing Imuran.

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.

In patients with renal and/or hepatic insufficiency, dosages should be given at the lower end of the normal range (see Special Precautions for Use for further details).

Use in the elderly (see Renal and/or hepatic insufficiency)

There is a limited experience of the administration of Imuran 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 Imuran, it is recommended that the dosages used should be at the lower end of the range.

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

Reconstitution and dilution of Imuran Injection

Precautions should always be taken when handling Imuran Injection (see section 6.6 Instructions for Use, Handling and Disposal).

No antimicrobial preservative is included. Therefore reconstitution and dilution must be carried out under full aseptic conditions, preferably immediately before use. Any unused solution should be discarded.

The contents of each vial should be reconstituted by the addition of 5 ml to 15 ml of Water for Injections BP. The reconstituted solution is stable for up to 5 days when stored between 5°C and 25°C.

When diluted on the basis of 5 ml of reconstituted solution to a volume of between 20 ml and 200 ml of one of the following infusion solutions, Imuran is stable for up to 24 hours at room temperature (15 °C to 25 °C):

Sodium Chloride Intravenous Infusion BP (0.45% w/v and 0.9% w/v)

Sodium Chloride (0.18% w/v) and Glucose (4.0% w/v) Intravenous Infusion BP.

Should any visible turbidity or crystallisation appear in the reconstituted or diluted solution the preparation must be discarded.

Imuran Injection should ONLY be reconstituted with the recommended volume of Water for Injections BP and should be diluted as specified above.

Imuran Injection should not be mixed with other drugs or fluids, except those specified above, before administration.

Administration of Imuran Injection

Imuran Injection, when reconstituted as directed, is a very irritant solution with a pH of 10 to 12.

When the reconstituted solution is diluted as directed above, the pH of the resulting solution may be expected to be within the range pH 8.0 to 9.5 (the greater the dilution, the lower the pH).

Where dilution is not practicable, the reconstituted solution should be injected slowly over a period of not less than one minute and followed immediately by not less than 50 ml of one of the recommended infusion solutions.

Care must be taken to avoid perivenous injection, which may produce tissue damage.

4.3 Contraindications

Imuran is contra-indicated in patients known to be hypersensitive to azathioprine. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to Imuran.

Imuran therapy should not be initiated in patients who may be pregnant, or who are likely to become pregnant without careful assessment of risk versus benefit (see section 4.4 Special Warnings and Precautions for Use & section 4.6 Pregnancy and Lactation).

4.4 Special warnings and precautions for use

Monitoring

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

It is suggested that during the first 8 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.

Patients receiving Imuran should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression.

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 Imuran. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also it has been reported that decreased TPMT activity increases the risk of secondary leukaemias and myelodysplasia in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see section 4.8 Undesirable effects).

Renal and/or hepatic insufficiency

It has been suggested that the toxicity of Imuran may be enhanced in the presence of renal insufficiency, but controlled studies have not supported this suggestion. Nevertheless, it is recommended that the dosages used should be at the lower end of the normal range and that haematological response should be carefully monitored. Dosage should be further reduced if haematological toxicity occurs.

Caution is necessary during the administration of Imuran to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of Imuran may be impaired, and the dosage of Imuran should therefore be reduced if hepatic or haematological toxicity occurs.

Limited evidence suggests that Imuran 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 Imuran.

Mutagenicity

Chromosomal abnormalities have been demonstrated in both male and female patients treated with Imuran. It is difficult to assess the role of Imuran in the development of these abnormalities.

Effects on fertility

Relief of chronic renal insufficiency by renal transplantation involving the administration of Imuran has been accompanied by increased fertility in both male and female transplant recipients.

Carcinogenicity (see also section 4.8 Undesirable Effects)

Patients receiving immunosuppressive therapy are at an increased risk of developing non-Hodgkin’s lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. It has been reported that reduction or discontinuation of immunosuppression may be associated with partial or complete regression of non-Hodgkin’s lymphomas and Kaposi’s sarcomas.

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

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 minimize the risk of skin cancer and photosensitivity (see also section 4.8 Undesirable Effects).

Varicella Zoster Virus Infection (see also section 4.8 Undesirable Effects)

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.

4.5 Interaction with other medicinal products and other forms of interaction

Allopurinol/ oxipurinol/ thiopurinol

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.

Neuromuscular blocking agents

Imuran can potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine and can reduce the blockade produced by nondepolarising agents such as tubocurarine. There is considerable variation in the potency of this interaction.

Warfarin

Inhibition of the anticoagulant effect of warfarin, when administered with azathioprine, has been reported.

Cytostatic/myelosuppressive agents

Where possible, concomitant administration of cytostatic drugs, or drugs 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 Imuran and co-trimoxazole.

There has been a case report suggesting that haematological abnormalities may develop due to the concomitant administration of Imuran and captopril.

It has been suggested that cimetidine and indometacin may have myelosuppressive effects, which may be enhanced by concomitant administration of Imuran.

Other interactions

As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Imuran therapy (see section 4.4 Special Warnings and Special Precautions for Use).

Furosemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.

Vaccines

The immunosuppressive activity of Imuran could result in an atypical and potentially deleterious response to live vaccines and so the administration of live vaccines to patients receiving Imuran therapy is contra-indicated on theoretical grounds.

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 Imuran do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific antibody concentration.

4.6 Fertility, Pregnancy and lactation

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.

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

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.

Use in Pregnancy and Lactation

Imuran should not be given to patients who are pregnant or likely to become pregnant without careful assessment of risk versus benefit.

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.

Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after maternal administration of azathioprine.

Leucopenia 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.

Lactation

6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

For this product there is no modern clinical documentation that can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication. 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, > 1/10000 and < 1/1000; very rare, < 1/10000.

Infection and infestations

Transplant patients receiving Imuran in combination with other immunosuppressants.

Very common:    Viral, fungal, and bacterial infections.

Other indications.

Uncommon:    Viral, fungal and bacterial infections.

Patients receiving Imuran alone, or in combination with other immunosupressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection with varicella, herpes zoster and other infectious agents (see also section 4.4 Special Warnings and Precautions for Use).

Neoplasms benign and malignant (including cysts and polyps).

Rare:    Neoplasms including non-Hodgkin’s lymphomas,

skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ, acute myloid leukaemia and myelodysplasia (see also section 4.4 Special Warnings and Special Precautions for Use).

The risk of developing non-Hodgkin’s lymphomas 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 immunosuppressive drugs, 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

Depression of bone marrow function; leucopenia. Thrombocytopenia.

Anaemia.

Agranulocytosis, pancytopenia, aplastic anaemia, megaloblastic anaemia, erythriod hypoplasia.

Imuran may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, 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 Imuran when receiving concurrent allopurinol therapy.

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

Respiratory, thorasic and mediastinal disorders

Very rare:    Reversible pneumonitis.

Reversible pneumonitis has been described very rarely.

Gastrointestinal disorders

Uncommon:    Pancreatitis.

Rare:    Colitis, diverticulitis and bowel perforation reported

in transplant population, severe diarrhoea in inflammatory bowel disease population.

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 Imuran for inflammatory bowel disease. The possibility that exacerbation of symptoms might be drug-related should be borne in mind when treating such patients.

Pancreatitis has been reported in a small percentage of patients on Imuran therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease. There are difficulties in relating the pancreatitis to the administration of one particular drug, although re-challenge has confirmed an association with Imuran on occasions.

Hepato-biliary disorders

Uncommon:    Cholestasis and degeneration of liver function tests.

Rare:    Life-threatening hepatic damage.

Cholestasis and deterioration of liver function have occasionally been reported in association with Imuran therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Hypersensitivity reactions).

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

Skin and subcutaneous tissue disorders

Rare:    Alopecia, photosensitivity.

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. The relationship between alopecia and azathioprine treatment is uncertain.

Immune system disorders

Uncommon:    Hypersensitivity reactions

Very rare:    Stevens-Johnson syndrome and toxic epidermal

necrolysis.

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

In many cases, re-challenge has confirmed an association with Imuran.

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 Imuran, the necessity for continued administration of Imuran should be carefully considered on an individual basis.

4.9 Overdose

Symptoms and signs: Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with Imuran 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 leucopenia and mild abnormalities in liver function. Recovery was uneventful.

Treatment: There is no specific antidote. Gastric lavage has been used. Subsequent monitoring, including haematological monitoring, is necessary to allow prompt treatment of any adverse effects which may develop. The value of dialysis in patients who have taken an overdose of Imuran is not known, though azathioprine is partially dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

Mode of action: 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 thiol (-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 thio-analogues.

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 [ S]-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

Azathioprine is well absorbed following oral administration. After oral administration of [ S]-azathioprine, the maximum plasma radioactivity occurs at 1-2 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-MP have been determined, following intravenous administration of azathioprine, have estimated the mean plasma T_1/2 for azathioprine to be in the range of 6-28 minutes and the mean plasma T_1/2 for 6-MP to be in the range 38-114 minutes.

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-MP and 1-methyl-4-nitro-5-(S-glutathionyl)imidazole. A small proportion of the drug may be cleaved between the sulphur-atom and the purine ring. Only a small amount of the dose of azathioprine administered is excreted unmetabolised in the urine.

5.3 Preclinical safety data

No additional data of clinical relevance to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide pellets* BP 7.2 mg Sodium hydroxide pellets* to adjust pH Water for Injections EP

*In the form of a 1M solution in water for injections.

6.2 Incompatibilities

Imuran Injection should ONLY be reconstituted with the recommended volume of Water for Injections BP and should be diluted as specified above. Imuran Injection should not be mixed with other drugs or fluids, except those specified above, before administration.

6.3 Shelf life

3 years unopened

5 days when reconstituted with 5 ml to 15 ml water for injections and stored at 5 to 25°C.

1 day for 5 ml of the reconstituted injection further diluted with between 20 ml and 200 ml of an appropriate infusion solution and stored at 15°C to 25°C.

6.4 Special precautions for storage

Store below 25°C Keep dry Protect from light

6.5 Nature and contents of container

Neutral glass vials with synthetic butyl rubber closures and aluminium collars. Each vial contains the equivalent of 50 mg azathioprine.

6.6 Special precautions for disposal

Health professionals who handle Imuran Injection should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (e.g., the Royal Pharmaceutical Society of Great Britain Working Party Report on the Handling of Cytotoxic Drugs, 1983).

7. MARKETING AUTHORISATION HOLDER

Aspen Pharma Trading Limited 3016 Lake Drive Citywest Business Campus Dublin 24 Ireland

8    MARKETING AUTHORISATION NUMBER(S)

PL 39699/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11 February 1997

10 DATE OF REVISION OF THE TEXT

19/12/2013