AZATHIOPRINE

v. 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 regime 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 1-4 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 1-3 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 the medicinal product.

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.

2 Adults – Transplants). 2 Adults − Other Indications). 2). Elderly population There is limited experience of the administration of azathioprine to elderly patients. 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. 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. 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.

2). Most patients with heterozygous TPMT deficiency can tolerate recommended azathioprine doses, but some may require dose reduction. 2). 5). 4). 4). Genotypic testing of NUDT15 variants may be considered before initiating 6-mercaptopurine 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. 8). 5). 2).

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.

4). 4). 4). Neoplasms benign, malignant and unspecified (including cysts and polyps) 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 . 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 Hepato-biliary 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, the necessity for continued administration of azathioprine should be carefully considered on an individual basis. Gastrointestinal disorders Some patients experience nausea when first given azathioprine.

This appears to be relieved by administering the tablets after meals. ) 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 […]

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. 5). Co-administration of ribavirin and azathioprine is not advised. 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. 8). The patient should be informed about the symptoms of liver injury and advised to contact their doctor immediately if these occur. 6).

If cholestasis of pregnancy occurs, case by case assessment is necessary considering the risk-benefit profile of the product (potential withdrawal/dose reduction). Patients with TPMT deficiency 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. 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. 5, Cytostatic/myelosuppressive agents). 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.

Renal and/or hepatic impairment Caution is advised during the administration of azathioprine in patients with renal impairment and/or hepatic impairment. 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. 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.

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 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 […]

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