AZATHIOPRINE

Posology Tablets 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:

Transplantation Depending on the immunosuppressive regimen employed, a dose of up to 5 mg/kg body weight per day should be given on the first day of treatment, depending on the immunosuppressive regimen selected. 0 mg/kg body weight per day and must be adjusted in accordance with clinical requirements and haematological tolerance.

Treatment should be maintained indefinitely, even if only low doses are necessary, as cessation of Azathioprine therapy carries a risk of graft rejection. Other Conditions For the treatment of the conditions listed under “Therapeutic Indications”.

Generally, the starting dose should be 1 to 3 mg/kg body weight per day and should be adjusted, within these limits, in accordance with the clinical response and haematological tolerance. A therapeutic response may not be evident for weeks or months after initiation of Azathioprine therapy.

If no improvement in the patient’s condition is evident within three months, consideration should be given to withdrawal of Azathioprine. When a therapeutic response has been achieved, consideration should be given to reducing the dose to the minimum level necessary to maintain the response.

The maintenance dosage of Azathioprine may range from <1 mg/kg body weight per day to 3 mg/kg body weight per day, depending on the condition, its severity, the clinical response obtained and haematological tolerance. 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.

2 Adults – Transplants). 2 Adults Other Indications). 2). Elderly: see renal and hepatic impairment. Although experience with Azathioprine in elderly patients is limited, there is no evidence that the incidence of adverse events in elderly patients is higher than among the general patient population.

However, it is recommended that the doses administered to elderly patients should be at the lower end of the normal range. 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 azathioprine therapy.

In any case, close monitoring of blood counts is necessary. Method of administration For oral use. Swallow the tablets whole. Do not break, chew or crush the tablets. 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 […]

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). 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. 2). 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. 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. 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 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.

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 Administration of 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.

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 […]

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 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.

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). 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). 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. 2). 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. 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. 8): Patients receiving immunosuppressive therapy, including azathioprine, are at an increased risk of developing lymphoproliferative disorders and other […]

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