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AZATHIOPRINE is a brand name for Azathioprine. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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…
Verbatim from this product's MHRA label. Tap a section to expand.
Posology When the oral route is impractical, azathioprine injection may be administered by the IV route only, however, this route should be discontinued as soon as oral therapy can be tolerated once more. Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
Adults Transplants Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg bodyweight/day may be given orally or intravenously on the first day of therapy. 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 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.
2 Adults - Transplants). 2 Adults - Other Indications). 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.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response. Renal impairment Since azathioprine pharmacokinetics has not been formally studied in renal impairment, no specific dose recommendations can be given.
Summary of the safety profile 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 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 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Body System Frequency Side effects Very common Viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants. Uncommon Viral, fungal and bacterial infections in other patient populations.
4). 4). 4). Very common Bone marrow depression, leukopenia. Common Thrombocytopenia. Uncommon Anaemia. Blood and lymphatic system disorders Rare Agranulocytosis, pancytopenia, aplastic anemia, megaloblastic anaemia, erythroid hypoplasia.
Immune system disorders Very rare Stevens-Johnson syndrome and toxic epidermal necrolysis. Respiratory, thoracic and mediastinal disorders Very rare Reversible pneumonitis. Metabolism and nutrition disorders Not known Pellagra Nervous system disorders Not known Posterior reversible encephalopathy syndrome (PRES), tremor Gastrointestinal Common Nausea Uncommon Pancreatitis Very rare Colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population.
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.
Azathioprine 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 no 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. 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.
1. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to Azathioprine.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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. 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).
disorders Not known Sialoadenitis Uncommon Cholestasis and cholestasis of pregnancy. Rare Life-threatening liver injury. Hepatobiliary disorders Not known Non-cirrhotic portal hypertension, portosinusoidal vascular disease Investigations Uncommon Liver function test abnormal.
Skin and subcutaneous tissue disorders Not known Acute febrile neutrophilic dermatosis (Sweet’s syndrome), photosensitivity. 4). Neoplasms benign and malignant and unspecified (incl 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.
5). Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with azathioprine therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia are rare.
Immune system disorders Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of azathioprine tablets and injection. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, erythema nodosum, vasculitis, myalgia, arthralgia, hypotension, cardiac dysfunction, renal dysfunction, hepatic dysfunction and cholestasis (see 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 […]
This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. 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). 5). Anaesthesiologists should check whether their patients are administered azathioprine prior to surgery. 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 to 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 offspring 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 […]