Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
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:
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.
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.
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).
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).
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).
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).
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).
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 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.
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).
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.
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 years.
Store below 25°C. Protect from light.
Blister strips in a pack.
Pack sizes: 28, 30, 56, 60 and 100 tablets.
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.
Azathioprine tablets should be disposed of in a manner appropriate to the prevailing local regulatory requirements for the destruction of dangerous substances.
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