Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Sandoz Limited, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
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; and to reduce the corticosteroid requirements of renal transplant recipients. Azathioprine 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:
Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
When the oral route is impractical, azathioprine injection may be administered by the i.v. route only, however, this route should be discontinued as soon as oral therapy can be tolerated once more.
Azathioprine should be administered at least 1 hour before or 3 hours after food or milk (see section 5.2 Absorption).
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.
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.
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: See above Dosage in transplantation – adults.
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 Pharmacokinetics; Special Patient Populations; Overweight children).
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 Patients with renal and/or hepatic impairment).
In patients with renal and/or hepatic insufficiency, consideration should be given to reducing the dosage (see section 4.4).
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 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: Monitoring 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: Monitoring and section 5.2).
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine 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 6-mercaptopurine therapy. In any case, close monitoring of blood counts is necessary.
For oral use.
The tablet should be taken with at least a glass of liquid (200 ml).
For instructions on handling when nursing staff have divided the tablets of the medicinal product before administration, see section 6.6.
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 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.
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.
Shelf life: 3 years.
This medicinal product does not require any special storage conditions.
The film-coated tablets are packed in either polypropylene-aluminium blister or PVC/PVDC-aluminium blister in a carton box.
The pack contains 20, 28, 30, 50, 90 or 100 film-coated tablets.
Not all pack sizes may be marketed.
There are no risks associated with handling tablets with intact coating. In that case no special safety precautions are necessary.
However, cytotoxic agents should be handled in strict accordance with the instructions when nursing staff have divided or crushed the tablets (see sections 4.2 and 4.4).
Surplus medical products as well as contaminated appliances should be temporarily stored in clearly labelled containers. Any unused product or waste material should be disposed of in accordance with local requirements.
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