Shared Care
Guideline
Azathioprine tablets
For the treatment of:
Inflammatory arthritis, connective tissue
disease and vasculitis in adults
( 16 years old)
For the latest information on interactions and adverse affects, always consult the latest version
of the Summary of Product Characteristics (SmPC), which can be found at:
www.medicines.org.uk
These guidelines are based on the monitoring criteria of the British Society of Rheumatology,
published in the following reference:
Chakravarty, K., McDonald, H., Pullar, T. et al. (2008) BSR/BHPR guideline for diseasemodifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of
Dermatologists. Rheumatology 47(6), 924-925.
Authors: Dr Kelsey M Jordan (Consultant Rheumatologist, BSUH NHS Trust)
Dr Stewart E Glaspole (Pharmacist, BSUH NHS Trust/BHCPCT)
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 1 of 9
Drug Name
Azathioprine 25mg and 50mg tablets.
Indications for use within the protocol
Inflammatory arthritis, connective tissue disease and vasculitis diagnosed by a
Rheumatologist, usually supported by indices of inflammation.
Duration – most drugs require up to 3 to 4 months trial to assess efficacy (including
the time required for dose stabilisation). Therapy is continued providing the drug is
working and that any side effects are tolerated by the patient. Relapse is common
after withdrawal of therapy.
Background
Azathioprine is used as a disease modifying agent to induce and maintain remission
in several types of rheumatic disease. It can reduce inflammation and affect the
immune system and is therefore used for a number of Rheumatological conditions.
Pharmacology
Azathioprine is an antimetabolite agent which has been shown to exert antirheumatic
and immunosuppressive activity making it an effective drug in many rheumatological
conditions. There are many suggested mechanisms of action with no single apparent
pathway.
Dosage and administration
Prior to starting azathioprine, best practice recommends checking the TPMT
(thiopurine s-methyltransferase) activity; this enzyme is involved in the metabolism of
azathioprine and its activity is controlled by a genetic polymorphism. TPMT testing,
initial dosing and subsequent dose adjustments will be the responsibility of the
specialist team.
The usual dose of azathioprine is between 1-3mg/kg/day. The maximum dose differs
between individuals.
Contraindications to use
Azathioprine is contra-indicated in:

Immunization with live vaccines (see additional cautions)

Pregnancy and breast feeding except in clinically indicated cases (see section on
pregnancy and lactation)

TPMT deficiency (homozygous state): Avoid, can be fatal

Individuals with Lesch-Nyhan Syndrome due to congenital hypoxanthine-guanine
phosphoribosyl transferase (HGPRT) deficiency.

Patients taking allopurinol (see interactions)
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 2 of 9
Additional cautions

All patients contemplating becoming pregnant must be seen by a consultant
Rheumatologist at the earliest opportunity to discuss the complex issues
surrounding therapy with azathioprine

Patients receiving azathioprine must not receive immunization with live vaccines.
Inactivated polio is available although suboptimal response may be seen

Annual flu and pneumovax vaccination are recommended

In patients receiving azathioprine exposed to chickenpox or shingles, passive
immunization should be carried out using varicella zoster immunoglobulin (VZIG).
Please contact the specialist team for more information.
Monitoring
The British Society for Rheumatology (BSR) recommends precise monitoring to be
carried out for this drug. The requirements are summarised in the following table.
a. Pre-treatment
assessment
b. Ongoing Monitoring
c. Following

FBC, U&E, creatinine, LFTs,

TPMT assay.

These tests will be carried out by the initiating
hospital specialist.

FBC and LFTs weekly for 6 weeks and continue every
2 weeks until dose stable for 6 weeks; then monthly

If maintenance dose is achieved and stable for 6
months consider discussing with patient to reduce
monitoring to 3 monthly.

Repeat FBC and LFTs 2 weeks after dose change and
then monthly.

U&E and creatinine should be repeated 6 monthly
(unless more frequent testing is clinically indicated).

ESR and/or CRP every three months (not required but
useful)
changes in dose
Additional monitoring
Actions to be taken
9
WBC<3.5x10 /l
Withhold until discussed with specialist team
9
Neutrophils<2.0x10 /l
Withhold until discussed with specialist team
Platelets<150x109/l
Withhold until discussed with specialist team
AST, ALT>twice upper limit of normal
Withhold until discussed with specialist team
Rash or oral ulceration
Withhold until discussed with specialist team
MCV>105 fl
Check serum folate and B12 & TSH. Treat
any underlying abnormality. If results normal
discuss with specialist team.
Abnormal bruising or severe sore
throat
Withhold until FBC results available and
discuss with the specialist team.
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 3 of 9
Undesirable effects
The most common side effects (affecting approximately 20% of patients) are flu-like
symptoms (myalgia, headache, diarrhoea) which characteristically occur 2-3 weeks
after initiating treatment and usually subside if treatment is continued.
The most important complication is bone marrow suppression causing leucopenia or
thrombocytopenia (both more likely to develop in those with a low TPMT activity) and
is most likely to occur in the first few weeks of treatment.
It is important that patients are informed that they should consult either their GP or
specialist team1 should they develop symptoms of possible myelosuppression such
as sore throat (or other signs of infection) or easy bruising. In the case of such
presentation an urgent FBC should be carried out.
A FBC must also be performed on any patient on azathioprine who becomes
unwell as profound myelosuppression can develop between routine blood
tests. If a patient is found to be myelosuppressed, azathioprine therapy should
be stopped immediately and medical advice should be sought1
Should a FBC suggest myelosuppression (total white cell count <3.5x109 /l or platelet
count < 100x109/l) or LFTs become deranged (progressive rise in AST/ALT) urgent
advice from an appropriate consultant should be sought using the contact details
provided. Relative neutropenia (<2.0 x109/l) requires close monitoring.
Please note that lymphopenia should be expected (lymphocyte count <1.0 x109/l
suggests compliance with treatment).
Pregnancy and Lactation

Women of childbearing potential should be advised to use effective contraceptive
precautions. Evidence of mutagenicity is equivocal in men. In most cases,
azathioprine should not be prescribed if there is a possibility of pregnancy,
although there may be some circumstances where the benefit of continuing
treatment outweighs the possible risks related to the unborn child. A careful
assessment of risk vs benefit is advised.

Women treated with azathioprine should not breast feed
1
See section on contacting the specialist team
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 4 of 9
Interactions

Allopurinol: Do not use. Discuss alternatives with a Rheumatologist if urate
lowering drugs are required

Warfarin: Azathioprine inhibits the anticoagulant effects of warfarin. Monitor INR
and alter the dose of warfarin accordingly

Phenytoin, sodium valproate,
absorption of these drugs

Angiotensin-converting enzyme (ACE) inhibitors: Co-prescription of azathioprine
may cause anaemia (if significant, consider alternative to ACE inhibitor or
different DMARD)

Aminosalicylates i.e. mesalazine, olsalazine, balsalazide or sulfasalazine, may
contribute to bone marrow toxicity

Co-trimoxazole and trimethoprim can cause life threatening haematoxicity and
should not be used in patients taking azathioprine
carbamazepine:
Azathioprine
reduces
the
Consultant / hospital responsibilities
It is the specialist team’s responsibility to:

Identify those patients who will benefit from treatment with azathioprine

Undertake pre-treatment monitoring as detailed above

Perform the TPMT activity tests and select initiation doses

Inform the GP of the reasons for initiating azathioprine

Initiate and prescribe the medication. Decide on the dose and duration of therapy
and subsequent dosage adjustments

Ensure that patients understand the nature and possible complications of
azathioprine and their role in reporting adverse effects promptly

Agree to discuss promptly with the GP questions regarding treatment with
azathioprine and review patients promptly if requested by the GP

Provide the patient with monitoring blood forms whilst on treatment with copies of
results sent to the GP (unless the GP chooses to take responsibility for both
prescribing and monitoring)

Undertake responsibility to act on pathology lab results (unless the GP chooses
to take responsibility)

Review efficacy of treatment at regular intervals and ensure any drug treatment
changes are communicated to the GP

Communicate any changes in frequency of pathology testing to the GP

Provide access to back up and support facilities

Report any adverse events to the CSM

Evaluate any adverse events reported by the GP.
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 5 of 9
GP responsibilities
It is the GP’s responsibility to:

Return the shared care agreement letter to the consultant to indicate agreement
with this guideline. If for any reason the GP is unhappy with the arrangements
they should contact the appropriate hospital specialist

Prescribe azathioprine at the dose recommended by the hospital specialist. Any
decision to alter or discontinue treatment should be taken after discussion with
the hospital specialist

Check for possible drug interactions when newly prescribing or stopping
concurrent medication (see interaction section)

Report any suspected or actual adverse drug reactions to the hospital specialist
and the CSM

Undertake an urgent full blood count to check for leucopenia in patients
developing significant infection, or multiple mouth ulcers
Patient responsibilities
It is the patient’s responsibility to:

Report side effects to any member of the health care team

Patients are expected to attend for blood tests when required, to ensure safe and
effective ongoing treatment.
Information to the patient
The outpatient clinic will provide the patient with information about their treatment.
Information about the patient to be received by the GP from the consultant
Please refer to the shared care request letter attached. Two copies of this letter will
be sent to the GP for each patient initiated on therapy.
Patient information to be received by the consultant from the GP
In order for GPs to agree formally to this shared care protocol, it is requested that
both the shared care request letters attached be signed and one returned to the
hospital specialist requesting shared care.
Contacting the specialist team
If the patient’s Consultant is not available, one of the other Consultants or Specialist
Registrars will be able to help. Please call the Rheumatology department at RSCH
on 01273 696955 x4631/3553 or PRH on 01444 441881 x 5432/5984
Out of hours
Urgent problems should be referred to the medical team on call, contacted via RSCH
switchboard on 01273 696955 or the PRH switchboard on 01444 441881
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 6 of 9
References
1 Paice EW. Giant cell arteritis: difficult decisions in diagnosis, investigation and
treatment. Postgrad Med J 1989;65:743–7.
2 Konstantopoulou M, Belgi A, Griffiths KD, Seale JR, Macfarlane AW. Azathioprine
induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte
thiopurine methyltransferase. Br Med J 2005;330:350–1.
3 Imuran Summary of product characteristics 25 & 50mg: 23 July and 5 August,
Glaxo Smith Kline. http://emc.medicines.org.uk
4 British National Formulary 54. Pharmaceutical Press, 2007.
5 Cronstein BN. Pharmacogenetics in the rheumatic diseases. Ann Rheum Dis
2004;63(Supp. 2):ii25–7.
6 Rivier G, Khamashta MA, Hughes GR. Warfarin and azathioprine: a drug
interaction does exist. Am J Med 1993;95:342.
7 Jenner E. Immunisation against infectious disease. Bicentenary Edition 1996. Her
Majesty’s Stationary Office, Department of Health, London UK. www.dh.gov.uk/
8 Ramsey-Goldman R. Treatment of inflammatory rheumatic disorders in pregnancy:
what are the safest treatment options? Drug Saf 1998;19:389–410.
9 Ostensen M. Disease Specific problems related to drug therapy in pregnancy.
Lupus 2004;13:746–50.
10 Clunie GPR, Lennard L. Relevance of thiopurine methyltransferase status in
rheumatology patients receiving azathioprine. Rheumatology 2004;43:13–8.
11 Tavadia SMB, Mydlarski PR, Reis MD et al. Screening for azathioprine toxicity: a
pharmacoeconomic analysis based on a target case. J Am Acad Dermatol
2000;42:628–32.
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 7 of 9
Confidential shared care request
Consultant name
Consultant address
Date
GP Name
GP Address
Azathioprine in inflammatory arthritis, connective tissue disease and vasculitis
in adults ( 16 years old)
Patient Name: Patient Hospital number: Patient Address: Patient NHS Number: Dear Dr.
Your patient has been commenced on:
Azathioprine, at a dose of:
It would be appropriate for this patient’s therapy to be shared between primary and
secondary care. The enclosed Shared Care Guideline provides additional
information to support you in this. Please sign both copies of this letter to indicate
your agreement and return one copy to my office; the other should be placed in the
patient’s notes at your practice.
Yours sincerely,
Consultant name
GP signature
Print name
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 8 of 9
Date
Confidential shared care request
Consultant name
Consultant address
Date
GP Name
GP Address
Azathioprine in inflammatory arthritis, connective tissue disease and vasculitis
in adults ( 16 years old)
Patient Name: Patient Hospital number: Patient Address: Patient NHS Number: Dear Dr.
Your patient has been commenced on:
Azathioprine, at a dose of:
It would be appropriate for this patient’s therapy to be shared between primary and
secondary care. The enclosed Shared Care Guideline provides additional
information to support you in this. Please sign both copies of this letter to indicate
your agreement and return one copy to my office; the other should be placed in the
patient’s notes at your practice.
Yours sincerely,
Consultant name
GP signature
Print name
AZASCG
Document status Final/Draft: Final 13 Jan 2009
Date of next review if final: 13 Jan 2010
Page 9 of 9
Date