Download the file - General Practice

Brighton and Sussex
University Hospitals NHS
Trust
WORKING IN
PARTNERSHIP WITH
Brighton and Hove Clinical Commissioning Group
High Weald Lewes Havens Clinical Commissioning Group
OPT-OUT SHARED CARE GUIDELINE
It is assumed that shared care will be accepted unless the specialist is informed otherwise
within 28 days of receipt of the request at the end of this document.
MEDICATION NAME: Azathioprine/mercaptopurine (+/- allopurinol)
INDICATION(S) COVERED (including whether for adults or children):
Crohn’s disease, ulcerative colitis and autoimmune hepatitis for adults
NHS Brighton and Hove CCG, Crawley CCG, Horsham and Mid-Sussex CCG and High Weald Lewes
Havens CCG Traffic Light System Classification: Amber
NOTES to the general practitioner (GP) or primary care prescriber
For medicines which require specialist initiation and/or dose titration and specific ongoing monitoring. For
initiation, dose stabilisation and prescribing (including monitoring) by a specialist until the patient is stabilised
(usually for 3 months) after which the GP may be asked to work under shared care through the use of approved
shared care guidelines.
The expectation is that these guidelines should provide sufficient information to enable GPs or primary care
prescribers to be confident to take clinical and legal responsibility for prescribing these medicines.
The questions below will help you confirm this:
 Is the patient currently under your care (e.g. shared care should not be agreed if the patient is currently in
intermediate care following hospital discharge)?
 Do you have the relevant knowledge, skills and access to equipment to allow you to monitor treatment as
indicated in this shared care guideline?
 Have you been provided with relevant clinical details including monitoring data?
If you can answer YES to all these questions (after reading this shared care guideline), then it is
appropriate for you to accept prescribing responsibility. It is assumed that shared care will be accepted
unless the specialist is informed otherwise within 28 days of receipt of this request.
If the answer is NO to any of these questions, you should not accept prescribing responsibility. You
should inform the consultant or specialist within 28 days, outlining your reasons for NOT prescribing. If
you do not have the confidence to prescribe, we suggest you discuss this with your local Trust or
specialist service, who will be willing to provide training and support. If you still lack the confidence to
accept clinical responsibility, you still have the right to decline. Your CCG medicines management
pharmacist will assist you in making decisions about shared care if you are unsure.
Prescribing unlicensed medicines or medicines outside the recommendations of their marketing authorisation
alters (and probably increases) the prescriber’s professional responsibility and potential liability. The prescriber
should be able to justify and feel competent in using such medicines.
The GP or primary care prescriber has the right to refuse to agree to shared care, in such an event the total clinical
responsibility will remain with the consultant or specialist.
Reason for update: New SCG
Prepared by: Archna Parmar, Specialist
Gastroenterology Pharmacist
Updated by: Archna Parmar, Specialist
Gastroenterology Pharmacist
Approved by (Specialist or Consultant): Dr Melissa Smith
Approved by (Chief Trust Pharmacist): Niall Ferguson
Approved by (CCG Medicines Management Pharmacist): Dr Stewart Glaspole
Approved by Brighton and Hove and High Weald Lewes Havens CCG on: September 2016
Azathioprine/mercaptopurine/allopurinol SCG Version: 1
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Review date: 07/2019
Information
This page should include general information relevant to the specific medication and indication(s). It should include
information on the dose of the medicine for the indication, cautions, contraindications, common side effects and
interactions to look out for. This section should have input from a specialist or consultant in the field.
This information sheet does not replace the Summary of Product Characteristics (SPC), which should be read
in conjunction with this guidance. Prescribers should also refer to the appropriate paragraph in the current
edition of the BNF.
1. Link to the relevant SPC website:
Azathioprine: https://www.medicines.org.uk/emc/medicine/26877
Mercaptopurine: https://www.medicines.org.uk/emc/medicine/24688
Allopurinol: https://www.medicines.org.uk/emc/medicine/25729

Background to use for the indication(s), including licence status:
Azathioprine:
 Azathioprine is used as an immunosuppressant antimetabolite either alone or in combination with
other agents which influence the immune response.

This guideline covers the treatment of Crohn’s disease, ulcerative colitis and autoimmune hepatitis
in adults. Azathioprine has a marketing authorisation for the following indications: severe
rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, autoimmune
chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune haemolytic anaemia,
chronic refractory idiopathic thrombocytopenic purpura. Therefore, the use of azathioprine in IBD
and autoimmune hepatitis is classed as off-label.

A large body of evidence exists, supporting the use of thiopurines such as azathioprine and
mercaptopurine in Crohn’s disease and ulcerative colitis1. If treatment is still effective after 4 years,
it may be continued long term following an appropriate discussion with the patient.

Link
to
Crohn’s
and
Colitis
azathioprine
information
leaflet:
http://s3-eu-west1.amazonaws.com/files.crohnsandcolitis.org.uk/Publications/azathioprine-mercaptopurine.pdf
Mercaptopurine:
 Mercaptopurine is used as an immunosuppressant antimetabolite either alone or in combination
with other agents which influence the immune response.

This guideline covers the treatment of Crohn’s disease, ulcerative colitis and autoimmune hepatitis
in adults. Mercaptopurine is a metabolite of azathioprine. It is an anti-neoplastic agent that is
licensed for the treatment of acute leukaemia and chronic myeloid leukaemia in combination with
other treatments. Therefore, the use of mercaptopurine in IBD and autoimmune hepatitis is classed
as off-label.

It also exerts immunosuppressant properties and has been used in autoimmune inflammatory
bowel disease for many years. A large body of evidence exists, supporting the use of thiopurines in
Crohns disease and ulcerative colitis1. If treatment is still effective after 4 years, it may be continued
long term following an appropriate discussion with the patient.

Link to Crohn’s and Colitis mercaptopurine information leaflet: http://s3-eu-west1.amazonaws.com/files.crohnsandcolitis.org.uk/Publications/azathioprine-mercaptopurine.pdf
Allopurinol:
 Allopurinol is a xanthine oxidase/dehydrogenase inhibitor, is licensed for the prophylaxis of gout
and uric acid/calcium oxalate renal stones, as well as hyperuricaemia associated with cancer
chemotherapy.

Allopurinol is used off-label to augment thiopurine therapy in the treatment of inflammatory bowel
disease, by optimising thiopurine metabolite profiles and improving treatment response. This
combination treatment has been especially effective in patients with high thiopurine
methyltransferase (TPMT) enzyme activity profile. Patients with this trait have a higher risk of both
hepatotoxicity and thiopurine non-response. Initiation will be based on TGN/MMP profile2.
2. Dose & administration:
Prior to starting azathioprine or mercaptopurine, the patient’s TPMT (thiopurine methyltransaminase)
activity will be checked by the specialist via a blood test. This enzyme is involved in the metabolism of
mercaptopurine (a metabolite of azathioprine) and its activity is controlled by a genetic polymorphism.
TPMT testing, initial dosing, TDM and subsequent dose adjustments will be the responsibility of the
specialist team.
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Azathioprine:
 Azathioprine is usually dosed at 1-3mg/Kg/day, though actual dose will be titrated by the specialist
team.

Azathioprine in combination with allopurinol may be prescribed to increase response and or
tolerability of medication2. When used in combination with allopurinol, the dose of azathioprine is
reduced to 25% of the standard dose (i.e. a 75% dosage reduction). Therapeutic drug monitoring is
used to guide the dose of azathioprine in order to avoid toxicity (TDM measuring TGN (thioguanine
nucleotide) and MMP (methyl mercaptopurine) levels). Therapeutic drug monitoring and its
interpretation will be the responsibility of the specialist team. Any dosage adjustments can only be
made by the specialist team when azathioprine is used in combination with allopurinol.

Azathioprine is available as 25mg and 50mg tablets.
Mercaptopurine:
 Mercaptopurine is usually dosed at 1-1.5mg/Kg/day, though the actual dose will be titrated by the
specialist team.

Mercaptopurine in combination with allopurinol may be prescribed to increase the response and or
tolerability of the medication. When used as a combination with allopurinol, the dose of
mercaptopurine is reduced to 25% of the standard dose (i.e. a 75% dosage reduction). Therapeutic
drug monitoring is used to guide the dose of mercaptopurine in order to avoid toxicity (TDM
measuring TGN (thioguanine nucleotide) and MMP (methyl mercaptopurine) levels). Therapeutic
drug monitoring and its interpretation will be the responsibility of the specialist team. Any dosage
adjustments can only be made by the specialist team when mercaptopurine is used in combination
with allopurinol.

Mercaptopurine is available as 50mg tablets (there is also a liquid preparation available, however
this should not be used due to safety issues with dosing and administration).
Allopurinol:
 For use in combination with thiopurines, allopurinol is used at a dose of 100mg daily.

Please note clinical systems will trigger a warning when azathioprine or mercaptopurine and
allopurinol are co-prescribed.

Allopurinol is available as 100mg tablet (there is also a 300mg tablet available, however this should
not be used due to dosing issues).
3. Cautions (including for pregnancy & lactation where relevant):
Azathioprine:
 Do not stop medication without consulting the specialist team if patient is pregnant or
contemplating pregnancy. Current evidence would suggest that the risks of discontinuing
therapy are higher than the risks of continuing, due to the severe impact of a flare in
pregnancy.

All patients with IBD who are pregnant, planning a pregnancy or breast-feeding, should ensure that
the IBD team is aware of this, so that their medication and well-being can be optimised during this
important time. The specialist team will make all patients aware of this at initiation of therapy.
Mercaptopurine:
 Do not stop medication without consulting the specialist team if patient pregnant or
contemplating pregnancy. Current evidence would suggest that the risks of discontinuing
therapy are higher than the risks of continuing, due to the severe impact of a flare in
pregnancy.

All patients with IBD who are pregnant, planning a pregnancy or breast-feeding, should ensure that
the IBD team is aware of this, so that their medication and well-being can be optimised during this
important time. The specialist team will make all patients aware of this at initiation of therapy.
Allopurinol:
 Data describing allopurinol use in human pregnancy are extremely limited.

However, because exposure to allopurinol in pregnancy is rare, but a similar pattern of birth defects
has been described in more than one exposed infant, the possibility that allopurinol is a teratogen
needs to be highlighted. Until more research is carried out to confirm or refute this, allopurinol
should be used during pregnancy only where benefits of treatment clearly outweigh the potential
risk of birth defects, and provided the available data have been fully discussed with the patient.

All IBD patients on allopurinol who are pregnant, planning a pregnancy or breast-feeding, should
immediately be referred to the IBD team for review with the likelihood of allopurinol needing to be
stopped. The specialist team will make all patients aware of this at initiation of therapy.
This list is not exhaustive; refer to the Summary of Product Characteristics (SPC) or BNF for further guidance.
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
Contraindications:
Azathioprine:
 Pregnancy is NOT a contraindication for patients on existing treatment with azathioprine.

Azathioprine is contraindicated in patients with absent TPMT activity.
Mercaptopurine:
 Pregnancy is NOT a contraindication for patients on existing treatment with mercaptopurine.

Mercaptopurine is contraindicated in patients with absent TPMT activity.
Allopurinol:
 Should not be started in patients during an acute gout attack, but can be continued if an attack
develops when a patient is already taking allopurinol.
This list is not exhaustive; refer to the Summary of Product Characteristics (SPC) or BNF for further guidance.
4. Side effects:
Azathioprine:
 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. However, bone marrow suppression can still occur even
in those with a normal TPMT activity after many months and therefore continued monitoring is
essential.

Other known side effects include pancreatitis, cholestasis and alopecia.

It is important that patients are informed that they should consult either their GP or specialist team
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.
The specialist team will make all patients aware of this at initiation of therapy.
Mercaptopurine:
 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.

Other known side effects include pancreatitis, cholestasis and alopecia. Pancreatitis is reported to
be more common in patients with inflammatory bowel disease than with other conditions.

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 team
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.
The specialist team will make all patients aware of this at initiation of therapy.
Allopurinol:
 Gastro-intestinal disturbances and rashes are the most commonly experienced side effects of
allopurinol.

Alopecia, aplastic anaemia and blood disorders have also been reported.
A FBC must also be performed on any patient on azathioprine or mercaptopurine who becomes unwell as
profound myelosuppression can develop between routine blood tests. If a patient is found to be
myelosuppressed, azathioprine/mercaptopurine therapy should be stopped immediately and medical advice
should be sought.
This list is not exhaustive; refer to the Summary of Product Characteristics (SPC) or BNF for further guidance.
Azathioprine/mercaptopurine/allopurinol SCG Version: 1
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5. Notable drug interactions:
Many GP/CP computer systems will classify the azathioprine/mercaptopurine and allopurinol co-prescription to
be a serious drug interaction. The evidence presented above, together with the doses used and the robust
monitoring schedule means this interaction can be adequately managed in primary care and can promote an
enhanced patient outcome.
Azathioprine:
DO NOT GIVE ALLOPURINOL TO PATIENTS ON AZATHIOPRINE/MERCAPTOPURINE UNLESS
ADVISED BY THE SPECIALIST AS EXPLAINED UNDER POINT 2.

Trimethoprim and co-trimoxazole cause an increased risk of haematological toxicity, therefore we
suggest avoiding using these antibiotics if possible unless used for PCP prophylaxis according to ECCO
guidelines
for
patients
on
triple
immunosuppression.
(https://www.eccoibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2014_OI_Update_COREGuidelinesText_Vol8_
443-468.pdf).

Other interactions of note include coumarins, febuxostat and ribavirin. Prescribers are advised to check
the BNF or ask a pharmacist for advice where required.

Contact the appropriate specialist for advice if above drugs are considered essential for patient.
Mercaptopurine:
DO NOT GIVE ALLOPURINOL TO PATIENTS ON AZATHIOPRINE/MERCAPTOPURINE UNLESS
ADVISED BY THE SPECIALIST AS EXPLAINED UNDER POINT 2.

Trimethoprim and co-trimoxazole cause an increased risk of haematological toxicity, therefore we
suggest avoiding using these antibiotics if possible unless used for PCP prophylaxis according to ECCO
guidelines
for
patients
on
triple
immunosuppression
(https://www.eccoibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2014_OI_Update_COREGuidelinesText_Vol8_
443-468.pdf).

Other interactions of note include coumarins, febuxostat and clozapine. Prescribers are advised to
check the BNF or ask a pharmacist for advice where required.

Contact the appropriate specialist for advice if above drugs are considered essential for patient.
Allopurinol:
DO NOT GIVE ALLOPURINOL TO PATIENTS ON AZATHIOPRINE/MERCAPTOPURINE UNLESS
ADVISED BY THE SPECIALIST AS EXPLAINED UNDER POINT 3.

Allopurinol should not be used with capecitabine or didanosine.

Allopurinol can increase theophylline levels, therefore close monitoring of serum theophylline levels
are required.
Vaccines
 Severe or fatal infections may occur if a live vaccine is given concurrently with azathioprine or
mercaptopurine. AVOID LIVE VACCINES:
- BCG
- Live attenuated influenza vaccine (LAIV)
- MMR
- Rotavirus
- Oral thyphoid vaccine
- Varicella
- Yellow fever
- Zoster (see guidance link below)

Inactivated vaccines such as the standard influenza vaccine are safe to use although they may elicit
a lower response.

Herpes zoster vaccine
http://tinyurl.com/nvdeqp2
is
not
contraindicated
in
these
patients.
Please
see
This list is not exhaustive; refer to the Summary of Product Characteristics (SPC) or BNF for further guidance.
Criteria for use:

Chronic inflammatory conditions as determined by the appropriate specialist.
6. Any further information (e.g. supporting therapies):
7. References:
1.
2.
Gut. 2006 January; 55(1): 6–8
M.Smith, et al. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescribing of allopurinol. JCrohn’s Colitis 2012;6:905-12
Azathioprine/mercaptopurine/allopurinol SCG Version: 1
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RESPONSIBILITIES and ROLES
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2
3
4
5
6
7
8
9
10
11
12
13
Consultant or specialist responsibilities
Confirm diagnosis and indication for treatment with azathioprine/mercaptopurine (+/- allopurinol).
To discuss fully the aims, benefits, risks and side effects of treatment and a treatment plan with the patient and/or carer
and for written information to be supplied to the patient and/or carer.
Inform GP when initiating treatment so the GP is aware what is being prescribed and can add to GP clinical record.
Undertake baseline monitoring as required.
Record other medications and address potential medicine interactions before starting therapy.
To discuss the potential implications of pregnancy and breastfeeding in women of child bearing potential and agree a
risk minimisation strategy where appropriate.
To initiate treatment by prescribing and monitoring usually for a minimum of 3 months.
Undertake monitoring if dose changed.
Monitor and prescribe according to guidelines until handover is appropriate (including when dose changes are made).
Discuss the possibility of shared care with the patient and/or carer and ensure that they understand the plan for their
subsequent treatment.
Supply GP with a summary of the patient’s review (including anticipated length of treatment) and a link to, or a copy of,
the shared care guideline when requesting transfer of prescribing to GP or primary care prescribers.
Advise GP if treatment dose changes or treatment is discontinued.
Inform GP if patient does not attend annual planned follow-up.
GP or primary care prescriber responsibilities
Continue prescribing of azathioprine/mercaptopurine (+/- allopurinol) at the dose recommended and undertake
monitoring requirements.
Undertake all relevant monitoring as outlined in the monitoring requirements section below, and take appropriate action
as set out in this shared care guideline.
Monitor for adverse effects throughout treatment and check for medicine interactions on initiating new treatments.
Add information about the medicine to the patient record, initially as “hospital prescribed”, and highlight the importance
that this medicine is only to be prescribed under a shared care guideline in primary care.
Inform the consultant or specialist of any issues that may arise.
Provide patient with yearly flu vaccination and regular pneumovax vaccination unless contra-indicated.
Refer patient back to the Consultant/Specialist if any concerns.
Ensure that if care of the patient is transferred to another prescriber, that the new prescriber is made aware of the
shared care guideline (e.g. ensuring the patient record is correct in the event of a patient moving surgery).
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2
3
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5
6
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8
Primary Care Monitoring requirements and appropriate dose adjustments
U&Es, FBC and LFTs at monthly intervals from handover to month 6, and 3 monthly thereafter.
Perform an urgent FBC on any patient on azathioprine who becomes unwell to check for myelosuppression.
If total WCC <3.5x109/L ± neutrophils <1.5x109/L ± platelets < 150x109/L: withhold and seek specialist advice.
If ALT/AST x 2 ULN: withhold and seek specialist advice.
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2
3
4
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2
3
4
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Patient and/or carer role
Make sure that you understand the treatment and ask for more information, if needed.
Share any concerns in relation to treatment with whoever is prescribing this medicine for you.
Tell the prescriber of this medication about any other medication being taken, including over-the-counter products.
Read the patient information leaflet included with your medication and report any side effects or concerns you have to
whoever is prescribing this medicine for you.
Attend any follow up appointments with the consultant or specialist.
Attend any monitoring appointments (eg blood tests).
Azathioprine/mercaptopurine/allopurinol SCG Version: 1
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SHARED CARE GUIDELINE
MEDICATION NAME:
INDICATION:
DATE OF REQUEST:
Agreement to transfer prescribing to general practice or primary care prescriber:
Patient details:
Name:
Address:
DoB:
NHS No:
Hospital No:
Medication name, form and strength:
The following tests and investigations have been carried out:
Date treatment initiated:
At the last patient review the medication appeared to be effectively controlling symptoms or providing benefit:
Yes/No
The patients has now been stabilised on a dose of:
The patient has been given written information about their medication:
Yes/No
The patient understands that this medication is being prescribed under a shared care agreement between their
GP and specialist and that they have responsibilities under the agreement to ensure they attend their GP to be
regularly monitored.
Yes/No
The patient has been informed that the GP can opt-out of taking on prescribing responsibility if they do not feel
clinically able to prescribe or if the patient persistently does not attend for monitoring:
Yes/No
Date of next clinic appointment:
If the practice declines shared care, then the named consultant or specialist should be informed within 28 days
of receipt of this request. Forms used to decline prescribing can be found here:
Brighton and Hove CCG and High Weald Lewes Havens CCG:
http://www.gp.brightonandhoveccg.nhs.uk/prescribing/joint-formulary-supporting-information
BACK-UP ADVICE AND SUPPORT
Name and position
Telephone
Email
Specialist or Consultant
Alternative specialist
(e.g. departmental
contact)
Specialist pharmacist
Out of hours (e.g.
medical team on call)
Link to full SCG:
http://www.gp.brightonandhoveccg.nhs.uk/prescribing/shared-care-guidelines
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