The Birmingham Children’s Hospital NHS Trust
Department of Gastroenterology & Nutrition
GP/PHYSICIAN GUIDELINES
AZATHIOPRINE IN CHILDREN WITH INFLAMMATORY BOWEL
DISEASE
The team: Professor IW Booth, Dr MS Murphy, Dr. S. Protheroe
Sister Ranjit Sandhu-Gastroenterology Liaison Nurse
Telephone 0121 333 8718/8720/8705
Fax 0121 333 8701
Please fax or send copies of all blood results to Gastroenterology Dept. at the
above address/fax
Introduction:
Inflammatory Bowel Disease (I.B.D) affects 1 in 10 000 children < 16 years of age.
Given the significant adverse effects of long-term steroid therapy, adjunctive or
alternative maintenance immunosuppressive therapy are often used and has been shown
to be effective in reducing serious adverse effects of steroid therapy and efficacious in
reducing complications of the disease.
Azathioprine is the safest and best-tried immunosuppressive drug treatment in
children.
Indication for therapy:
Azathioprine was found to be useful in inflammatory bowel diseases:
Maintenance of remission
As a steroid sparing agent ( in steroid dependant patients)
When steroids alone has not provided adequate disease control
(steroid resistant cases)
In fistulising Crohn’s Disease
Prevention of post-operative recurrence of Crohn’s Disease
Mechanism of action:
AZA is non-enzymatically converted in to 6-Mercaptopurine in the body. About 85% of
6-MP is converted to 6-Thiouracil, by xanthine oxidase. Remaining 15% is competitively
metabolised by two enzymes - Thiopurine methyl transferase (TPMT) converts 6-MP
into 6-methyl mercaptopurine. Both 6-TU and 6-MMP are inactive metabolites.
Hypoxanthine phosphorybosyl transferase (HPRT) converts 6-MP via a series of steps
into 6-Thioguanine nucleotides (6-TGN) which is the active metabolite. 6-TGN induces
apoptosis of T lymphocytes leading to immunosuppression.
Activity of TPMT enzyme is a genetically determined trait. One in 300 individuals have
absent or very low levels of this enzyme. These patients are at a very high risk of bone
marrow toxicity due to excessive production of 6-TGN nucleotides. About 11% of
population have intermediate levels and the rest of the population have normal or high
levels.
It is advisable to obtain TPMT level before starting AZA so that a safe dose could be
prescribed. Please use EDTA bottle (FBC bottle) and take 5 ml of blood.
1
Dose:
2 - 2.5mg /kg/day once daily .
This dose can be started straight away in in those with normal TPMT activity.
In those children with intermediate activity start a lower dose and increase gradually,
closely monitoring blood counts.
In those with absent or very low levels it will probably be necessary to avoid
Azathioprine - Please discuss with the consultant in charge of the patient.
White blood and neutrophil counts are good predictors of achieving and maintaining
remission. Lymphocyte count is not valuable for predicting remission or monitoring.
Side effects:
Non-dose dependent: nausea, vomiting, flu like illness, pancreatitis.
Dose dependant: bone marrow suppression (2-5%) severe infections
Hepatotoxicity – drug induced hepatitis (0.3%)
Patients should be warned to report promptly of infections especially severe sore throat,
varicella or herpes infection, unexplained bruising or bleeding.
If you are concerned about potential side effects please contact the team.
Azathioprine therapy should only be introduced by a hospital specialist trained in
paediatric gastroenterology.
Before starting Azathioprine, we will provide written information to the family
discuss in detail regarding the treatment and arrangements for monitoring .
Monitoring:
Monitoring for bone marrow toxicity is mandatory throughout the duration of
Azathioprine treatment. The following schedule is recommended:
Before start
Full blood count and differential (including platelets), ESR, Creatinine, CRP, LFT’s,
(AST or ALT), albumin, amylase, Varicella Zoster titre and TPMT activity.
During the first 8 weeks of therapy
Full blood count and differential, Creatinine, LFT’s should be performed weekly.
Thereafter, 3 monthly throughout treatment
Full blood count and differential, Creatinine, LFT’s, albumin,
LFT’s and amylase should be checked at any time if symptoms suggesting an
adverse drug effect develop
2
For families’ convenience, bloods may be drawn locally at the G.P’s surgery.
Please send copies of all results to Gastroenterology Department at above
address/fax. Blood results are entered into our Azathioprine register . Our
Liaison Nurse will contact parents if blood monitoring (according to protocol)
not received or needs repeating.
Adverse reactions: - Stop treatment immediately in the event of development of
neutropenia or thrombocytopenia & contact team if any of the following occur: FBC
Platelets < 150 x 109/l
WCC < 3.0 x 109/l
Neutrophils < 1.5 x 109/l
Repeat test in 1 week
If there is evidence of abnormal LFTs or amylase, the team should be informed
who will decide whether to discontinue azathioprine after careful consideration of
risk –benefits.
Please contact the team if you plan to reduce / stop Azathioprine for any reason.
The Gastroenterology team will supervise dose adjustment if required.
Treatment is resumed carefully at a lower individualised dose on the advice of the
Consultant Specialist after full blood count and /or platelet count has returned to
normal.
Monitoring should be maintained at weekly intervals until the blood count has become
stable.
Recovery of Azathioprine –induced myelosuppression is seen within one month after
cessation of treatment. Reintroduction of a lower dose is successful (without
development of leucopenia or thrombocytopenia) in about 50% of patients.
Duration of treatment:
Azathioprine has a slow onset of action. Response to treatment is generally seen in about
three months after starting therapy but could be delayed. Once started, Azathioprine is
continued for atleast 4 to 5 years . If a decision is made to attempt discontinuation, this
requires careful consideration of individual patients, previous difficulties, disease control
etc and the timing of discontinuation.
Refernces :
1. F N Aberra et al: Monitoring of immunomodulators in IBD
Aliment Pharmacol Ther 2005; 21 : 307-319
2. A G Fraser et al: The efficacy of azathioprine treatment; a 30 year review.
Gut 2002; 50: 85-489
3. M C Dubinsky: Azathioprine, 6-Mercaptopurine in IBD:haarmclogy, efficacy
and safety. Clin Gastroenterol Hepatol 2004; 2: 73-734
3
Shared care
A consultant may seek the paediatrician and GP’s involvement in sharing care and
prescribing for a child with Inflammatory Bowel Disease. This leaflet provides the
necessary information for the shared care of patients requiring Azathioprine therapy in
the management of I.B.D. and suggested ways in which the responsibilities for managing
the prescribing of Azathioprine can be shared between the specialist and general
practitioner.
Areas of responsibility for the sharing of care.
Aspects of care for which the Consultant Specialist is responsible: 1. Select patients requiring Azathioprine therapy with due consideration of the
contraindications and precautions. The consultant should inform the general
practitioner of the reasons for selection.
2. Decide on the dose, frequency, and duration of therapy and subsequent dosage
adjustments.
3. Initiate and prescribe until the dose is stable (normally for the first 8 weeks)
4. Ensure compatibility with other medication
5. Ensure that parents / patients understand the nature and complications of drug
therapy and their role in reporting adverse events promptly
6. Ask the GP whether she /she is willing to participate in shared care, and provide the
patient with a monitoring and dosage record.
7. Advise the GP when to adjust the dose, stop treatment, or consult with a specialist.
8. Perform baseline tests and recommend frequency of monitoring.
9. Monitor FBC each week for the first 8 weeks and 3 monthly thereafter for the
duration of therapy
10. Assess the patient’s condition and communicate promptly with the GP when the
treatment is changed.
11. Agree to review patients promptly if required by the general practitioner concerned.
12. Report adverse events to the CSM and GP.
13. Ensure that back up arrangements exist for GP’s to obtain advice and support.
Aspects of care for which the General Practitioner is responsible
1. Reply to the request for shared care as soon as possible
2. Prescribe Azathioprine at the dose recommended and adjust the dose as advised by
the specialist.
3. Ensure compatibility with other medication.
4. Fax copies of all blood results to Department of Gastroenterology.
5. Stop treatment on the advice of the specialist or immediately if an urgent need to
stop treatment arises.
6. Report adverse events to the specialist and CSM.
Aspects of care for which the patient/parent is responsible
1. Take the recommended dose and attend for regular blood tests.
2. Report to the specialist or GP if he or she does not have a clear understanding of the
treatment
3. Inform specialist or GP of any other medication being taken, including over the
counter products
4. Patents/parents should contact their general practitioner if they develop any signs of
infection (in order to exclude neutropenia) or bleeding (to exclude
thrombocytopenia).
4
Chicken pox contact
Chicken pox status is checked by history and serology.
( It is our practice to routinely check varicella titers in all children before they are put on
azathioprine)
Immunosuppressed patients include: -those being treated with Azathioprine or have received it during the last 3 months, and
-children who, within the last 3 months, have received prednisolone, orally or rectally, at
a daily dose (or equivalent) of 2mg/kg/day for at least a week, or 1mg/kg/day for 1
month (and are not on Azathioprine).
Advice is given on contact with chicken pox.
1. If VZ titers positive (immune) , no further action necessary
2. If VZ titre is negative (non immune) or not known, contact the team, if significant
contact with chicken pox
eg play or direct contact in same room for > 15 minutes in household, ward or school
during the infectious period (from 2 days before onset of rash until crusting of all
vesicles) or direct contact with exposed lesions of Herpes Zoster.
3. If less than 72 hours from contact, consider I.M Varicella Zoster Immunoglobulin
(VZIG prophylaxis)
Dose 250mg (1 vial) for age 0-5yrs
500mg (2 vials) for 6-10 years of age
750mg (3 vials) for 11-14 years of age
1000mg (4 vials) for 15 years and over.
TIMING: - VZIG should be give as soon as possible following exposure and not
later than 7 days after exposure.
ROUTE OF ADMINISTRATION: -VZIG is for intra muscular administration
only.
Do not treat : Contacts of a contact
Patients who have been exposed within 4 weeks of previous VZIG
administration
Patients in whom the contact occurred more than 7 days previously
4. If child develops chickenpox, stop Azathioprine and contact the team for further
advice. VZIG should not be given.
5. Alternative antiviral prophylaxis
Acyclovir may be given orally 400mg four times a day for 21 days (up to 2 years of age)
or 800mg four time a day (greater than 2 years of age) for 21 days. This is not a licensed
indication for Acyclovir.
VZIG is prepared from pooled plasma of from non-UK blood donors who are HIV,
hepatitis B and C negative. Because of the limited availability of suitable donors, use of
VZIG is restricted to those at greatest risk from chicken pox and for whom it is most
likely to be effective.
(From BCH Guidelines on the prescribing of VZIG, Departments of Pharmacy &
Microbiology 1999).
5
Vaccinations
Live vaccines should not be given while taking Azathioprine and should be
postponed to at least 6 months after stopping Azathioprine.
Live vaccines eg
Rubella vaccine
MMR vaccine
Oral polio vaccine
BCG vaccine
Oral typhoid vaccine
(this list is not exclusive)
Killed vaccines are safe.
Influenza vaccination is not a live vaccine and is recommended annually for
patients taking Azathioprine.
Back up advice and support
Contact details
Gastroenterology Department Dr Protheroe/ Prof Booth
Dr Murphy
Liaison Nurse
Hospital Interface Pharmacist
Revised July 2005 / M Ravikumara
S Protheroe
S Murphy
6
Tel no.
Fax
0121 333 8720 / 0121 333 8701
0121 333 8705 / 0121 333 8701
0121 333 8718 / 0121 333 8701
0121 333 9772/8 /0121 333 9771