Rabbit Anti-Thymocyte Globulin (thymoglobuline, rATG) Protocol

Publication: 01/10/2019  --
Last review: 01/01/1900  
Next review: 03/10/2022  
Standard Operating Procedure
CURRENT 
ID: 6140 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Standard Operating Procedure is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Rabbit Anti-Thymocyte Globulin (thymoglobuline, rATG) Protocol

Background and indications for standard operating protocol

Indication for Rabbit ATG:
The decision to give to be made by the on-call paediatric nephrology consultant. 
For use in the treatment of steroid resistant acute cellular rejection or vascular rejection in renal transplant.

Contraindications:

  • Patients with a history of allergy or anaphylaxis to rabbit proteins
  • Patients with an acute infective (bacterial, viral or fungal) illness.
  • Patients with thrombocytopenia (platelets<50 x 109 cells/L), lymphopenia (<0.1 x 109

cells/L),

Background:
Thymoglobuline (anti-thymocyte globulin [rabbit], rATG) is a purified, pasteurised, immunoglobulin G, obtained by immunisation of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. The mechanism of action for how it suppresses the immune responses is not fully understood. Possible mechanisms by which thymoglobuline may induce immunosuppression in vivo include: T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. 

In patients, T-cell depletion is usually observed within a day after initiating thymoglobuline therapy

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Procedure method (step by step)

1. Preparation of the patient:

Vascular access: Thymoglobuline should only be administered through a central line due to the risk of thrombophlebitis and thrombosis if administered peripherally. The patient will need to have appropriate central access.

Informed verbal consent: This will be taken by the on call paediatric nephrology consultant and documented in the patient’s medical notes.  This should include a description of the evidence in favour of using, the likely result of not doing so and the possible adverse effects

Adverse reactions:

The most common adverse reactions and laboratory abnormalities (incidence >5% higher than comparator) are urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, increased potassium levels in the blood, and low counts of platelets and white blood cells.

Other risks to counsel family for:

  • Increased risk of serious infection
  • May increase the incidence of malignancies, including lymphoma or lymphoproliferative disorders.
  • Acute immune mediated reactions such as anaphylaxis and cytokine release syndrome.

Pre-medication:

 The following medications should be prescribed on the “when required” tab of eMEDS and administered 60 minutes before every infusion of thymoglobuline starts.

Pre-medication

Age

Dose

Hydrocortisone

(Intravenous)

1month - 5 months  

25mg

6months -  5 years    

50mg

Over 6 years             

100mg

Chlorphenamine maleate

(Intravenous)

1- 5years

2.5mg

6-11 years

5mg

Over 12 years

10mg

Paracetamol

(Oral)

Dose as per BNFc

 

Treatment Course

Dose

The dose is 1.5mg/kg/day and is given for 7-14 days. Dose should be rounded to the nearest 25mg and confirmed with a pharmacist. To avoid excessive dosing in obese patients, calculate dose based on Ideal body weight (IBW)Appendix 1.

If a dose has been rounded down and there are concerns around drug efficacy, on day 3 a blood test for CD3 level should be sent in liaison with the immunology lab at STJH. If the CD3 level remains above 0.05x109/L it should be discussed with the On call Consultant nephrologist and renal pharmacist to consider a dose increase. Other paediatric renal centres have used a dose of up to 2mg/kg1,2. The course of the treatment should not exceed a cumulative dose of 21mg/kg, as per the SPC for rATG.

Indications for dose reduction:

The dose should be halved if:

  • Total WCC is between 2-3 x 109/L
  • Platelet count is between 50-75 x109/L

The thymoglobuline course should be stopped if:

  • Total WCC < 2 x 109/L
  • Platelet count is < 50 x109/L

Route of Administration

Administered via a central venous access device to avoid potential venous irritation.

Thymoglobuline should be given through a separate line and not mixed with other fluids or drugs.

Preparation and Administration

The infusion will be prepared by LTHT aseptics and has an expiry date of 24 hours. Once prepared the drug needs to be stored in a fridge (2-8oC).

Each 25mg vial should be diluted with 5mls of 0.9% Sodium Chloride and further diluted with 0.9% Sodium Chloride to give a solution that does not exceed a concentration of 2mg/ml.

Due to the risk of anaphylaxis the first infusion should be started in normal working hours and given over 12 hours. If this is tolerated without adverse reactions subsequent infusion time can be reduced by 2 hours each day to a minimum time of 6 hours. The infusion should be given through a 0.2 micron inline filter via a central line.

See nursing information summary appendix 2. Keep a copy in the nursing kardex.

 

Monitoring during infusion

The patient should have their vital signs monitored (HR, BP, RR, oxygen saturations and temperature with a PAWS score calculated) initially every 15mins for the first hour, every 30mins for the second hour, then hourly for the remainder of the infusion.

If signs of anaphylaxis (e.g. marked skin redness, itching, rhinitis, choking or laryngeal oedema, bronchospasm, tachycardia and hypotension), stop the infusion and request urgent medical review and start emergency management (as per BNFc)

If signs of an infusion reaction occur, urgent medical review should be sought

  • For mild reactions e.g. chills, fever, mild dyspnoea and vomiting, the infusion can be continued but at a slower infusion rate

 

Prophylaxis medications:

Due to the immunosuppressive actions of thymoglobuline the patient should be on the following medications:

 

Age

Dose

Duration

Co-trimoxazole

(Oral)

PCP prevention

Less than 6 years  

240mg once a day

3 months

Over 6 years    

480mg once da day

Valganciclovir

(Oral)

Cytomegalovirus (CMV) prevention

All ages

Dose(mg) = 7× BSA × eGFR once daily

Maximum dose of 900 mg

 

BSA= Body Surface Area

eGFR (mL/min/1.73 m2)

=     40 × height (cm)

     creatinine micromol/L)

                [capped at 75mL/min]

3 months

Anti-fungal prophylaxis can be either of below depending on concordance:-

Nystatin

All ages

100,000 units four times a day

3 months

Fluconazole

All ages

3mg /kg  once a day

(May effect tacrolimus levels)

3 months

 

Immunosuppression modulation:

The immunosuppression medications need to be altered whilst receiving thymoglobuline and all changes should be done in discussion with paediatric nephrology consultant on call

  • Prednisolone - this should be continued.
  • Azathioprine and Mycophenolate Mofeteil (MMF) should be stopped and recommenced once there is white cell count (total WCC > 4.0 x109/L) and platelet recovery.
  • Tacrolimus can be continued, dose reduced or stopped. If it is stopped it should be re-started 3 days before the end of the thymoglobuline course to allow stabilisation of drug levels.

 

Monitoring during thymoglobuline treatment

The patient will have daily:

  • Clinical review including assessment of response to therapy
  • U&E  - to monitor for response to treatment
  • FBC -  to monitor response and to guide need to alter dose or stop thymoglobuline

On day 3 if concerns of response to therapy a CD3 cell count can be requested via immunology at SJUH (available Monday -Friday 9am-5pm). A CD3 count of below 0.05x109/L (<50/microlitre) is aimed for.

 

Precautions post thymoglobuline course

Irradiated and CMV negative blood components

The family and patient should be informed that the patient should receive irradiated blood products due to risk of Graft versus Host Disease (GvHD).  An information leaflet and alert card for the family can be obtained from LTHT transfusion service and requesting “Information for patients needing irradiated blood” leaflet. Further information on this can be found on the LTHT guideline pathway “Guideline for the Use of Irradiated and CMV negative Blood / Blood Components in Transfusion.” Found here

The blood transfusion services at LTHT should be informed to update the patient record

Live attenuated vaccination

The child should not receive live attenuated vaccines for at least 2 years. NB patients on maintenance immunosuppression post renal transplantation should not receive these either.

 

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Provenance

Record: 6140
Objective:
Clinical condition:
Target patient group: Paediatric renal medical, nursing and pharmacy teams.
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

References

1. Nottingham Children’s Hospital Paediatric Transplantation guideline

https://www.nuh.nhs.uk/download.cfm?doc=docm93jijm4n855 

accessed on 12/3/19 at 21.28  (C)

2. Evelina London Paediatric Formulary, accessed via App. 12/3/19  (C)

Appendix 1  How to calculate ideal body weight

Calculating ideal body weight (IBW)

Use the reverse BMI Method which uses the equation for BMI in reverse to determine the IBW 

IBW = BMI50 x height (m2)

where BMI50 represents the 50th centile of a BMI chart, which is the ideal BMI for their height, age and gender.

BMI charts are available from the Royal College of Paediatrics and Child Health website

https://www.rcpch.ac.uk/resources/body-mass-index-bmi-chart

For example:

A 7 year old girl who is 1.2metres tall

BMI50 = 15.6kg/m2 (using Girls UK Body Mass Index 2-20years chart)

IBW = BMI50 x height (m2) = 15.6 x1.2 x 1.2 =22.5kg

Therefore their ideal body weight for prescribing would be 22.5kg

 

Appendix 2

Thymoglobuline - Rabbit Anti-Thymocyte Globulin (rATG)

Nurses Administration guide

Pre-medication:

The following medications should be prescribed on the “when required” tab of the eMeds chart and administered 60minutes before the start of every infusion of thymoglobuline.

  • Hydrocortisone (IV)
  • Chlorphenamine (IV)
  • Paracetamol (Oral)

 

Treatment Course

Dose

The dose is 1.5mg/kg and is given for 7-14 days.

Dose should be rounded to the nearest 25mg and confirmed with a pharmacist. To avoid excessive dosing in obese patients, the dose is based on ideal body weight (IBW).

 

Dose should be prescribed on a fluid chart and annotated to be given via 0.2 micron filter. Cross reference chart must also be prescribed on eMeds stating “ATG/thymoglobuline” in the qualifier.

 

Administration

The infusion should be given through a 0.2 micron inline filter via a central line.

It is administered via a central venous access device to avoid potential venous irritation.

Thymoglobuline must be given through a separate line and not mixed with other fluids or drugs.

 

Due to the risk of anaphylaxis the first infusion should be started in normal working hours and given over 12 hours. If this is tolerated without adverse reactions subsequent infusion times can be reduced by 2 hours each day to a minimum time of 6 hours.

 

Preparation The infusion will be prepared by LTHT aseptics and has an expiry date of 24 hours. Once prepared the drug needs to be stored in a fridge (2-8oC) until it is given.

 

Monitoring

The patient should have their vital signs monitored (HR, BP, RR, oxygen saturations and temperature). Patients need to be monitored during and after every dose.

  • Every 15 mins for 1st hour
  • Every 30 mins for 2nd hour
  • Then hourly for the remainder of the infusion.

 

If signs of anaphylaxis (e.g. marked skin redness, itching, rhinitis, choking or laryngeal oedema, bronchospasm, tachycardia and hypotension), stop the infusion and request urgent medical review and start emergency management (as per BNFc)

 

If signs of an infusion reaction urgent medical review should be sought

  • For mild reactions e.g. chills, fever, mild dyspnoea and vomiting, the infusion can be continued but at a slower infusion rate

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

Conflict in Interest

None

Aims 

To standardize the process for administration of thymoglobuline (rATG)

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