Infliximab infusion for inflammatory bowel disease

Paediatric guidelines (in development)
NHS Lothian

Objectives

The purpose of this guideline is to ensure all nursing, medical and pharmacy staff working under the gastroenterology team within NHS Lothian Paediatric services are aware of how to prescribe, prepare, administer and monitor infliximab infusions for children and young people with inflammatory bowel disease.

Scope

This guideline applies to all nursing and medical staff caring for children and young people with inflammatory bowel disease treated with intravenous infliximab under the gastroenterology team within NHS Lothian paediatric services.

Audience

NHS Lothian paediatric services

Roles and responsibilities

It is the responsibility of all staff involved in the care of a patient receiving an infliximab infusion to have read and understood this guideline. If any member of staff has any concerns, they should address these with a trained member of staff before proceeding.

Introduction and indications

Introduction
Infliximab is an anti-inflammatory monoclonal antibody, derived from human and mouse cells. Infliximab inhibits the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha). It has been shown to be effective in the management of all forms of inflammatory bowel disease.

Indications for Use(4)

  • Crohn’s Disease – Induction and maintenance of remission of moderate to severe, active Crohn’s disease in patients aged 2 to 18 years old who have normally not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contra-indications for such therapies.
  • Ulcerative Colitis/Inflammatory Bowel Disease Unclassified (IBDU) - Induction and maintenance of remission of ulcerative colitis/IBDU for patients aged 2 to 18 years old who have normally not responded to conventional therapy including corticosteroids (acute severe disease) and mercaptopurine or azathioprine (chronic active disease), or who cannot tolerate, or have medical contraindications to, such therapies and where surgery is not indicated or is refused.
  • As primary treatment for significant perianal Crohn’s disease without the need for previous other therapies along with surgical care as needed.

Other indications out with the above indications for use require approval from the Clinical Director or nominated deputy via a Non-Approved Medicine Request Form which must be completed and approved before starting therapy.

Cautions and contraindications

Contraindications (2)

  • History of hypersensitivity to infliximab, other murine proteins or to any of the excipients
  • Tuberculosis
  • Severe infections e.g. sepsis, abscesses, and opportunistic infections
  • Moderate or severe heart failure
  • Pregnancy


Cautions (5)

  • Pre-existing or recent onset of demyelinating disorders
  • History of malignancy
  • Chronic hepatitis B infection
  • Heart failure
  • Predisposition to infection
  • Risk of delayed hypersensitivity reactions if drug free interval exceeds 12 weeks.
  • Severe needle phobia and potential vascular access problems

Baseline assessment

Initiation of therapy and baseline assessment (1)

  • Full clinical history
  • Height, weight, pubertal status
  • Measurement of Paediatric Crohn’s Disease Activity Index (wPCDAI) or Paediatric Ulcerative Colitis Activity Index (PUCAI)
  • Immunisation history – Consider delaying infusion until 3 months post administration of live vaccinations. If disease state requires urgent biologic treatment the interval from last live vaccination can be decreased to 4 weeks on decision of a consultant gastroenterologist. Please note: Vaccination history and delivery is ideally done previously around the time of diagnosis.
  • Bloods including FBC, ESR, U&E’s, LFTs, creatinine, CRP.
  • Varicella Zoster serology, hepatitis B and C status, HIV status, EBV and CMV IgG should be checked if not done previously and only repeated if thought to be clinically relevant.
  • Faecal calprotectin
  • Chest X-ray: To be performed and resulted prior to commencing infliximab. If a CXR has been performed in the last 3 months and no relevant symptoms have developed, a repeat CXR is not required.
  • Quantiferon gold (can use Mantoux as an alternative if quick result needed)
  • Pregnancy test for all females over 12 years of age who have reached menarche.
  • Patient information to be given and discussed with the patient and carers
  • Responsible consultant to discuss risks and benefits of treatment including written consent when possible.

Dosing

Prescribing instruction
Infliximab must be prescribed by brand name. Remsima® is the infliximab biosimilar used in NHS Lothian paediatric services. Infliximab should be prescribed on the intravenous fluid chart and also on the once only section of the medicine prescription and administration chart.

Standard dosing (1,2,3)

Induction of remission
Infliximab will be administered at a dose of 5-10mg/kg as an intravenous infusion over a 2-hour period using the following regimen:

1st Dose – Week 0
2nd Dose – Week 2
3rd Dose – Week 6

An accelerated induction regimen with shorted interval spacing can be used as decided by a consultant gastroenterologist.

 

Maintenance of remission
Standard dosing is 5-10mg/kg as an intravenous infusion every 4-8 weeks, adjusted depending on response and trough drug levels. Dose and frequency will be adjusted in response to clinical response / remission plus therapeutic drug monitoring.
Infusions 1 to 4 should be administered over 2 hours and patients monitored for 1-hour post-administration.

For patients on CO-IMMUNOSUPRESSION doses 5 and beyond of maintenance therapy may be infused over 1 hour. Patients must have tolerated 4 infusions of 2 hours duration and be receiving maintenance therapy as decided by the gastroenterology team. Patients must be monitored for 30 minutes post-administration of a 1-hour infusion.

For patients on infliximab MONOTHERAPY doses 9 and beyond of maintenance therapy may be infused over 1 hour. Patients must have tolerated 8 infusions of 2 hours duration and be receiving maintenance therapy as decided by the gastroenterology team. Patients must be monitored for 30 minutes post-administration of a 1-hour infusion.

Dose rounding, pre dose monitoring & premedication

Dose Rounding

All doses should be rounded to the nearest full 100mg vial. For doses which are ≤10% over the nearest full vial, the dose should be rounded down to the nearest 100mg full vial. See worked examples below.
Example:
Weight 22.5kg, dose 10mg/kg i.e. 225mg – more than 10% over 200mg, so round up to 300mg
Weight 11kg, dose10mg/kg i.e. 110mg – 10% above 100mg so round down to 100mg

Monitoring Prior to Infusion

Ensure the following is complete before commencing the infusion:

  • Pregnancy test for all females over 12 years of age who have reached menarche.
  • Enquire to ensure no symptoms of current underlying infection.
  • Site an intravenous cannula in an appropriate vein.
  • Take bloods to check FBC, U&E’s, creatinine, LFTs, CRP, and ESR – do not wait for blood results before starting infusion.
  • Infliximab levels and antibodies if requested by GI team.
  • Baseline temperature, pulse, respiratory rate, blood pressure. Record these immediately prior to commencing the infusion.

Hydrocortisone pre-medication

All patients on an induction schedule of infliximab should receive hydrocortisone premedication for the initial 3 loading doses. On completion of the initial 3 infusions no further hydrocortisone premedication is required if no adverse effects are experienced during these infusions, or if no significant levels of anti-drug antibodies are detected.

Patients noted to have significantly high anti-drug antibodies should receive hydrocortisone premedication for their next three infusions at least. After this set of infusions, a consultant gastroenterologist will decide whether to continue the patient on infliximab with or without hydrocortisone.

Hydrocortisone (sodium succinate) intravenous injection dosing:

• 4mg/kg (Maximum 200mg) immediately prior to infliximab infusion.

As Required Medication
All patients should have IV chlorphenamine prescribed in the as required section of their Medication Prescription and Administration Chart prior to the first infliximab dose and should therefore not need re-prescribed subsequently.

IV hydrocortisone should be prescribed with every dose of infliximab for as long as needed initially (see Hydrocortisone Pre-medication section above) and then in the as required prescription for subsequent doses. See appendix A for dosing information. Unless the patient is due pre-medication, chlorphenamine and hydrocortisone are for mild/moderate infusion reactions.

Preparation and administration

Preparation(6)

To prepare the infliximab infusion:

  • Calculate the required volume of reconstituted infliximab (Remsima®) for the prescribed dose.
  • Reconstitute each 100mg vial of infliximab (Remsima®) with 10mL of water for injection directing the stream of water to the glass wall of the vial. Final concentration 10mg/ml.
  • Gently swirl the solution by rotating the vial to dissolve the powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE.
  • Allow the reconstituted solution to stand for 5 minutes.
    Check that the reconstituted solution is colourless or light yellow. Do not use if opaque particles, discolouration, or other foreign particles are visible.
  • Withdraw the required infliximab (Remsima®) volume from a 250ml sodium chloride 0.9% infusion bag, ensuring that the final dose of infliximab (Remsima®) does not exceed 1000mg. For doses above 1000mg contact pharmacy for advice.
  • Slowly add the total volume of reconstituted infliximab (Remsima®) to the infusion bag and mix gently.
    Visually inspect the infusion for particulate matter, discolouration, or foreign particles.
  • The infusion of 250ml is now ready to be administered.

Example: for a 25kg patient prescribed 300mg Infliximab, 30mL of sodium chloride 0.9% should be withdrawn from the bag and 30mL (300mg) of Infliximab should be added.

Administration

  • Prior to starting the infusion ensure emergency drugs are available in the ward area in case of any adverse reaction.
  • All medications should be given in accordance with NHS Lothian Safe Use of Medicines Policy.
  • Check all prescribed doses of infliximab are correct for the patient.
  • Administer any prescribed premedication if required.
  • Administer infliximab (Remsima®) infusion using an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micron or less).
  • Infuse at 125ml/hr for doses over 2 hours, or 250ml/hr for doses over 1 hour for doses less than 1000mg. For doses above 1000mg contact pharmacy for advice.
  • Once infliximab infusion is complete, flush with 30ml of sodium chloride 0.9% at the same rate as the infliximab (Remsima®) infusion.

Monitoring

Monitoring Prior to Infusion

Ensure the following is complete before commencing the infusion:

  • Pregnancy test for all females over 12 years of age who have reached menarche.
  • Enquire to ensure no symptoms of current underlying infection.
  • Site an intravenous cannula in an appropriate vein.
  • Take bloods to check FBC, U&E’s, creatinine, LFTs, CRP, and ESR – do not wait for blood results before starting infusion.
  • Infliximab levels and antibodies if requested by GI team.
  • Baseline temperature, pulse, respiratory rate, blood pressure. Record these immediately prior to commencing the infusion.

During the infusion

  • Monitor pulse, temperature, respiratory rate, and blood pressure every 30 minutes during the infusion.
  • Acute infusion reactions may develop anytime during or after the infusion.
  • If a patient develops a reaction, follow the infusion related reaction treatment guidance in appendix A.


Post infusion

  • Monitor pulse, temperature, respiratory rate, and blood pressure every 30 minutes for 1 hour post a 2-hour infusion
  • Monitor pulse, temperature, respiratory rate, and blood pressure every 30 minutes for 30 minutes after a 1-hour infusion.
  • If a patient develops a reaction, follow the infusion related reaction treatment guidance in appendix A.
  • Advise patients and carers to report any signs of infection or possible side effects. Delayed hypersensitivity-like reactions may appear 1-14 days after the infusion.
  • Advise patients and carers to seek immediate medical advice if hypersensitivity symptoms occur. Delayed reactions are more likely to occur if a patient has had a previous course of infliximab.

Exit Strategy
Patients should be reviewed after the initial induction infusions and every 6 months of treatment to assess the continued need for infliximab.

Possible side effects

See BNFc or Summary of Product Characteristics for full list of side effects.(2,5)

Common or very common

  • Anaemia
  • Constipation
  • Dizziness
  • Fatigue
  • Gastrointestinal discomfort
  • Hypertension/hypotension
  • Increased risk of infection
  • Infusion related reaction
  • Skin reactions

Uncommon

  • Anxiety
  • Heart failure
  • Seizure
  • Thrombocytopenia

Rare or very rare

  • Cyanosis
  • Demyelinating disorders
  • Pancytopenia

Frequency not known

  • Bone fracture

Appendix A - infusion reactions and anaphylaxis drug doses

Reaction

Symptoms

Action

Mild

Pruritus

Mild rash

Headache

No respiratory distress or CVS instability

• Half current rate of infusion

• Administer IV chlorphenamine

• If symptoms persist treat as moderate reaction

Moderate

Urticaria/rash

Tachycardia

Nausea

• Stop infusion

• Call emergency 2222

• Lay patient flat and secure airway. Check vital signs

• Administer IV hydrocortisone and IV chlorphenamine

• If worsening treat as severe reaction

• Seek medical advice before restarting infusion

 

Severe

Hypotension

Respiratory - Distress/Stridor/Wheeze

Swollen lips/airways

Reduced conscious level

Reduced oxygen saturation

Flushed/pale

• Stop infusion permanently

• Call emergency 2222

• Lay patient flat and secure airway

• Give facial oxygen and monitor oxygen saturation

• Administer IM adrenaline 1:1000

• If respiratory distress administer nebulised salbutamol

• Monitor oxygen saturation, pulse, blood pressure

• Repeat adrenaline if no clinical improvement

• Patient must stay overnight and be assessed by consultant prior to discharge

 

MILD & MODERATE

Route

Drug

Age

Dose

IV

Chlorphenamine

6 months - 5 years

2.5mg by intravenous injection

IV

Chlorphenamine

6 - 11years

5mg by intravenous injection

IV

Chlorphenamine

Over 12 years

10mg by intravenous injection

These doses can be repeated if necessary with max 4 doses in 24 hours

IV

Hydrocortisone

All ages

4mg/kg (Max 200mg)

 

SEVERE

Route

Drug

Age

Dose

IM

Adrenaline (1:1000)

Under 6 years

150 micrograms (0.15ml) by IM injection*

IM

Adrenaline (1:1000)

6 -11 years

300 micrograms (0.3ml) by IM injection*

IM

Adrenaline (1:1000)

Over 12 years

500 micrograms (0.5ml) by IM injection*

*Repeat dose of adrenaline after 5 minutes if no improvement in patient’s condition

NEB

Salbutamol

Under 5years

2.5mg up to 8 times daily as required†

NEB

Salbutamol

Over 5 years

5mg up to 8 times daily as required†

†Doses may be increased up to 1 - 2 hourly in acute severe cases

Pre-infusion checklist / Infliximab infusion checklist

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Editorial Information

Last reviewed: 29/06/2021

Next review date: 28/06/2024

Author(s): Professor David Wilson, Consultant Paediatric Gastroenterologist, Kat Armstrong, GI Nurse Specialist, Professor Richard Russell, Consultant Paediatric Gastroenterologist, Dr Paul Henderson, Consultant Paediatric Gastroenterologist, Ewan Swann, Pharmacist.

Approved By: P&ND&T

Related resources

Definitions

IBD - Inflammatory bowel disease
CD – Crohn’s disease
UC – Ulcerative colitis
U & E – Urea and electrolytes
FBC – Full blood count
LFT – Liver function tests
ESR – Erythrocyte sedimentation rate
CRP – C reactive protein
HIV – Human immunodeficiency viruses
EBV – Epstein-Barr virus
CMV – Cytomegalovirus
IBDU – Inflammatory bowel disease unclassified

References
  1. Turner D et al. (2018) Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Aug; 67(2):257-291
  2. Turner D et al. Management of paediatric ulcerative colitis, Part 2: acute severe colitis; an evidence-based consensus guideline from ECCO and ESPGHAN. Journal of Pediatric Gastroenterology and Nutrition 2018; 67: 292-310.
  3. Electronic Medicines Compendium (2019). Remsima (Infliximab). Available at [https://www.medicines.org.uk/emc/medicine/29978#gref] Accessed 10/12/19.
  4. Paediatric Formulary Committee. BNF for children (2019). London:BMJ Group, Pharmaceutical Press, and RCPCH Publications http://www.medicinescomplete.com ( Accessed on 13th May 2019)
  5. Lothian Joint Formulary (2019) Gastro-Intestinal System Table. Available at [https://www.ljf.scot.nhs.uk/LothianJointFormularies/Child/1.0/Pages/default.aspx]. Accessed 10/12/19.
  6. Joint Formulary Committee. British National Formulary (Online) London: BMJ Group and Pharmaceutical Press. Available at [http://www.medicinescomplete.com]. Accessed 10/12/19.
  7. Medusa IV Monographs (2019). Infliximab. Available at [https://medusa.wales.nhs.uk/]. Accessed 10/12/19.