IV Infliximab infusion protocol
Infliximab is one of a group of anti-inflammatory agents that work by blocking the action of the pro-inflammatory cytokine, Tissue Necrosis Factor-alpha (TNF-α).
Background
Infliximab is one of a group of anti-inflammatory agents that work by blocking the action of the pro-inflammatory cytokine, Tissue Necrosis Factor-alpha (TNF-α). TNF-α is a signalling protein that increases the activity of cells involved in inflammation and infliximab stops TNF-α from binding to cells, thereby reducing inflammation.
Indications for use
Infliximab is available for prescription via Special Authority if patient fulfils recognised indications (see https://schedule.pharmac.govt.nz/2022/08/01/SA2082.pdf)
Gastroenterology
Infliximab is used for treatment of patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy and for patients with fistulising Crohn’s disease. It is also used in patients with severe ulcerative colitis (UC), either as “rescue therapy” in acute severe colitis to avoid the need for colectomy or for disease refractory to immunomodulatory therapy.
Qualification for infliximab therapy requires demonstration of active disease. Endoscopic and/or radiological reassessment of disease should be carried out no more than 3 months prior to commencing infliximab in order to confirm disease activity.
Rheumatology
Infliximab is used in the treatment of a number of rheumatological conditions, including Juvenile Idiopathic Arthritis, Uveitis, Juvenile Dermatomyositis and vasculitides. In patients with active disease, TNF-α level is elevated. In arthritis patients, a persistently high TNF-α level contributes to tissue damage. Infliximab is used in patients who do not respond to standard treatments.
Absolute contraindications to use
untreated chronic infection, such as tuberculosis (TB)
presence of undrained abscesses (including perianal)
patients with moderate to severe congestive heart failure
known hypersensitivity/anaphylaxis to murine proteins or any other component of the product
Cautions/relative contraindications to use
chronic hepatitis B carriage
history of Guillain-Barré Syndrome, optic neuritis or Multiple Sclerosis
pregnancy
stricturing disease
intercurrent febrile illness (see below)
Pre-treatment
Once the decision has been made that a patient requires infliximab, this must be fully discussed with the patient and/or caregiver. A written patient information leaflet should be provided and the patient and/or caregiver given the opportunity to discuss the treatment with the medical team.
Responsible consultant (or Paediatric Rheumatology Nurse Specialist) to document discussion regarding risks/benefits of treatment (including serious risks) in full in patient case notes.
Direct questioning is required re:
recent/current infections
personal/family history and/or risk factors for TB
personal/family history of Guillain-Barré Syndrome, optic neuritis or Multiple Sclerosis
possibility of pregnancy and advice re use of contraception during treatment
Before commencing infliximab, it is important to exclude the possibility of TB. See https://starship.org.nz/guidelines/immunosuppression-infection-and-immunisation-in-rheumatology/#screening-prior-to-immunosuppressive-therapy for details of tests needed.
Further pre-treatment investigations:
FBC, ESR
U&E, LFT, albumin, CRP
ANA, dsDNA (if not performed within previous 3 months)
Varicella Zoster serology (unless previously documented as immune)
Measles serology (unless perviously documented as immune)
Hep B serology (HBsAg, AntiHBcAb, Anti-HBsAb)
Consider Hepatitis A serology (and immunisation if non-immune)
Hepatitis C serology
Urinalysis
Consider pregnancy testing in females of childbearing age.
Gastroenterology patients: document disease activity scores at baseline
PCDAI (Crohn’s patients)
PUCAI (ulcerative colitis patients)
Rheumatology patients: Baseline assessment with relevant disease activity score
cJADAS 10 for JIA
Consider CHAQ and full therapy assessment
On admission and prior to each infusion
Prior to each infusion, interval symptoms should be enquired about.
Ask about recent infections (colds, URTIs, fevers etc). If these are present, discuss with responsible Consultant prior to commencing infusion. It may be prudent to defer the infusion for a week to allow recovery from the infection.
Patient should be weighed at each admission and prescription amended to account for significant change (please discuss changes with consultant)
Nurse to take baseline TPR, BP and facilitate IV access.
Obtain bloods for FBC, ESR, CRP, Electrolytes, U and Cr, LFT's, Albumin.
Medical review, particularly if patient febrile
Dosage and Administration
Regimen
Gastroenterology
Induction therapy
The induction regimen consists of infusions at 0, 2 and 6 weeks.Maintenance therapy
Clinical review should be carried out 4-6 weeks after the third induction dose in order to determine if:maintenance therapy is appropriate
8 weekly maintenance infusions should be continued if appropriate.
Rheumatology
Induction therapy
The treatment regimen usually consists of intravenous infusions at 0, 2 and 6 weeks.Maintenance therapy
Subsequent infusions are given 4, 6 or 8 weekly thereafter, depending on clinical response. The exact regimen will be decided by the Rheumatology Consultant. For Ophthalmology patients, this decision will depend on disease control and the need for systemic and/or topical steroids.Treatment with other DMARDs like methotrexate, unless not tolerated, is usually continued along with infliximab.
Infusion
The infliximab dose is usually 5 mg/kg IV (dose range 3-10 mg/kg). Any variation from standard dosage should be under advice from the responsible Consultant.
Dilute infliximab in 250 mL of 0.9% normal saline.
Infuse using intravenous giving set with an in-line low protein-binding filter pore (1.2 microns or less)
When reconstituting medicine DO NOT SHAKE THE VIAL. A swirling action can be used.
First four infusions:
Infuse over 2 hours unless otherwise stated and documented by medical staff
The patient must remain on the ward for 2 hours post-infusion for observation, as delayed reactions to the drug can occur.
Subsequent infusions:
Infuse over 1 hour if no previous infusion reaction unless otherwise stated and documented by medical staff
The patient must remain on the ward for one hour post-infusion for observation
Flush line with 0.9% sodium chloride to complete infusion
Note: No premed is required unless there has previously been an infusion reaction (see below)
Chart IM adrenaline and antihistamines in PRN section of prescription chart, as per anaphylaxis guidelines
IM adrenaline 0.01 mL/kg of 1:1,000 (minimum dose 0.1 mL, maximum dose 0.5 mL)
Cetirizine/loratadine dose 0.5 mg/kg PO (max 25 mg)
Patient monitoring
Temperature, Pulse, Respiratory rate and BP as follows:
At baseline
¼ hourly for 1 hour
½ hourly thereafter until one hour post-infusion
Observe for signs of adverse drug reaction - see below
Observations during infusion
Pulse and BP every 15 minutes for the first hour and then every 30 minutes thereafter
Temperature every hour
As above, for first 4 infusions, the patient should remain in unit/ward for 2 hours post–infusion, as delayed reactions can occur. If no infusion-related reactions with first 4 infusions, observe for 1 hour post-infusion.
Infusion-related reactions
(see also management flow chart below)
Infliximab has been associated with acute infusion-related reactions including anaphylaxis and delayed hypersensitivity reactions. Routine use of premedication has not been demonstrated to reduce the frequency or severity of infusion reactions, though this should be considered in patients who have previously experienced an infusion reaction (see below).
Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available.
Signs and symptoms of infusion-related reactions
Approximately 5% of infliximab infusions are accompanied by acute reactions and these can be classified as mild, moderate and severe with 3.1% of these being reported as mild and 1% as severe:
1% are characterised by urticaria, pruritis, fever and/or chills.
1% are severe reactions and are characterised by chest pain, hypotension, hypertension and/or shortness of breath.
Delayed reactions occurred in approximately 1% of infusions, i.e. rash, fever, polyarthalgia, headaches and sore throat (Cheifetz et al 2003).
Potential infusion-related symptoms:
hypotension
fever/chills
chest/abdominal pain
pruritis/urticaria
shortness of breath/cough/wheeze/stridor
Reduced level of consciousness
Nausea and vomiting
If a reaction occurs, stop infusion and obtain medical review. Further antihistamines/steroids may need to be given.
Severe infusion reaction/anaphylaxis
Symptoms/Signs: Hypotension, respiratory distress, persistent cough or wheeze, swelling / tightness in throat, difficulty talking or change in voice, reduced or lost consciousness, reduced oxygen saturations, flushed or pale appearance.
Action: If an anaphylactic reaction occurs, STOP infusion, lay patient flat and immediately call 777. Refer to flow chart below for further management.
Moderate hypersensitivity reaction
Symptoms/Signs: Urticaria/rash, mild hypertension, tachycardia, mild wheeze, nausea
Action:
STOP infusion immediately
Lay patient flat and maintain airway
Obtain medical review
Administer cetirizine/loratadine and IV hydrocortisone (see below for doses)
Check vital signs and oxygen saturation
Medical decision to restart infusion, if symptoms resolve
Seek further medical advice - if reaction continuing/worsening treat as severe reaction.
Admit for overnight assessment
Discharge following medical review, if well.
Mild hypersensitivity reaction
Symptoms/Signs: mild rash, pruritus, headaches, pyrexia
Action:
STOP infusion immediately
Obtain medical review
Administer cetirizine/loratadine for rash or itch, and/or paracetamol for headache or pyrexia (see below for doses).
If symptoms resolve, restart infusion rate after 30 minutes at halved rate.
If symptoms persist or recur after restarting infusion, STOP infusion and administer 4 mg IV hydrocortisone (max 200 mg) and a further cetirizine/loratadine dose 0.5 mg/kg PO (max 25 mg) and treat as a moderate reaction.
If improvement, continue with infusion at the halved rate and monitor closely for any further signs of hypersensitivity.
Patients can be discharged after 2 hours post-infusion, provided there are no further signs of hypersensitivity.
Instruct patient to report any further reaction on discharge immediately by contacting Daystay Unit or Children's Emergency Department (after 7pm).
Infusion reaction management flow chart
If previous infusion reaction
Pre-medication
Loratadine or cetirizine (oral) - dose 0.5 mg/kg (max 25 mg). Give 30 - 60 minutes prior to the infusion.
Loratadine/cetirizine dose may be repeated in the event of a reaction
Paracetamol (oral) 15 mg/kg/dose (maximum dose is 60 mg/kg/day or 4 grams/day): give 15 - 30 mins before infusion
Hydrocortisone (IV) 4mg/kg (max 200 mg): give 15 - 30 minutes prior to infusion
Review and follow-up
Gastroenterology
Patients on maintenance infliximab therapy should be reviewed a minimum of 6 monthly by the relevant Consultant. Exit strategy or on-going management plan documented in medical notes at each Consultant review.
Co-immunosuppression with a thiopurine or Methotrexate will normally be given in conjunction with infliximab.
When there is loss of effect after a clear initial response to infliximab, several strategies have been employed (see below). These decisions need to be taken on an individual patient basis by the Gastroenterology Consultant responsible for care.
Rheumatology
Patients on maintenance infliximab therapy should be reviewed a minimum of every 6 months by the relevant Consultant with the exception of Ophthalmology patients who should be reviewed at least annually.
Therapeutic drug monitoring
The precise role of therapeutic drug monitoring in use of infliximab remains to be determined. However, it is recognised that trough concentrations below 7 mg/L are associated with reduced control of luminal inflammation in inflammatory bowel disease (Barclay et al. Proc. NZ Soc. Gastroenterology ASM, 2014). Higher trough levels (>12 mg/L) may be required for optimal management of fistulising disease.
If there is clinical or biochemical evidence of loss of response to infliximab, assessment should include:
exclusion of non-inflammatory pathology (eg infection, stricturing disease, functional diagnoses)
Assessment of adherence to concomitant medical therapy
Measurement of Infliximab levels +/- antibodies
Management strategies for loss of response
Low infliximab levels without antibody formation – consider increasing infliximab dose and/or decreasing the dosing interval (see above).
Low infliximab levels and high titre neutralising antibodies (ADA) - this is likely to indicate a permanent loss of response to infliximab. Consider switch to alternate biological therapy, an alternate medication with a different mechanism of action and/or role for surgical intervention.
Patients who experience loss of response to one anti-TNF agent due to ADA formation are at greater risk of developing ADA to an alternate anti-TNF drug. Ensuring that these patients remain on a concomitant immunomodulator with good adherence may mitigate this risk.
Low infliximab levels with low titre or non-neutralising antibodies – this antibody response may be overcome by increasing dose and/or decreasing the dosing interval. Consider temporary increase in dose to 10 mg/kg for three infusions, then reassess clinically and repeat drug levels. Ensure adherence to concomitant immunomodulatory drug.
