INFLIXIMAB PROTOCOL FOR PAEDIATRIC RHEUMATOLOGY 1. Background and indications Infliximab is a drug that blocks a key protein of all inflammatory processes called Tumour Necrosis Factor (or TNF). TNF is a signalling protein that increases the activity of cells involved in inflammation and in patients with arthritis its concentration is particularly high. It has been shown in arthritis patients that persistently high levels contribute to tissue damage. Infliximab stops TNF from binding to cells, thereby reducing inflammation. Infliximab should only be used in patients who do not respond to other treatments. Patients receiving infliximab should continue to receive methotrexate or a similar type of drug. Infliximab is not currently licensed for use in JIA or uveitis. Infliximab is NICE approved for children aged 6-17 years with severe Inflammatory Bowel disease (Crohn s and ulcerative colitis) and in adults with severe psoriasis, psoriatic arthritis, Rheumatoid arthritis and Inflammatory Bowel Disease (Crohn's and Ulcerative colitis). However it is widely used for the treatment of severe juvenile arthritis and/or refractory uveitis and in select cases of refractory Juvenile Dermatomyositis and other rare autoimmune/autoinflammatory conditions, by physicians in the UK and worldwide, with a reasonably good efficacy/ safety profile. If specific details needed, please contact the Paediatric Rheumatology team for latest evidence on this. 2. Dose and frequency The dose for infliximab given for JIA or uveitis is 6mg/kg but can go up to 10mg/kg Induction involves three doses at weeks 0, 2, and 6 For maintenance, most patients will then receive infliximab every 4-6 weeks 3. Procedures 3.1. Consent Written informed consent should be taken by a clinician at SpR or Consultant grades or equivalent, and should be filed in the medical notes. If taken at NOC, this will be scanned and filed on EPR records. 3.2. Pre-treatment tests Prior to the first infusion, all patients should have had the following (unless reason for deviation recorded by Consultant in the medical notes): TB Elispot (within the last 6 months or sooner if recent travel to a TB-endemic area) +/- CXR HIV, HBV, and HCV serologies if high risk The dates of these tests should be completed on the biologics checklist (scanned and filed in EPR records)
3.3. Cannulation and bloods on the day Cannulation is usually undertaken by one of the day ward ANPs. If they are not available it should be undertaken by a member of the medical team. Routine bloods should be sent (FBC, ESR, U&Es, LFTs, CRP) No need to wait for results prior to infusion unless abnormal results from previous admission. 3.4. Clerking Clinicians or specialist nurses trained in clerking for infliximab infusions should complete the biologics clerking form and ensure that patients are documented fit for infliximab prior to administration In the following circumstances please discuss with one of the paediatric rheumatology team as it may be necessary to withhold the infliximab. Latest blood results show: o Low blood cell count (Hb <100, platelets <150) or symptoms and signs which may include bruising, bleeding, pallor o Neutrophils < 1.5 cells x 10 9 / l o Liver Function - ALT >120 If patient has a temperature of 38 C or above. Evidence of an infection or contact with an infectious disease. The infection could be an open cut or sore, a chest infection or an infection that affects the whole body (such as the flu or chicken pox). The patient has heart failure or other heart conditions, multiple sclerosis, or Guillain- Barré syndrome, or if the patient has experienced numbness, tingling, or had a seizure. Lived in or visited an area of the country where an infection called histoplasmosis or coccidioidomycosis (an infection caused by a fungus that affects the lungs) is common. The patient has recently received any live vaccinations: o Live vaccines such as oral polio, rubella, MMR, chicken pox, BCG and yellow fever should not be given whilst patient is on infliximab. o Annual flu vaccines (IM only) are safe, recommended and should be given annually.
Infliximab SHOULD NOT BE GIVEN if the patient: Has had a severe allergic reaction to Infliximab or any other product that was made with murine (mouse) proteins. Has had TB (tuberculosis), unless suitable antibiotics are being given to treat TB, or if there has been recent contact with someone who might have TB. A CXR (+/- mantoux/elispot if considered high risk) must have been performed in all patients. 3.5. Pre-medication Prescribe IV Hydrocortisone 4 mg/kg (maximum 200mg) to be administered prior to infusion. Antihistamines should not be routinely prescribed. 3.6 Drug preparation Store in a refrigerator (2 C - 8 C). Infliximab is available in 100 mg vials Reconstitute each 100 mg vial with 10 ml water for injections. Insert the syringe needle into the vial through the centre of the rubber stopper and direct the stream of water for injections to the glass wall of the vial. Do not use the vial if the vacuum is not present. Gently swirl or slowly roll the vial until completely dissolved. Do not shake. Foaming may occur (normal). Allow the reconstituted solution to stand for 5 minutes. Solution should be yellow, opalescent and not cloudy. Calculate dose of infliximab and fluid volume to be withdrawn Dilute required dose to 250 ml in 0.9% saline Infliximab must be administered using a giving set with a low protein binding filter of 1.2 microns or less. The IV line must not be used for any other medications or fluids. 3.7. Administration rate and monitoring Impact of gradual increase in infusion rate on infusion reaction incidence has never been validated in controlled studies. Data on beneficial effect of corticosteroid co-administration are limited, and antihistamines may paradoxically increase the rate of infusion reaction. Meta-analysis showed no impact of impact of rapid infusion on incidence of infusion reactions across 10 studies comprising >8000 infusions for a variety of indications. There are limited data on safety of 1-hour protocols in PIBD, although in fact the practice may be quite common. Adult patients at the JR and NOC who are established on infliximab routinely receive infusions over 30-60 minutes. In deciding on administration duration, consult the following decision tree, the objective of which is to facilitate provision of 1-hour infusion to children established on treatment with infliximab, who have tolerated at least 4 doses, and have not had treatment interruption or infliximab hypersensitivity. [adapted from gastro protocol]
Administration Schedule A: Infusate: prescribed dose of infliximab made up to 250 ml with 0.9% saline Infuse at: 20ml/h for 15 minutes, then 60ml/h for 30 minutes, then 80ml/h for 30 minutes, then 150 ml/h for the remainder of the infusion Monitor observations every 30 minutes during the infusion. Monitor observations every 30 minutes for 120 minutes (2 hours) after completion of the infusion. Administration Schedule B: Infusate: prescribed dose of infliximab made up to 250 ml with 0.9% saline Infuse at: 100 ml/h for 15 minutes, then 300 ml/h for the remainder of the infusion Monitor observations every 30 minutes during the infusion and for 60 minutes after the infusion. If there is a history of infusion related reactions: In the presence of medical staff give an intravenous test dose of 3ml filtered medication over 15minutes. If a reaction occurs stop infusion and treat If no reaction occurs, continue as recommended infusion schedule.
4. Side effects and infusion reactions Possible side effects during the infusion Most patients do not experience side effects, but possible infusion related reactions include headache, fever, facial flushing, pruritus, myalgia, nausea, chest tightness, dyspnoea, vomiting, erythema, abdominal discomfort, shivers, hypertension, light headedness, hypotension and palpitations. For many patients these reactions resolve with slowing the infusion rate. From previous studies it has been shown that infusion reactions experienced were generally mild to moderate and they decreased in frequency with repeated dosing. Some patients have had allergic reactions 3 to 12 days after receiving Infliximab. The symptoms of this type of delayed reaction may include fever, rash, headache, and muscle or joint pain. If these symptoms or any other unusual symptoms occur the paediatric rheumatology team should be informed as well as the GP. Infusion reactions Infliximab has been associated with immediate infusion reactions. These may result from classical IgE-mediated allergy, or from immune-driven release of vasoactive mediators ( cytokine storm ). Reactions can be graded as mild, moderate or severe: Mild: pruritus; flushing; myalgia; low-grade fever Moderate: chest tightness; urticaria; hypertension; high-grade fever Severe: bronchospasm; angioedema; hypotension Management depends on severity of the reaction and is summarised in the decision tree below. If in doubt, prioritise safety at all times: stop the infusion and call for help.
Management of Infliximab infusion reactions in paediatric rheumatology
Contacts for Paediatric Rheumatology Team 1. Paediatric Rheumatology Nurse Specialists 01865 (7)37341 cnspaedrheum@ouh.nhs.uk 2. Paediatric Rheumatology consultant on-call via switchboard 3. Out of hours contact can be made with the on-call Paediatric Rheumatology consultant via switchboard References SPC for Infliximab found at www.medicines.org.uk Ruperto, N et al (2007) A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular course juvenile rheumatoid arthritis; Arthritis and Rheumatism. 26-53. Kendall,E, Inness, E, Parsons, E, Wilkinson, N (2012) Audit of Blood Monitoring for Patients receiving Biologic Therapies. Oxford Paediatric and Adolescent Rheumatology Centre. Nuffield Orthopaedic Centre. Oxford University Hospitals NHS Foundation Trust (2016) Infliximab monograph Modified from the Paediatric Gastroenterology Infliximab Protocol. Oxford Children s Hospital. OUH Trust.