Tocilizumab Protocol for SPARN

TITLE Guideline on the use of Tocilizumab for Rheumatology Patients

Responsibility: Last Update: Review Date: Medical and nursing staff within Feb 2014 the Paediatric Rheumatology Teams.

Nursing staff within the Ambulatory Day Investigation Unit and inpatient areas

Statement: Children and young people requiring Tocilizumab as identified by medical staff will have their treatment undertaken using this guideline and following the pathways identified below.

Contents: 1. Tocilizumab over view 2. Indications for use – Rheumatology 3. Pre-treatment 4. Dosage and administration 5. Patient Monitoring 6. Precautions 7. Speciality specifics

1) Tocilizumab over view IL-6 is a pro inflammatory cytokine produced by a number of cells including T and B cells. Tocilizumab is an IL-6 receptor inhibitor and binds to soluble and membrane bound IL-6 receptors inhibiting the inflammatory response. It is increasingly being used to treat a number of autoimmune disorders including Systemic onset Juvenile Idiopathic Arthitis (SoJIA) and Polyarticular Juvenile Idiopathic Arthritis (pJIA).

2) Indications for use - Rheumatology 2.1 SoJIA: Tocilizumab is licensed for children with SoJIA over 2 years of age, who have responded inadequately to steroids and NSAID’s. It can be given with or without methotrexate (MTX). It has Scottish Medicines Consortium (SMC) approval for SoJIA. 2.2 Polyarticular JIA: Tocilizumab is licensed and SMC approved for the treatment of children over 2 years of age with pJIA who have

www.sparn.scot.nhs.uk Review date – February 2016 responded inadequately to methotrexate therapy. It can be used in combination with Methotrexate or as monotherapy. 2.3 Other paediatric inflammatory conditions. There are case reports of Tocilizumab successfully being used to treat a number of other paediatric inflammatory conditions including Takayasus Arteritis, autoinflammatory conditions and uveitis. Tocilizumab is not currently labelled for use in these conditions.

3) Pre treatment 3.1 Nurse specialist will give patient information leaflet to patient and/or carer 3.2 Consultant will document full discussion regarding risks/benefits of treatment in the patients case notes. 3.3 Ensure no contraindications to use of tocilizumab: 3.3.1 These include a history of hypersensitivity to tocilizumab; active infection including TB; pregnancy 3.3.2 Relative contraindications include previous TB; previous or FH demyelinating disease; previous malignancy 3.4 Patients should be given a Rheumatology Drug and blood monitoring booklet, ensure the booklet has a Tocilizumab information card. 3.5 Take and record a weight & Height. 3.6 Review immunisation history 3.7 Direct questioning about recent/current infections 3.8 Tuberculosis testing – Interferon-Gamma Release Assay (IGRA) prior to first dose, (if from a high risk group and the test is over a year old, consider a repeat test), TB testing to be discussed at local level IGRA testing (T-spot, Elispot and Quantiferon TB Gold) is the preferred test although chest xray and Mantoux (Tuberculin Sensitivity Test, Pirquet test, or PPD test for Purified Protein Derivative) may be a suitable substitute if IGRA not available. 3.9 Baseline bloods: Full Blood Count (FBC), Erythrocyte Sedimentation Rate(ESR)(if availble), Urea & Electrolytes(U&E), Amylase, Liver Function Tests(LFT), C-Reactive Protein(CRP) & Varicella Zoster Titre (if not already available), anti-nuclear antibodies (ANA), double stranded DNA & lipids. For SoJIA a serum ferritin and an Amyloid level are also required. 3.10 Record core outcome data for JIA patients 3.11 Record base line activity data for other conditions eg Uveitis. 3.12 Pre-treatment checklist completed by rheumatology team 3.13 If your Hospital takes part in the Biologics for Children with Rheumatic Diseases study (BCRD), Patients should be given information on this. The Study team should be made aware that the patient is commencing Tocilizumab.

www.sparn.scot.nhs.uk Review date – February 2016 4) Dosage 4.1 SoJIA: for patients weighing below 30kg, 12mg/kg is administered every two weeks. In patients whose weight is 30kg or above, 8mg per kg is given every two weeks. When good disease control is achieved the interval between doses may be increased to every three or four weeks depending on response. If significant neutropenia (<1.0 x10^9/L) occurs either the total dose or frequency may be decreased at the prescribing consultants discretion. 4.2 Polyarticular JIA : for patients weighing below 30kg, 10mg/kg is administered every four weeks. In patients whose weight is 30kg or above, 8mg per kg is given every four weeks. If significant neutropenia (<1.0 x10^9/L) occurs the dose may be decreased at the prescribing consultants discretion. 4.3 Other conditions: The dose to be used will be chosen by the prescribing Consultant but will be within the above parameters.

5) Prior to each infusion 5.1 Tocilizumab should not be given to patients who have a febrile illness caused by an active infection. If there are any signs of present or recent infections please consult with the relevant Paediatric Rheumatology team before administering the infusion. (In the case of SoJIA Pyrexia may be due to the disease process rather than infection). 5.2 Possible pregnancy must be considered and pregnancy test undertaken if appropriate 5.3 If the child or young person has had a previous severe reaction to Tocilizumab infusion, Tocilizumab should not be given again. 5.4 The child or young person should be weighed at least 3 monthly and dose adjusted accordingly. 5.5 Record baseline TPR and BP 5.6 Check previous blood results. If there are any abnormalities discuss this with the Paediatric Rheumatology team before administering the infusion. If the Patient has had previous Neutropenia with Tocilizumab (<1.0 x10^9/L), bloods should be obtained, and reviewed prior to commencing infusion (these bloods can be taken up to 48 hours prior to infusion) 5.7 At every infusion, ESR (if availble), FBC, CRP, LFT, U&E should be obtained. 5.8 Cholesterol and triglyceride levels should be checked every 3 months. 5.9 For patients with SoJIA a serum Ferritin should be checked every 3 months. 5.10 For any patient whose baseline serum amyloid level was raised, a repeat level should be obtained every 3 months. 5.11 Ongoing blood monitoring sheet & checklist should be completed by a Paediatric Rheumaotology team member.

www.sparn.scot.nhs.uk Review date – February 2016 5.12 Prior to the infusion, inform the patient of small risk of potential hypersensitivity reactions. They can range from mild to severe. • Mild to moderate reactions include: —Hypertension —Headache —Skin reactions, such as rash, pruritus and urticaria —Epigastic discomfort —Arthralgia —loose stools • Severe reactions are rare. Anaphylaxis is reported at 0.2% with doses of 8mg/kg

6) Infusion preparation; 6.1 Ensure child is fit to receive infusion and cannula is in situ prior to making up Tocilizumab (Tocilizumab is very expensive and should not be wasted) 6.2 Confirm the dose required according to the patient’s body weight (see note above) Check to see if patient has been prescribed any pre- treatment medication 6.3 Items needed; Tocilizumab (Tocilizumab is available in 80mgs (4mls), 200mgs (10mls) and 400mgs (20mls) vials each containing 20mgs/ml Tocilizumab), Syringes and needles, 2x 100ml 0.9% NaCl IV bags (if patient under 30kg 2 x 50ml bags of 0.9% NaCl), infusion set & alcohol wipes. 6.4 Tocilizumab is a ready-mix solution and requires no reconstitution. Tocilizumab vials require refrigeration. This concentrate for IV infusion should be diluted to 100 mL as per local hospital aseptic protocol. The made up bags can be stored refrigerated and protected from light for up to 24 hours, however, the made up solution should be administered at room temperature. 6.5 Manufactures guidelines state that the ml volume of Tocilizumab which is to be added to Infusion bags should be withdrawn prior to adding Tocilizumab (i.e. if you are adding 10mls of Tocilizumab, you should remove 10ml of saline from the bag before you add the Tocilizumab) 6.6 To mix the solution, gently invert the bag to avoid foaming 6.7 Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Only solutions which are clear to opalescent, colourless to pale yellow and free of visible particles should be diluted. 6.8 Dispose of needle and syringe in sharps containers when finished 6.9 Tocilizumab should not be infused concomitantly in the same IV line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Tocilizumab with other drugs.

www.sparn.scot.nhs.uk Review date – February 2016 7) Administration of Tocilizumab and Patient monitoring 7.1 Ensure oxygen and suction are working at the patients’ bedside. 7.2 Tocilizumab should be administered in a unit with the facility to deal with potential infusion reactions. 7.3 Patients require only pre and post infusion TPR observations. 7.4 The infusion should be administered over 1 hour. It must be administered with an infusion set and should never be administered as an IV push or bolus. 7.5 Once the infusion is completed, remove the IVC and dispose of all supplies as per hospital protocol. The patients TPR should be checked prior to discharge 7.6 Report any adverse reaction using the ‘yellow card’ system.

8) Precautions 8.1 If the patient is unwell on presentation, a review by a Paediatric Rheumatology Team member or local physician should occur prior to commencing the infusion. 8.2 Tocilizumab works by blocking the effects of IL6. This may result in patients being unable to produce a fever or rise in CRP in response to infections. From clinical experience; the full blood count, ESR and CRP may be normal even in the face of severe infection. These patients are at increased risk of serious bacterial infection due to immunosuppression and must be assessed urgently by a senior physician if they appear unwell.

Supporting Literature

1.De Benedetti et al.(2012) Randomized Trial of Tocilizumab in Systemic Juvenile Idiopathic Arthritis. N Engl J Med 2012; 367:2385-2395. Dec. 2012

2. National Institute for Clinical Excellence. NICE Technology Appraisal guidance 238: Arthritis (juvenile idiopathic, systemic) - tocilizumab http://guidance.nice.org.uk/TA238

3. Imagawa et al. ‘Safety and efficacy of Tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis’ Modern Rheumatology vol.10.1007. 2011

4. De Benedetti et al. PReS-FINAL-2180: Efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA): 2- year data from CHERISH. Pediatric Rheumatology 2013, 11, (Suppl 2):O15

5. Royal College of Nursing (2009) ‘Assessing, managing and monitoring biologic therapies for inflammatory arthritis – guidance for rheumatology practitioners’ London

www.sparn.scot.nhs.uk Review date – February 2016 6. Scottish Medicines Consortium: http://www.scottishmedicines.org.uk/SMC_Advice/Advice/930_13_tocilizumab_R oActemra_ABBREVIATED/tocilizumab_RoActerma

Authors: Drew Fell, CNS Rheumatology NHS GG&C Joyce Davidson Consultant Rheumatologist NHS GG&C Gillian Coyle CNS Rheumatology NHS GG&C Imogen Kelly CNS Rheumatology NHS Lothian Vanessa lewis CNS rheumatology NHS Lothian Karen Mcintyre CNS Rheumatology NHS Tayside Alison Ross CNS Rheumatology, NHS Grampian Neil Martin Consultant Rheumatologist NHS GG&C

On behalf of Scottish Paediatric and Adolescent Rheumatology Network

Created: February 2014 Review date:

www.sparn.scot.nhs.uk Review date – February 2016