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Child Health Guideline Identifier

Rheumatology - Tocilizumab (Actemra®) for Juvenile Idiopathic Arthritis

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Background

Tocilizumab is one of the biologic DMARDs (disease modifying anti-rheumatic drug) that block the action of the pro-inflammatory cytokine, interleukin-6 (IL 6). Tocilizumab is a recombinant humanized anti-human monoclonal antibody directed against the IL 6 receptor1. IL 6 has been implicated as a major cytokine involved in the pathogenesis of systemic onset Juvenile Idiopathic Arthritis (JIA). Elevated levels correlate with disease activity1 and drives CRP levels.

Clinical trials of tocilizumab in systematic and polyarticular JIA have demonstrated success in the control of symptoms with periodic infusions of this agent. It is considered when other standard treatments have failed.1,2,3

The treatment regimen usually consists of intravenous infusions every 2 weeks for systemic JIA and every 4 weeks for polyarticular JIA1. Once there is a clinical response, the interval between infusions may be increased.

Contraindications

Absolute contra-indications

  • Untreated chronic infection, such as tuberculosis
  • Any active infection or pyrexia
  • Known hypersensitivity to any component of the product

Relative contraindications/cautions

  • Chronic hepatitis B carriage
  • History of Guillain-Barré Syndrome, optic neuritis or Multiple Sclerosis
  • Pregnancy
  • Underlying conditions which predispose infection (e.g. Crohn's, diabetes)
  • Cytopenia, abnormal liver enzymes

Before treatment commences

Before starting Tocilizumab (or any other biologics), it is important to exclude possible pre-existing infections. Children should have the following:

  • TB excluded with TB quantiferon gold, Mantoux (preferred if ≤5yrs) and CXR
  • Viral serology - Measles Mumps and Rubella IgG, VZV IgG, Hep A, B, C, HIV. It is recommended that immunisations are up to date before commencing Tocilizumab if possible depending on degree of urgency and immunosuppression1Where possible any catch up immunizations should be given one month before starting Tocilizumab.
  • Medical review prior to infusion if unwell, particularly FEVER, active or suspected infection or recent exposure to infectious diseases
  • FBC and LFT results (taken the day before infusion)

Delay infusion and discuss with Consultant

  • If absolute neutrophil count <1 000/mm3
  • If platelets <50 000/mm3 (delay until count >100 000/mm3)
  • If ALT>3x upper limit normal (delay until <3x normal)

It is important that:

  • The medical team have fully discussed the treatment with the patient and/or carer and that a written patient information leaflet has been provided.
  • Responsible consultant to document discussion regarding risks/benefits of treatment (including serious risks) in full, either in patient case notes or on consent form.

On admission and prior to Tocilizumab infusion

  1. Check the patient and family have no outstanding questions regarding the infusion
  2. Check a rheumatologist is available on call during infusion
  3. Check that Tocilizumab and pre-medications are charted as per dosing outlined below.
  4. Check that adrenaline is charted - see anaphylaxis guideline for recommended adrenaline dosing
  5. Obtain the following:
    1. Baseline temperature, pulse rate, blood pressure and respiratory rate
    2. Height and weight
    3. IV access
    4. Blood tests if not done the day before (FBC, electrolytes, urea, creatinine, LFTs, ESR, CRP, ferritin. For ongoing monitoring ESR preferable to CRP)
    5. History of any recent infections (colds, URTIs, fevers), exposure to infectious diseases such as chicken pox or measles
    6. Medical admission and review
  6. Delay infusion if:
    1. Patient is febrile and/or infection is present, especially if severe infection is suspected - discuss with Fellow or Consultant as infusion should be postponed for at least a week.
    2. Absolute neutrophil count <1 000/mm3
    3. If platelets <50 000/mm3 (delay until count >100 000/mm3)
    4. ALT>3x upper limit normal (delay until <3x normal)

Pre-medication prior to Tocilizumab infusion

Pre-medication (oral, give 30-60mins before infusion)

  1. Loratadine or cetirizine
      1-2 years <30kg ≥30kg
    Loratidine (daily) 2.5mg 5mg 10mg
       <2 years  2-6 years  6-12 years  >12 years
    Cetirizine (twice daily*)  0.25mg/kg/dose  2.5mg  5mg  10mg
    *dose may be repeated in the event of a reaction    
  2. Paracetamol 15mg/kg/dose (maximum dose is 60mg/kg/day, or 4grams/day)

Tocilizumab dosage

This is a hazardous medicine. Please ensure you follow your local policy with regards to protection when preparing and administering it

For systemic onset JIA patients

  • Patients < 30kg, tocilizumab dose is 12mg/kg/dose every 2 weeks (unless already has response to previous dose)
  • Patients ≥ 30kg, tocilizumab dose is 8mg/kg/dose every 2 weeks

For polyarticular JIA patients

  • Patients < 30kg, tocilizumab dose is 10mg/kg/dose every 4 weeks
  • Patients ≥ 30kg, tocilizumab dose is 8mg/kg/dose every 4 weeks

Preparation

Tocilizumab is ordered from Pharmacy at least 24 hours before the infusion. Tocilizumab is available in 80mg/4ml and 200mg/10ml vials.

  • Dilution:
    • For patients <30kg, dilute to 50ml with 0.9% saline solution
    • For patients ≥30kg, dilute to 100mls with 0.9% saline solution
  • The prepared solution can be stored for up to 24 hours prior to infusion, in the refrigerator (2-8 degrees C).
  • The solution may be stored at room temperature for a maximum of 6 hours prior to administration of the infusion.
  • All infusions must be administered at room temperature over one hour. Infusions that have to be interrupted for safety reasons should be completed over a maximum of 6 hours.

Prescribing Quick Reference Table

Tocilizumab <30kg >30kg
Dose Systemic JIA 12mg/kg/dose 8mg/kg/dose
Polyarticular JIA 10mg/kg/dose 8mg/kg/dose
Total Volume   50ml 100ml
Flush   Volume needed to clear giving set
Rate  1st 10mins 10ml/hr 10ml/hr
Thereafter Calculate rate required to complete total volume over ONE hour
Premedication 1-2yrs <30kg
≥30kg
Loratadine Once daily dosing 2.5mg 5mg 10mg
Cetirizine Twice daily dosing 0.25mg/kg/dose 2-6yr 6-12yr >12yr
2.5mg 5mg 10mg

Administration

Administer intravenously at room temperature by controlled infusion over ONE hour as follows:

Observations during infusion

  1. Pulse and BP every 15 minutes for the first hour and then every 30 minutes thereafter
  2. Temperature every hour
  3. The patient should remain in unit/ward for at least 1 hour post infusion as delayed reactions can occur (NB: for first infusion observe for 2 hours post infusion)

Adverse reactions

Allergic reactions have been reported with tocilizumab infusions

If an anaphylactic reaction occurs (ie significant respiratory or haemodynamic instability), stop infusion and call 777. See  Starship Analphylaxis Clinical Guideline

If a reaction occurs, STOP the infusion until medical review.

Reported symptoms of allergic reactions to Tocilizumab include:

  • Hypo/hypertension
  • Shortness of breath/wheezing
  • Chest/abdominal pain
  • Fevers/chills
  • Headache/dizziness
  • Pruritis/urticaria

If the patient has any of the signs and symptoms above and remains haemodynamically stable and maintains normal respiratory function:

  • The infusion rate must be slowed down (at least halved) and the infusion time extended.
  • If the patient continues to display signs and symptoms of hypersensitivity, an oral dose of antihistamine must be administered.

Other mild adverse reactions

  • Skin rashes - usually reported 24-48 hours after the second or third infusion, and can last several days before resolving. Usually managed with antihistamine.
  • Conjunctivitis
  • Abdominal pain (an increased risk of lower intestinal bowel perforations have been reported in small, adult case studies4)
  • Non-specific headaches
  • Temporary changes to WCC and ALT results

Discharge Planning

Rebook for next infusion in two - four weeks, depending on regimen. Ensure family have a blood test form to use the day prior to the next booked infusion date.

Patients and families should be reminded to avoid contact with infections and to notify the rheumatology service if there is a known or suspected chickenpox or measles contact.

Live vaccines and live attenuated vaccines are contraindicated for patients on Tocilizumab. An annual influenza vaccine is not a live vaccine and is recommended.

Review and Follow up

  • Rheumatology review at each infusion visit with documentation of core set variables, any side effects and systemic symptoms for systemic JIA.
  • Clinic review at minimum of 6 monthly intervals.
  • When there is loss of effect after a clear initial response to tocilizumab, then the patient should be evaluated and if dose is optimal, then other treatment options should be considered.

Family Information


References

  1. Medsafe NZ. Medsafe. Medsafe Datasheets. [Online] 14 October 2014. [Cited: 20 October 2016.] http://www.medsafe.govt.nz/profs/datasheet/a/Actemrainf.pdf.
  2. Schoels M, van der Heijde D, Breedveld, F et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systemic literature review and meta-analysis forming a concensus statement. Ann Rheum Dis. 2013, Vol. 72.
  3. Brunner H, Ruperto N, Zuper Z et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile ideopathic arthritis: results from a phase 3, ranomised, double blind withdrawal trial. Ann Rheum Dis. 2015;74:1110-1117
  4. .Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Strangefield A, Richter A, Siegmund B, et al. s.l. : Ann Rheum Dis, 2017, Vols. 76:504-510. 
  5. ADHB policy for cytotoxic and hazardous medicine administration

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Document Control

  • Date first published: 07 June 2017
  • Date last published: 07 June 2017
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Rheumatology
  • Author(s): Jackie Yan, Rebecca Dean, Rosalie Olding
  • Owner: Paediatric Rheumatology
  • Editor: Greg Williams
  • Review frequency: 2 years

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