Hospital inpatients: Tocilizumab and Sarilumab (COVID-19)

What's New

20.07.2022

Please note: Due to concerns over the efficacy of sotrovimab against the current circulating Omicron variants of SARS-CoV-2 (BA.2 and others), sotrovimab is not currently being offered routinely.  Please discuss any individual patient requirements with one of the Infectious Diseases consultants.

NHS Highland Guidance on use of interleukin-6 inhibitors (tocilizumab or sarilumab) for adult hospital in-patients with confirmed SARS-CoV-2 infection

(based on CEM/CMO/2021/016 interim clinical commissioning policy published 12th September 2021)

NOTE:   this is an unlicensed indication for tocilizumab and sarilumab – prescriber takes full responsibility for use

Tocilizumab and sarilumab are  monoclonal antibodies that bind to the receptor for IL-6, blocking IL-6 signalling and reducing inflammation. 

Tocilizumab is licensed for use in patients with rheumatoid arthritis and for use in patients aged at least 2 years with chimeric antigen receptor (CAR) T-cell induced or life-threatening cytokine release syndrome.

Sarilumab is licensed for use in combination with methotrexate (MTX) for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs).

Severe COVID-19 is associated with a hyper-inflammatory state with elevated ESR, C-reactive protein, D-dimers, lactate dehydrogenase, ferritin and increased levels of pro-inflammatory cytokines including IL-1 and IL-6.  There have been published and unpublished (pre-print) case series reports of the successful treatment of COVID-19 patients with IL-6 inhibitors. 

A single UK Interim Clinical Commissioning Policy has now been published, recommending that equal consideration is given to two potential interleukin-6 (IL-6) inhibitor treatment options - tocilizumab or sarilumab - for adult patients (aged 18 years and older) hospitalised due to COVID-19 in accordance with the agreed criteria. The combined policy replaces previous separately published policies for sarilumab and tocilizumab respectively. The policy takes into account evidence from the RECOVERY and REMAP-CAP trials, a rapid evidence review undertaken by the National Institute for Health and Care Excellence (NICE), updated guidelines (July 2021) from the World Health Organization (WHO) and currently available supplies of both medicines as a treatment for COVID-19 and other existing (routine) indications.

NB: Sarilumab should only be used when tocilizumab is unavailable due to supply disruption

Criteria for use

CRITERIA FOR USING TOCILIZUMAB OR SAILUMAB (INTRAVENOUS)
NB must meet ALL criteria

  • Adults aged 18 or over
  • COVID-19 infection confirmed or suspected using clinical and/or radiological information
  • Admitted for treatment of COVID-19 pneumonia
  • Have not received tocilizumab or sarilumab during this admission
  • Already be receiving steroid as per current recommendations  (dexamethasone or equivalent) unless contra-indicated 
  • AND
    • Hypoxemia with a measured CRP of 75mg/L or more AND oxygen saturation of less than 94% (see local NHS Highland oxygen policy) or on low flow oxygen
  • OR 
    • Within 48 hours of commencing additional respiratory support defined as high flow nasal oxygen, continuous positive airway pressure (CPAP) or non-invasive ventilation or invasive ventilation.

Note: therapy with tocilizumab or sarilumab should be considered within 24 hours of meeting the inclusion criteria.

Exclusion criteria
  • Known hypersensitivity to tocilizumab or sarilumab
  • Administration of another interleukin-6 inhibitor during this admission
  • Sarilumab only: Baseline platelet count of less than 150 x 109/L

 

Cautions

CAUTIONS (from SmPC) Tocilizumab Sarilumab:

  • Clear evidence of active bacterial, fungal, viral (other than COVID-19) or other infection that might be worsened by IL-6 inhibitor therapy.
  • Baseline ALT or AST levels at 5 times the upper limit of normal.
  • Pre-existing condition or treatment resulting in ongoing immunosuppression
  • Current neutropaenia or thrombocytopaenia

Pregnancy and breast feeding are not contra-indications but tocilizumab and sarilumab should not be used during pregnancy unless clinically necessary.  Follow the Royal College of Obstetrics and Gynaecology guidance on coronavirus (COVID-19) infection and pregnancy.  Women of child-bearing potential should be advised to use effective contraception for 3 months after treatment.

See manufacturer’s summary of product characteristics (tocilizumab or sarilumab) for more information, section 4.6. 

Tocilizumab use in children remains part of the ongoing RECOVERY trial at this time.

Approved prescribers

Due to the unlicensed status of tocilizumab and sarilumab in the treatment of COVID-19, prescribing is restricted to the consultant caring for the patient that day, who takes full responsibility.

Dosing schedule

Tocilizumab 

Dose is 8mg/kg as an intravenous infusion with a maximum dose of 800mg.  A second dose should not be considered due to uncertainty of additional benefit and to maximise available supply.

Use the dosing table below as per RECOVERY trial.  

  • Dilute the required dose in 100mL of sodium chloride 0.9%
  • Give over one hour at the following rate:
    • 10mL/hour for 15 minutes.
    • 130mL/hour for the remaining 45 minutes.

 Weight*

Dose

>40 and ≤65 kg

400mg

>65 and ≤90 kg

600mg

>90kg

800mg

*For lower weights, dosing should be 8mg/kg rounded to the nearest 20mg

 

Sarilumab

Dose is 400mg as a once only intravenous infusion.  Use 2 x 200mg pre-filled syringes to make the 400mg dose.

  • Allow the pre-filled syringes to come to room temperature.
  • Inject the contents of the two syringes into a 100mL sodium chloride 0.9% infusion bag (dose volume = 2.3mL). 
  • Invert bag at least 10 times to ensure through mixing.
  • Use ONLY B Braun semi-rigid 100mL sodium chloride 0.9% bags to prepare sarilumab as the pre-filled syringe needle may not be long enough to pierce the injection port of the Baxter Viaflex bags.
    B Braun sodium chloride 0.9% bags will be kept in stock specifically for administration of sarilumab.
  • Sarilumab must be administered using a volumetric pump and given over 1 hour, via a 0.2 micron low-protein binding filter (PALL AEF1) which are kept in stock in ICU1.
  • Give at the following rate:
    • 10mL/hour for 15 minutes.
    • 130mL/hour for the remaining 45 minutes.

Compatibility for either drug with other IV medication is not known – do not co-infuse with other intravenous medication using the same IV line.  Flush well with sodium chloride 0.9% after the dose has been given.

Co-administration with other COVID-19 treatments

There is no interaction expected between tocilizumab or sarilumab and dexamethasone, hydrocortisone or remdesivir.  For further information, please visit the University of Liverpool COVID-19 Drug Interactions website (https://www.covid-19-druginteractions.org/checker).

Safety reporting

As both drugs are currently unlicensed for treating COVID-19 infection, any suspected adverse drug reactions (ADRs) for patients receiving tocilizumab or sarilumab for this indication should be reported directly to the MHRA via the new dedicated COVID-19 Yellow Card reporting site at: https://coronavirus-yellowcard.mhra.gov.uk/

Handover in hospital and discharge information for GP to be added to the IDL

Tocilizumab and sarilumab can cause immunosuppression that renders patients at risk of bacterial and fungal infections. Low clinical threshold for identification and management of infection must be used.  CRP level may be a less reliable marker of active infection and procalcitonin may be negative. All handovers of clinical care (including between hospitals if patients are transferred, between levels of care and clinical teams within hospitals, and between hospitals and primary care) must explicitly mention that an IL-6 inhibitor has been given and the date of administration. Clinicians must ensure the GP is aware the patient has received an IL-6 inhibitor and provide information to the patient to such effect.

The following standard text should be added to the hospital discharge letter:

**** Your patient received tocilizumab/sarilumab on../../.. Immune function will be suppressed for the next 3 months.  Clinical assessment is required to diagnose and manage infection as inflammatory markers will be unreliable ****

Clinical Outcome reporting

The Deputy Chief Medical Officer recommends that data on all patients with COVID-19 should be captured through the ISARIC 4C Clinical Characterisation Protocol (CCP) case report forms (CRFs), as coordinated by the COVID-19 Clinical Information Network (CO-CIN) (link to forms).

Patient and GP information leaflet

The patient and GP information leaflet can be accessed here

Glossary

ALT: alanine aminotransferase
AST: aspartate aminotransferase
CRP: C-reactive protein
eGFR: estimated glomerular filtration rate
ESR: erythrocyte sedimentation rate
ICU: intensive care unit (consultant)
ID: infectious disease (consultant)
IL: interleukin
ISARIC 4C: UK-wide consortium of doctors and scientists
IV: intravenous
LFT: liver function test
MHRA: Medicines and Healthcare Products Regulatory Agency
NNT: numbers needed to treat
SmPC: (manufacturer's) summary of product characteristics
TB: tuberculosis

Editorial Information

Last reviewed: 09 December 2021

Next review: 28 February 2022

Author(s): Alison MacDonald, Antimicrobial Pharmacist and Jane Wylie, ICU Pharmacist

Version: 2

Approved By: Clinical Response Group

Reviewer Name(s): Infectious Diseases Consultant

Document Id: COVID099