Interleukin-6 inhibitors

Patients must meet all of the eligibility criteria and none of the exclusion criteria. Hospitalised patients are eligible to be considered for an IL-6 inhibitor (tocilizumab or sarilumab) if:

• COVID-19 infection is confirmed by microbiological testing or where a multidisciplinary team has a high level of confidence that the clinical and/or radiological features suggest that COVID-19 is the most likely diagnosis;

AND

• They have not already been treated during this episode with tocilizumab or sarilumab

AND

• They are receiving (or have completed a course of) dexamethasone or an equivalent corticosteroid unless contraindicated.

AND

Either

• • Hypoxaemia with evidence of inflammation but not yet critically ill requiring respiratory support defined as:
    • C-reactive protein level of at least 75mg/L; AND
    • an oxygen saturation of <92% on room air OR requirement for supplemental oxygen;

Or

• • In the early stages of critical illness requiring respiratory support (if an IL-6-inhibitor has not been already administered for COVID-19) defined as:
    • Within 48 hours of commencement of respiratory support (high-flow nasal oxygen, continuous positive airway pressure (CPAP) or non-invasive ventilation, or invasive mechanical ventilation), regardless of C-reactive protein level.

• Tocilizumab should not be administered in the following circumstances:
  • Known hypersensitivity to tocilizumab
  • Liver enzymes [alanine aminotransferase (ALT) or aspartate aminotransferase (AST)] more than ten times the upper limit of normal
  • Absolute neutrophil count of less than 1 x 10⁹/L
  • Platelet count of less than 50 x 10⁹/L

Please refer to the Summary of Product Characteristics (SmPC) for tocilizumab for special warnings and precautions for use, although some may not be relevant for use in the acute setting, as the licensed indications address long-term use.

• Co-existing infection that might be worsened by IL-6 inhibitor therapy
• A pre-existing condition or treatment resulting in ongoing immunosuppression.

Caution is also necessary when prescribing IL-6 inhibitors to patients with neutropenia or thrombocytopaenia. Please note that C-reactive protein (CRP) levels may be depressed for some time after treatment with IL-6 inhibitors.

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including IL-6 inhibitors. While being on antibiotics per se is not a contraindication, IL-6 inhibitor treatment generally must not be initiated in patients with active, severe bacterial (including active tuberculosis), fungal, viral, or other infection (besides COVID19). Healthcare professionals should exercise caution when considering the use of IL-6 inhibitors in patients with a history of recurring or chronic infections.

Of note is that the limited trial evidence of using IL-6 inhibitors in COVID-19 has not demonstrated significant safety concerns, which may be in part due the fact that only one or two doses were given as opposed to repeated doses over weeks or months.

The SmPC states that patients should be screened for latent tuberculosis (LTBI). However, data on a large number of tocilizumab exposed patients from clinical trials indicate a very low or absent risk of TB reactivation [Cantini et al.] It is likely not feasible to screen for LTBI prior to commencing tocilizumab for severe COVID-19.

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for rheumatoid arthritis. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded. However, screening for viral hepatitis was not required for RECOVERY or REMAP-CAP. Given the acuity of the presentation of patients with COVID-19 screening would not be feasible in a timely manner prior to consideration of tocilizumab. Instead, clinicians should be aware of the theoretical risk, and blood borne virus serology could be undertaken with routine bloods in due course. Patients with active hepatitis B or C infection should be discussed with the infectious diseases team.

No specific monitoring is required post infusion. Raised ALT/AST and neutropenia can occur, particularly with longer treatment courses.

Both tocilizumab and sarilumab cause prolonged depression of CRP levels, making CRP a less reliable marker of active infection. 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 tocilizumab or sarilumab and provide information to the patient to such effect.

Please see SmPC for full list.

Biologics should be prescribed by brand name as per NHSL Medicines policy (pharmacy will advise on which brand is currently preferred). The recommended dose of tocilizumab is 8mg/kg to be administered as an intravenous infusion. The total dose per infusion should not exceed 800mg. A single dose is to be administered (no repeat dosing) given the uncertainty over evidence of additional benefit of repeat dosing.

Tocilizumab should be diluted in a 100mL bag of 0.9% sodium chloride, after removing an equivalent volume of saline (total volume 100mL) and given over 1 hour. Please refer to the NHS Injectable Medicines Guide MEDUSA).

Tocilizumab should not be infused concomitantly in the same IV line with other medications.

The use of IL-6 inhibitor therapy (tocilizumab or sarilumab) for the indication of COVID-19 pneumonitis in NHSL requires documentation on Trak using a specific shortcode. It is important that the shortcode (see below) is used as pharmacy will monitor use through a BOXI report which requires this particular shortcode.

The consultant in charge of the patient should:

• Check the patient meets the IL-6 inhibitor therapy approval criteria as detailed above.
• Where possible gain the agreement of the patient to use this medicine.
• Contact the clinical pharmacist responsible for their clinical area to advise which IL-6 inhibitor is currently in stock for use (this may change depending on supplies).
• The consultant in charge of the patient is responsible for:
  • Documenting the use of IL-6 inhibitor therapy in the patient’s TRAK notes using the following short code: \IL6COV
  • Reporting any adverse drug reactions on the COVID-19 yellow card reporting site.
• Important! With the exception of critical care areas, IL-6 inhibitors will only be supplied by pharmacy 9am to 4pm (Mon to Fri) and during pharmacy opening-hours at weekends, which vary across the acute hospitals. Out of hours requests from non-critical care areas will not be processed until the following morning unless an urgent supply is requested by the ID consultant on call.
• Pharmacy staff will check Trak documentation by accessing the completed shortcode entry on TRAK (this will also inform stock holding).
• Locally stock will be held at all acute sites in NHS Lothian; RIE, WGH and SJH.

Any suspected adverse drug reactions (ADRs) for patients receiving tocilizumab or sarilumab should be reported directly to the MHRA via the new dedicated COVID-19 yellow card reporting site.

The REMAP-CAP trial excluded pregnant women, whereas the RECOVERY trial has included pregnant women. Please check the relevant SmPC for either tocilizumab or sarilumab. The SmPC for sarilumab and tocilizumab currently states: “Women of childbearing potential must use effective contraception during and up to 3 months after treatment.” In relation to use in pregnancy, the SmPC for tocilizumab states there is no adequate data for the use in pregnant women. In relation to use in pregnancy, the SmPC for sarilumab states there is limited data for the use in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose with tocilizumab. Tocilizumab or sarilumab should not be used during pregnancy unless clearly clinically necessary. The Royal College of Obstetrics & Gynaecology state that tocilizumab should be considered if the woman fulfils above eligibility criteria.

For women who are breast-feeding, the SmPC states:

The use of IL-6 inhibitor therapy in pregnant patients should ideally be discussed with the obstetric and/or infectious diseases team.

There is no interaction of tocilizumab/sarilumab with either dexamethasone or hydrocortisone expected. There is no interaction of tocilizumab/sarilumab with remdesivir expected.

For drug interactions please also see the COVID-19 drug interaction checker: 

\IL6COV

This is the Trak short code to be used to document the use of IL-6 inhibitors (tocilizumab/sarilumab).