Tocilizumab

CLASS OF DRUG

  • Interleukin-6 receptor (IL6R) antagonist
  • recombinant monoclonal antibody

PHARMACEUTICS

  • Recombinant humanised IgG1 monoclonal antibody (148 kDa) produced in Chinese Hamster Ovary (CHO)cells
  • sterile, clear, colourless to pale yellow, preservative-free solution
  • protect from light and store at 2–8 °C
  • 180mg/ 1 mL for injection
  • 400mg/20mL (20mg/mL) for infusion

DOSING

IV

  • 8 mg/kg (max. dose 800 mg in adults)
    • every 4 weeks for chronic rheumatological conditions
    • single dose only for COVID19
  • Diluted in 0.9% NaCl to a volume of 100 mL and give over 1 hour

SC (rheumatoid arthritis, GCA)

  • 162 mg once weekly, administer to abdomen, thigh or upper arm (adults)

INDICATIONS

  • rheumatoid arthritis (RA) (moderate-to-severe)
  • giant cell arteritis
  • polyarticular juvenile idiopathic arthritis (patients 2 years of age or older)
  • systemic juvenile idiopathic arthritis (patients 2 years of age or older)
  • chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (patients 2 years of age or older)
  • COVID19
    • consider using tocilizumab for the treatment of COVID-19 in adults who require supplemental oxygen, particularly where there is evidence of systemic inflammation. (see Australian Guidelines)
    • consider using baricitinib in preference to tocilizumab (see TGA recommendation in Australia)

CONTRA-INDICATIONS / PRECAUTIONS

  • Severe active infection (non-COVID19)
  • Neutropenia (<2 x 10E9/L)
  • Liver disease
    • Caution in patients with elevated ALT or AST > 1.5 times the upper limit of normal (ULN), except in cases of cytokine release syndrome. 
    • discontinue tocilizumab in patients who develop:
      • elevated ALT or AST > 5 times ULN
      • Neutropenia (<0.5 x 10E9/L)
      • Thrombocytopenia (<50 x 10E9/L)

Precautions:

  • History of diverticulitis
  • history of intestinal ulceration
  • history of recurrent or chronic infection 
  • Neutropenia
  • Thrombocytopenia
  • Predisposition to infection (interrupt treatment if serious infection occurs)
  • Latent tuberculosis (treat with standard therapy before starting tocilizumab)

Other:

  • Live and live attenuated vaccines should not be given concurrently with Actemra as clinical safety has not been established. 
  • Not recommended for use with other biological agents including TNF antagonists, anakinra, rituximab and abatacept

PREGNANCY/ LACTATION

  • Category C – avoid in pregnancy unless absolutely necessary (toxicity in animal studies reported)
  • Contraception required during and 3 months after treatment
  • Unknown safety in lactation

MECHANISM OF ACTION

  • Tocilizumab binds to both soluble and membrane-bound IL-6 receptors and inhibits sIL-6R and mIL-6R-mediated signalling. 
  • IL6 is a multi-functional cytokine involved in immunoglobulin secretion, T-cell activation, induction of hepatic acute phase proteins and stimulation of haematopoiesis. 
  • IL-6 is thought to have role in the pathogenesis of:
    • inflammatory diseases, including rheumatoid arthritis
      • Tocilizumab can rapidly decrease inflammatory markers such as CRP, ESR, serum amyloid A, and fibrinogen.
      • Tocilizumab increases haemoglobin levels and iron availability, by blocking Il6 effects on hepcidin production
    • COVID19
      • Some COVID19 patients have elevated serum IL6, ferritin, and CRP levels and higher concentrations of IL-6 in serum are associated with higher levels of SARS-CoV-2 viremia, prolonged viral RNA shedding, progression to mechanical ventilation, and death

PHARMACOKINETICS

  • A: SC has bioavailability of 80-95% with absorption t1/2 of 2-4 days.
  • D: VD ~0.1L/kg
  • M: intracellular catabolism by lysosomal degradation to amino acids after uptake by pinocytosis or endocytosis
  • E: Clearance ~0.1-0.2 mL/kg/h; terminal t1/2 of ~20-30 days (shorter at lower doses as clearance is saturatable)

ADVERSE EFFECTS

Common (>1%):

  • Infections (including opportunistic)
  • Neutropenia
  • Hypofibrinogenaemia
  • elevated AST/ALT, gastritis, mouth ulcers
  • Hypertension
  • Dyslipidemia
  • infusion-related reactions (below)
  • antibodies to tocilizumab
  • rash, itch, headache, dizziness

Infrequent (0.1–1%):

  • GI perforation, including diveriticulitis (possibly dose-related)
  • Thrombocytopenia
  • hypersensitivity reactions (e.g. urticaria, angioedema) 
  • dyspnoea, cough, conjunctivitis
  • Stevens-Johnson syndrome

Rare (<0.1%):

  • Serious hepatotoxicity
    • including acute liver failure, hepatitis and jaundice, and in some rare cases treatment has required liver transplant
    • severe liver injury reported from 2 weeks to >5 years after commencement of treatment
  • Pancreatitis
  • Pulmonary fibrosis

DRUG-DRUG INTERACTIONS (DDI)

  • IL6 induces cytochrome P450 1A2, 2C9, 2C19 and 3A4, so tocilizumab may affect drugs metabolised by these enzymes when commenced.

MONITORING

  • Monitor for 4-8 weeks after starting treatment then as required
    • Lipid profile
    • Liver function tests (then every 12 weeks after 6 months treatment)
    • Full blood count (neutrophils, platelets)
  • Monitor for demyelinating disorders
  • Baseline testing for hepatitis B, HCV and tuberculosis 

EVIDENCE

COVID19

  • Prior to the REMAP-CAP and RECOVERY trial results, randomised controlled trials predominately found no benefit from IL-6R antagonists, although the majority of patients included in these trials were not critically ill and the trials generally had limited power due to small sample sizes.
    • BACC trial (Stone et al, 2020) –  n=243, 5% non-invasive ventilation [NIV]/ high-flow-nasal-cannula [HFNC]/ mechanical ventilation [MV] at baseline – no significant difference
    • CORIMUNO-TOCI-1 (Hermine et al, 2021) – n=130, 0% NIV/HFNC/MV at baseline – no significant difference
    • RCT-TCZ-COVID-19 (Salvarini et al, 2021) – n=126, P/F ratio of 200-300, allowed HFNC at baseline but not mechanical ventilation – no significant difference
    • EMPACTA (Salama et al, 2021) – n=389, 0% receiving NIV/MV – statistically significant decrease in patients who required ventilation or died < 28 days in tocilzumab group
    • COVACTA (Rosas et al, 2021): n=452, 67% receiving NIV/MV/ECMO at baseline – no significant difference
  • The larger REMAP-CAP (The REMAP-CAP trial investigators, 2021) and RECOVERY (The RECOVERY trial investigators, 2021) trials both found benefit from IL6R antagonists, though they likely overstate the benefit due to their open-label designs.
    • REMAP-CAP (The REMAP-CAP trial investigators, 2021)  – open label randomised adaptive trial (n=895 in the immunomodulation arm) that found greater organ support free days to day 21 with the use of the IL6R antagonists (tocilizumab or Sarilumab). Both hospital and 90 day mortality were also significantly decreased. This effect appears to be in addition to the clinical benefit conferred by dexamathasone. 
    • RECOVERY trial (The RECOVERY trial investigators, 2021)- large open label randomised platform trial (n=4116 in the tocilizumab arm) found that hypoxic COVID19 patients with evidence of systemic inflammation (CRP ≥75 mg/L). The tocilizumab arm had decreased 28 day mortality (31% vs 35%; rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028) and were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids (82% of patients also received corticosteroids).
  • Based on current evidence it is likely, but not certain, that IL6R antagonists are beneficial in the treatment of COVID19, at least for some patient sub-groups (timing, phase of illness, and systemic inflammatory response may be important determinants of benefit).

Rheumatoid arthritis

  • Cochrane review (Singh et al, 2010) – eight RCTs (n=3334) were systematically reviewed; Tocilizumab was found to be beneficial in decreasing RA disease activity and improving function. The author’s stated that larger safety studies are needed to address safety concerns.

OTHER

The COVID19 pandemic resulted in worldwide shortages of tocilizumab. Strategies to conserve tocilizumab in Australia recommended by the TGA are:

  • Baricitinib should be used instead of tocilizumab for patients receiving supplemental oxygen but who are not mechanically ventilated.
  • IV tocilizumab reserved for patients with COVID-19 when baricitinib is not clinically appropriate.
  • When used for COVID-19 patients only one dose of IV tocilizumab should be administered.

Use in rheumatological disease

  • rheumatoid arthritis:
    • severe, active and progressive disease, not previously treated with methotrexate 
    • Moderate-to-severe disease, in combination with methotrexate or as monotherapy if methotrexate is not tolerated or contra-indicated
  • Giant cell arteritis
    • Used in combination with a tapering course of glucocorticoid or alone following discontinuation of glucocorticoid

REFERENCES

FOAM and web resources

Journal articles

  • Khiali S, Khani E, Entezari-Maleki T. A Comprehensive Review of Tocilizumab in COVID-19 Acute Respiratory Distress Syndrome. J Clin Pharmacol. 2020 Sep;60(9):1131-1146. doi: 10.1002/jcph.1693. Epub 2020 Jul 27. PMID: 32557541; PMCID: PMC7323169. [article]
  • Hermine O, Mariette X, Tharaux PL, et al; CORIMUNO-19 Collaborative Group. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):32-40. doi: 10.1001/jamainternmed.2020.6820. Erratum in: JAMA Intern Med. 2021 Jan 1;181(1):144. Erratum in: JAMA Intern Med. 2021 Jul 1;181(7):1021. PMID: 33080017; PMCID: PMC7577198. [article]
  • RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355. [article]
  • REMAP-CAP Investigators, Anthony C. Gordon, Paul R. Mouncey, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv 2021.01.07.21249390; doi: https://doi.org/10.1101/2021.01.07.21249390 [preprint article]
  • Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, Criner GJ, Kaplan-Lewis E, Baden R, Pandit L, Cameron ML, Garcia-Diaz J, Chávez V, Mekebeb-Reuter M, Lima de Menezes F, Shah R, González-Lara MF, Assman B, Freedman J, Mohan SV. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jan 7;384(1):20-30. doi: 10.1056/NEJMoa2030340. Epub 2020 Dec 17. PMID: 33332779; PMCID: PMC7781101. [article]
  • Salvarani C, Dolci G, Massari M, et al; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615. PMID: 33080005; PMCID: PMC7577199. [article]
  • Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD008331. doi: 10.1002/14651858.CD008331.pub2. PMID: 20614469. [article]
  • Stone JH, Frigault MJ, Serling-Boyd NJ, et al; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333-2344. doi: 10.1056/NEJMoa2028836. Epub 2020 Oct 21. PMID: 33085857; PMCID: PMC7646626. [article]
CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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