tocilizumab; atlizumab (Actemra, RoActemra, Tofidence, Tyenne)
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Indications
- rheumatoid arthritis[2][5]
- initial therapy, TNF-alpha inhibitor failure[9]
- alone or in combination with methotrexate
- idiopathic juvenile arthritis
- giant cell arteritis refractory to glucocorticoids[6][8][11][12]
- Castleman disease[2]
- cytokine release syndrome (cytokine storm) FDA-approved 8/2017[13]
- may reduce need for mechanical ventilation & reduce mortality in patients with COVID-19[14]
- reduces mortality in COVID-19 patients requiring mechanical ventilation 46% (18% vs 36%)[15]
- may reduce progression to mechanical ventilatiom in hospitalized patients with COVID-19 but does not improve survival[17]
- role of cytokine storm in COVID-19 mortality in question
- plasma IL-6 levels are not elevated & IL-6 blocking Ab tocilizumab not effective[16]
- may confer increased risk for mortality in patients with severe or critical COVID-19[18]
- may confer benefit to patients with high serum CRP[22]
- not enough data to recommend for or against the use of tocilizumab or sarilumab to treat COVID-19 in patients admitted to the ICU[19]
- Infectious Diseases Society of America recommends tocilizumab for COVID-19 SIRS[20] (see page 43 of ref 20)
- reduces mortality in hospitalized COVID-19 patients with hypoxia, 31% vs 35%[21]
- favorably affects hospital discharge within 28 days 57% vs 50%[21]
- emergency use authorization by FDA for hospitalized patients receiving glucocorticoid[23]
- also see IL-6 inhibitors for COVID-19
* may be coadministered with methotrexate
Contraindications
- avoid in patients with diverticulitis (risk for intestinal perforation)
Dosage
- 4-8 mg/kg IV every 4 weeks, max 800 mg/dose
- 20mg/mL (4-, 10-, & 20-mL single-dose vials [Actemra, Tofidence, Tyenne]
- injection, single-use autoinjector (ACTPen) for SC 162mg/0.9mL (Actemra)
- injection, single-use prefilled syringe for SC 162mg/0.9mL (Actemra, Tyenne)
* Biosimilars to Actemra
- Tofidence (tocilizumab-bavi)
- Tyenne (tocilizumab-aazg) more...
Monitor
- screening for tuberculosis[2]
- CBC, basic metabolic panel, LFTs at baseline & with each infusion or every 2-3 months
- lipid panel every 3-6 months[2]
Adverse effects
- common[6]; at least 1 fatality reported[6]
- infections, infestations (< 3%), invasive aspergillosis[14]
- increased risk off superinfections (54% vs 26%), mostly driven by ventilator-associated pneumonia[15]
- abdominal pain
- headache, dizziness
- rash, pruritus
- hypertension
- neutropenia, leukopenia, thrombocytopenia
- hyperlipidemia, hypercholesterolemia[2]
- elevated serum transaminases
- intestinal perforations in 0.65%[2][10]
- drug adverse effects of immunosuppressive agents
- drug adverse effects of biologic immunosuppressive agents
- drug adverse effects of pharmaceutical monoclonal antibodies
Mechanism of action
- humanized monoclonal antibody[2]
- inhibits interleukin-6 receptor
- 90% response[1]
Management
- whenever possible bring patients up to date on vaccinations prior to initiating biologic immunosuppressive agent[2]
More general terms
- IL-6 receptor inhibitor
- biologic immunosuppressive agent
- pharmaceutical monoclonal antibody
- disease-modifying antirheumatic agent (DMARD)
References
- ↑ 1.0 1.1 Smolen JS et al, Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-bind, placebo-controlled, randomized trial. Lancet 2008, 371:987 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18358926
Yokota S et al, Efficacy and Safety of tocilizumab in patients with systemic- onset juvenile idiopathic arthritis: A randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008, 371:998 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18358927
Bongartz T, Tocilizumab for rheumatoid and juvenile idiopathic arthritis. Lancet 2008, 371:961 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18358909 - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2022.
- ↑ Genovese MC, McKay JD, Nasonov EL et al Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008 Oct;58(10):2968-80 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18821691
- ↑ Jones G, Sebba A, Gu J et al Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010 Jan;69(1):88-96 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19297346
- ↑ 5.0 5.1 Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD008331 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20614469
- ↑ 6.0 6.1 6.2 6.3 Loricera J et al. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Semin Arthritis Rheum 2015 Jun; 44:717 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25697557
- ↑ Unizony S, Arias-Urdaneta L, Miloslavsky E et al Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012 Nov;64(11):1720-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22674883
- ↑ 8.0 8.1 Villiger PM et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016 Mar 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26952547
- ↑ 9.0 9.1 Bijlsma JWJ et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): A multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016 Jun 7; PMID: https://www.ncbi.nlm.nih.gov/pubmed/27287832
Scott DL. Beyond methotrexate monotherapy for early rheumatoid arthritis. Lancet 2016 Jun 7 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27287831 - ↑ 10.0 10.1 Xie F, Yun H, Bernatsky S, Curtis JR. Brief report: Risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments. Arthritis Rheumatol 2016 Nov; 68:2612 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27213279
- ↑ 11.0 11.1 FDA News Release. May 22, 2017 FDA approves first drug to specifically treat giant cell arteritis. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559791.htm
- ↑ 12.0 12.1 Stone JH, Tuckwell K, Dimonaco S et al Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 2017; 377:317-328. July 27, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28745999 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1613849
Hellmann DB. Giant-cell arteritis - more ecstasy, less agony. N Engl J Med 2017 Jul 27; 377:385 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28745998 <Internet> http://www.nejm.org/doi/10.1056/NEJMe1706439 - ↑ 13.0 13.1 Gever J FDA Approves CAR T-Cell Therapy for Leukemia. 'First gene therapy available in the United States,' says agency. MedPage Today. August 30, 2017 https://www.medpagetoday.com/HematologyOncology/Leukemia/67615
FDA News Release. Aug 30, 2017 FDA approval brings first gene therapy to the United States. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm - ↑ 14.0 14.1 14.2 Guaraldi P, Meschiari M, Cozzi-Lepri A et al Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatology. 2020 Aug;2(8):e474-e484. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32835257 PMCID: PMC7314456 Free PMC article https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30173-9/fulltext
- ↑ 15.0 15.1 15.2 Somers EC, Eschenauer GA, Troost JP Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clinical Infectious Diseases, ciaa954, Published: July 11, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32651997 https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa954/5870306
- ↑ 16.0 16.1 AMA News. Nov 9, 2020 American Medical Association
Hermine O, Mariette X, Tharaux PL et al Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia. A Randomized Clinical Trial. JAMA Intern Med. Published online October 20, 2020. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080017 PMCID: PMC7577198 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
Gupta A, Wang W, Hayek SS et al Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080002 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772185
Stone JH, Frigault MJ, Serling-Boyd NJ et al Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Oct 21 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33085857 https://www.nejm.org/doi/full/10.1056/NEJMoa2028836 - ↑ 17.0 17.1 Salama C, Han J, Yau L et al Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med 2020, Dec 17 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33332779 https://www.nejm.org/doi/full/10.1056/NEJMoa2030340
- ↑ 18.0 18.1 Veiga VC Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ 2021;372:n84 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33472855 PMCID: PMC7815251 Free PMC article https://www.bmj.com/content/372/bmj.n84
- ↑ 19.0 19.1 COVID-19 Treatment Guidelines. Last Updated: February 3, 2021 The COVID-19 Treatment Guidelines Panel's Statement on the Use of Tocilizumab (and Other Interleukin-6 Inhibitors) for the Treatment of COVID-19. https://www.covid19treatmentguidelines.nih.gov/statement-on-tocilizumab/
- ↑ 20.0 20.1 Bhimraj A, Morgan RL, Shumaker AH et al Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/idsa-covid-19-gl-tx-and-mgmt-v4.0.0.pdf
- ↑ 21.0 21.1 21.2 RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet 2021 May 1; 397:1637 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33933206 PMCID: PMC8084355 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00676-0/fulltext
- ↑ 22.0 22.1 Mariette X, Hermine O, Tharauxv PL et al Effectiveness of Tocilizumab in Patients Hospitalized With COVID-19. A Follow-up of the CORIMUNO-TOCI-1 Randomized Clinical Trial. JAMA Intern Med. Published online May 24, 2021. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34028504 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780021
- ↑ 23.0 23.1 Walker M FDA Authorizes IL-6 Inhibitor for Severe COVID-19 Patients. Tocilizumab received EUA for hospitalized patients receiving steroids. MedPage Today June 25, 2021 https://www.medpagetoday.com/infectiousdisease/covid19/93277
- ↑ Medscape: tocilizumab (Rx) https://reference.medscape.com/drug/actemra-tofidence-tocilizumab-999419