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tocilizumab; atlizumab (Actemra, RoActemra, Tofidence, Tyenne)

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] - temporal arteritis - Takayasu arteritis - 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) Pregnancy category: C [2] 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] 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]

Interactions

drug adverse effects of immunosuppressive agents monitor with immunosuppressive agents

General

IL-6 receptor inhibitor biologic immunosuppressive agent (biologic agent, biologic immune modulator) pharmaceutical monoclonal antibody disease-modifying antirheumatic agent (DMARD)

References

  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: 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: 18358927 - Bongartz T, Tocilizumab for rheumatoid and juvenile idiopathic arthritis. Lancet 2008, 371:961 PMID: 18358909
  2. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2022.
  3. 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: 18821691
  4. 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: 19297346
  5. Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD008331 PMID: 20614469
  6. Loricera J et al. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Semin Arthritis Rheum 2015 Jun; 44:717 PMID: 25697557
  7. 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: 22674883
  8. 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: 26952547
  9. 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: 27287832 - Scott DL. Beyond methotrexate monotherapy for early rheumatoid arthritis. Lancet 2016 Jun 7 PMID: 27287831
  10. 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: 27213279
  11. 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. 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 PMID: 28745999 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 PMID: 28745998 http://www.nejm.org/doi/10.1056/NEJMe1706439
  13. 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. 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: 32835257 PMCID: PMC7314456 Free PMC article https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30173-9/fulltext
  15. 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: 32651997 https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa954/5870306
  16. 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: 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: 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: 33085857 https://www.nejm.org/doi/full/10.1056/NEJMoa2028836
  17. Salama C, Han J, Yau L et al Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med 2020, Dec 17 PMID: 33332779 https://www.nejm.org/doi/full/10.1056/NEJMoa2030340
  18. 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: 33472855 PMCID: PMC7815251 Free PMC article https://www.bmj.com/content/372/bmj.n84
  19. 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. 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. 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: 33933206 PMCID: PMC8084355 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00676-0/fulltext
  22. 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: 34028504 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780021
  23. 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
  24. Medscape: tocilizumab (Rx) https://reference.medscape.com/drug/actemra-tofidence-tocilizumab-999419