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Tocilizumab Injection (Actemra®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The first interleukin-6 (il-6) receptor antagonist has been approved for the treatment of rheumatoid arthritis (RA). Tocilizumab is a recombinant, humanized, monoclonal antibody that specifically binds to both soluble and membrane-bound IL-6 receptors. It was developed in Japan and has been available outside the United States since 2008. It will be marketed in this country by Genentech as Actemra®.
Tocilizumab is indicated for the treatment of adults with moderately to severely active RA who have not achieved adequate response to one or more anti-TNF drugs.1
The recommended starting dose (as monotherapy or in combination with DMARDs) is 4 mg/kg every 4 weeks given by intravenous infusion over 1 hour.1 The dose may be increased to 8 mg/kg based on clinical response. Tocilizumab should not be started in patients with an absolute neutrophil count < 2000/mm3, platelet count < 100,000/mm3, or ALT or AST > 1.5 times the upper normal limit.1 Similarly, dose modification or interruption may be necessary with liver enzyme abnormalities, low neutrophil counts, or low platelet counts.
Tocilizumab is supplied in single-use 20 mg/mL concentrate vials (packaged in 4 mL, 10 mL, and 20 mL).
Tocilizumab inhibits a different proinflammatory cytokine (IL-6). The addition of tocilizumab to a DMARD provides additional benefit compared to the DMARD alone. It may slow the progression of structural joint damage.2,3
As with other biologic agents that affect the immune system (e.g., anti-TNF drugs) there is a warning for increased risk of serious infections such as tuberculosis, bacterial, viral, and fungal infections.1 Tocilizumab has been associated with increased risk of GI perforation (complication of diverticulitis), reduction of neutrophil and platelet counts, and elevation of liver transaminase and lipid parameters.1 Serious hypersensitivity reaction and demyelinating disorders have been reported. Leuko-encephalopathy with cognitive impairment was reported in one patient during the Phase III trials in Japan.4
The safety and efficacy of tocilizumab was evaluated in five randomized, double-blind trials in adult patients (n = 4087) with moderately to severely active rheumatoid arthritis (at least 8 tender and 6 swollen joints at baseline).1,5-8 The primary endpoint was achieving a 20% response on the American College of Rheumatology criteria (ACR20). In patients with no recent use of methotrexate or no previous treatment failure with methotrexate or an anti-TNF drug, 70% of patients on tocilizumab 8 mg/kg achieved ACR20 at 24 weeks compared to 53% for methotrexate.1,5 In patients with long-standing RA, tocilizumab 4 mg/kg and 8 mg/kg plus methotrexate or a DMARD were more efficacious than methotrexate or a DMARD alone.6,7 Results were similar in patients with one anti-TNF failure.8 In patients with inadequate response to methotrexate monotherapy, the addition of tocilizumab showed inhibition of progression of structural joint damage compared to the addition of placebo.2 In a 52-week study, more patients treated with tocilizumab had no radiographic disease progression compared to DMARDs, 56% vs 39% (P < 0.01).3 Tocilizumab is generally well tolerated. The discontinuation rates during clinical trials due to adverse events were 4%-10% for monotherapy and 4%-12% as combination therapy.9 The most common adverse events were upper respiratory tract infection, nasopharyngitis, headache, and hypertension. Changes in laboratory parameters included increased ALT and plasma lipids, and decreased neutrophils and platelets. ALT and AST levels and neutrophil and platelet counts should be monitored every 4-8 weeks. Lipid levels should be monitored every 4-8 weeks after initiation of treatment and approximately every 6 months thereafter. There are currently no comparative studies with other biological agents such as anti-TNF drugs.
Currently there are numerous antirheumatic biological agents with different mechanisms of action. Currently, anti-TNF drugs are first-line biological agents. Tocilizumab may be an effective option for patients who have long-standing, treatment-refractory moderate-to-severe RA or those who have failed at least one anti-TNF drug.
1. Actemra prescribing information. South San Francisco, CA: Genentech, Inc.; 2010.
2. Kremer JM, et al. The Annual European Congress of Rheumatology: Abstract OP-0157. Presented June 11, 2009.
3. Nishimoto N, et al. Study of active controlled mono-therapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI). Ann Rheum Dis 2007;66:1162-1167.
4. Kobayashi K, et al. Leukoencephalopathy with cognitive impairment following tocilizumab for the treatment of rheumatoid arthritis (RA). Intern Med 2009;48:1307-1309.
5. Jones G, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis. Ann Rheum Dis 2010;69:88-96.
6. Smolen JS, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study). Lancet 2008;371:987-997.
7. Genovese MC, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2008;58:2968-2980.
8. Emery P, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals. Ann Rheum Dis 2008;67:1516-1523.
9. Oldfield V, et al. Tocilizumab: A review of its use in the management of rheumatoid arthritis. Drugs 2009;69:609-632.