Etanercept

(BAN, USAN, rINN)
Synonyms: Étanercept; Etanerceptum; Etanersept; Etanersepti; rhuTNFR:Fc; TNR-001. A dimer of 1-235 tumour necrosis factor receptor (human) fusion protein with 236-467-immunoglobulin G1 (human
Cyrillic synonym: Этанерцепт.

💊 Chemical information

CAS — 185243-69-0.
ATC — L04AB01.
ATC Vet — QL04AB01.

💊 Adverse Effects and Precautions

As for Infliximab. Mild to moderate injection site reactions with symptoms of erythema, itching, pain, or swelling are common with etanercept. Other common reactions include headache, dizziness, asthenia, nausea and vomiting, abdominal pain, dyspepsia, and allergic reactions. Antibodies to etanercept may develop. Etanercept should be used with caution in patients with heart failure.
1. Sánchez Carazo JL, et al. Safety of etanercept in psoriasis: a critical review. Drug Safety 2006; 29: 675–85.

Wegener’s granulomatosis.

The addition of etanercept to standard therapy (including cyclophosphamide or methotrexate and corticosteroids) was not shown to be effective in patients with Wegener’s granulomatosis and was associated with an increased incidence of various non-cutaneous malignancies.1 Licensed product information recommends that etanercept should not be added to therapy in patients with Wegener’s granulomatosis.
1. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005; 352: 351–61.

💊 Interactions

As for Infliximab. The use of etanercept with sulfasalazine has resulted in decreased white blood cell counts; however, the clinical significance of this is unknown. For an increased incidence of malignancy when etanercept was added to standard immunosuppressive therapy in patients with Wegener’s granulomatosis, see above.

💊 Pharmacokinetics

After a single subcutaneous dose of etanercept, UK licensed product information states that the mean halflife is about 70 hours, and the time to peak serum concentration 48 hours. In contrast, US information gives the half-life as 102 hours and the time to peak concentration as about 70 hours, although with a considerable range. Repeated dosing was noted to result in a two- to sevenfold increase in serum levels of etanercept in some patients.
1. Korth-Bradley JM, et al. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother 2000; 34: 161–4
2. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005; 45: 490–7
3. Yim D-S, et al. Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis. J Clin Pharmacol 2005; 45: 246–56
4. Don BR, et al. The pharmacokinetics of etanercept in patients with end-stage renal disease on haemodialysis. J Pharm Pharmacol 2005; 57: 1407–13
5. Sullivan JT, et al. Bioequivalence of liquid and reconstituted lyophilized etanercept subcutaneous injections. J Clin Pharmacol 2006; 46: 654–61
6. Nestorov I, et al. Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis. Br J Clin Pharmacol 2006; 62: 435–45
7. Elewski B, et al. Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis. Br J Dermatol 2007; 156: 138–42.

💊 Uses and Administration

Etanercept is a recombinant version of soluble human tumour necrosis factor (TNF) receptor that binds specifically to tumour necrosis factor and blocks its interaction with endogenous cell-surface TNF receptors. This interaction prevents the important effect of TNF in the inflammatory processes of rheumatoid arthritis; elevated TNF levels are also found in psoriatic plaques, in the synovium of patients with psoriatic arthritis, and in the serum and synovium of patients with ankylosing spondylitis. Etanercept is used in the treatment of moderately to severely active rheumatoid arthritis and active and progressive psoriatic arthritis. In the UK, it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs although, in severe rheumatoid arthritis, it may be used in patients not previously treated with methotrexate. In the USA, it is licensed to treat early rheumatoid arthritis or psoriatic arthritis, to reduce the signs and symptoms, delay structural damage, and improve physical function. In both indications, it is given as a subcutaneous injection in a dose of 25 mg twice weekly at intervals of 3 or 4 days. The equivalent weekly dose of 50 mg may also be given either as a single 50-mg injection or as two separate 25-mg injections (given at about the same time). In the UK, NICE recommends, based on guidelines from the British Society of Rheumatology, that treatment be stopped if there is no adequate response after 6 months. Etanercept is also indicated in the treatment of severely active ankylosing spondylitis; in the UK, its use is again limited to those who have had an inadequate response to conventional therapy. Doses are similar to those used for rheumatoid arthritis. Etanercept is also used in the treatment of chronic, moderate to severe plaque psoriasis. In the UK, its use is usually limited to patients in whom other systemic treatments are not suitable. The recommended initial dose is 25 mg twice weekly. Alternatively, an initial dose of 50 mg twice weekly at intervals of 3 or 4 days may be given for 12 weeks; the dose should then be reduced to 25 mg twice weekly or 50 mg weekly. Initial doses of 25 or 50 mg once weekly have also been shown to be effective. Treatment should continue until remission is achieved, for up to 24 weeks. Etanercept should be stopped after 12 weeks in patients who show no response. For details of uses and dosage in children, see below.

Administration in children.

Etanercept is used in the treatment of moderately to severely active polyarticular juvenile idiopathic arthritis; UK licensed product information limits its use to those who have had an inadequate response to, or who are intolerant of, the disease-modifying antirheumatic drug methotrexate. In the UK, it is given subcutaneously to children aged 4 years and over in a dose of 400 micrograms/kg (up to a maximum dose of 25 mg) twice weekly at intervals of 3 or 4 days. In the USA, etanercept is licensed for use in children as young as 2 years old. Similar doses are used although they are expressed as 800 micrograms/kg (up to a maximum dose of 50 mg) weekly: doses to be given as 2 separate injections may either be given on the same day or 3 to 4 days apart. In the UK, NICE recommends, based on guidelines from the British Paediatric Rheumatology Group, that treatment be stopped in children if there is no response after 6 months, or an initial response is not maintained. For references on the use of etanercept in juvenile idiopathic arthritis, see Rheumatoid Arthritis, below.

Asthma.

TNF inhibitors such as etanercept have been investigated in the treatment of refractory asthma.1,2 There is some evidence that only a minority of patients will respond to such therapy, and that the benefits and risks must therefore be carefully assessed.3
1. Howarth PH, et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60: 1012–18
2. Berry MA, et al. Evidence of a role of tumor necrosis factor α in refractory asthma. N Engl J Med 2006; 354: 697–708
3. Brightling C, et al. Targeting TNF-α: a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008; 121: 5–10.

Dementia.

A small pilot study1 and individual case reports2have suggested that perispinal injection of etanercept, in doses of 25 to 50 mg weekly, may improve signs of dementia in patients with Alzheimer’s disease. However, randomised controlled studies are required to confirm any benefit.
1. Tobinick E, et al. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed 2006; 8: 25. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool= pubmed&pubmedid=16926764 (accessed 13/06/08
2. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008; 5: 2. Available at: http://www.jneuroinflammation.com/content/pdf/ 1742-2094-5-2.pdf (accessed 13/06/08)

Psoriasis.

Etanercept is effective in patients with moderate to severe plaque psoriasis.1-9 It has also been successfully tried in the treatment of erythrodermic psoriasis,10 and of plaque psoriasis in children and adolescents.11 Efficacy may be dose-related; in one study,1 25% of patients in the low-dose (25 mg once weekly) group showed at least a 75% improvement compared with 44% in the medium-dose group (25 mg twice weekly) and 59% in the high-dose group (50 mg twice weekly) after 24 weeks of etanercept treatment. However, a later multicentre study2 in patients with chronic plaque psoriasis found that the therapeutic effect of etanercept was maintained when the dose was reduced after 12 weeks from 50 mg twice weekly to 25 mg twice weekly. An open-label extension8 of these 2 studies found that efficacy was also sustained when patients who had received etanercept 25 mg twice weekly for at least 24 weeks had their dose altered to 50 mg once weekly.
1. Leonardi CL, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349: 2014–22
2. Papp KA, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005; 152: 1304–12
3. NICE. Etanercept and efalizumab for the treatment of adults with psoriasis: Technology Appraisal Guidance 103 (issued July 2006). Available at: http://www.nice.org.uk/nicemedia/pdf/ TA103guidance.pdf (accessed 13/06/08
4. Boehncke W-H, et al. European Dermatology Expert Group. Recommendations for the use of etanercept in psoriasis: a European dermatology expert group consensus. J Eur Acad Dermatol Venereol 2006; 20: 988–98
5. Woolacott N, et al. NHS Health Technology Assessment Programme. Etanercept and efalizumab for the treatment of psoriasis: a systematic review (issued November 2006). Available at: http://www.hta.ac.uk/fullmono/mon1046.pdf (accessed 13/06/08
6. Tyring S, et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 2007; 143: 719–26
7. Romero-Maté A, et al. Efficacy and safety of etanercept in psoriasis/psoriatic arthritis: an updated review. Am J Clin Dermatol 2007; 8: 143–55
8. Elewski B, et al. Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis. Br J Dermatol 2007; 156: 138–42
9. Ahmad K, Rogers S. Two years of experience with etanercept in recalcitrant psoriasis. Br J Dermatol 2007; 156: 1010–14
10. Esposito M, et al. Treatment of erythrodermic psoriasis with etanercept. Br J Dermatol 2006; 155: 156–9
11. Paller AS, et al. Etanercept Pediatric Psoriasis Study Group. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008; 358: 241–51.

Rheumatoid arthritis.

Some references to the use of etanercept in rheumatoid arthritis and juvenile idiopathic arthritis.
1. Weinblatt ME, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9
2. Moreland LW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 478–86
3. Lovell DJ, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 2000; 342: 763–9
4. Bathon JM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586–93. Correction. ibid. 2001; 344: 76
5. Johnson CJ, et al. Etanercept in juvenile rheumatoid arthritis. Ann Pharmacother 2001; 35: 464–71
6. Genovese MC, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002; 46: 1443–50
7. NICE. Guidance on the use of etanercept for the treatment of juvenile idiopathic arthritis: Technology Appraisal Guidance 35 (issued March 2002). Available at: http://www.nice.org.uk/ nicemedia/pdf/JIA-PDF.pdf (accessed 13/06/08
8. Klareskog L, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675–81
9. Genovese MC, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol 2005; 32: 1232–42
10. Bathon JM, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol 2006; 33: 234–43
11. van Riel PLCM, et al. ADORE (Add Enbrel or Replace Methotrexate) Study Investigators. Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study. Ann Rheum Dis 2006; 65: 1478–83
12. Moreland LW, et al. Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol 2006; 33: 854–61
13. van der Heijde D, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006; 54: 1063–74
14. Chen Y-F, et al. NHS Health Technology Assessment Programme. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness (issued November 2006). Available at: http:// www.hta.ac.uk/fullmono/mon1042.pdf (accessed 13/06/08
15. Weisman MH, et al. A placebo-controlled, randomized, doubleblinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases. Rheumatology (Oxford) 2007; 46: 1122–5
16. Dhillon S, et al. Etanercept: a review of its use in the management of rheumatoid arthritis. Drugs 2007; 67: 1211–41. Correction. ibid.; 1849
17. van der Heijde D, et al. Etanercept Study 400 Investigators. The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Ann Rheum Dis 2008; 67: 182–8
18. van der Heijde D, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2007; 56: 3928–39
19. NICE. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis: Technology Appraisal Guidance 130 (issued October 2007). Available at: http://www.nice.org.uk/ nicemedia/pdf/TA130guidance.pdf (accessed 13/06/08
20. Gartlehner G, et al. Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence. Clin Rheumatol 2008; 27: 67–76.

Spondyloarthropathies.

References to the use of etanercept in the treatment of ankylosing spondylitis and psoriatic arthritis.
1. Mease PJ, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356: 385–90
2. Brandt J, et al. Six-month results of a double-blind, placebocontrolled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 2003; 48: 1667–75
3. Davis JC, et al. Enbrel Ankylosing Spondylitis Study Group. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 3230–6
4. Mease PJ, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004; 50: 2264–72
5. Baraliakos X, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 2005; 53: 856–63
6. Mease PJ, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol 2006; 33: 712–21
7. NICE. Etanercept and infliximab for the treatment of adults with psoriatic arthritis: Technology Appraisal Guidance 104 (issued July 2006). Available at: http://www.nice.org.uk/ nicemedia/pdf/TA104guidance.pdf (accessed 13/06/08
8. Woolacott N, et al. NHS Health Technology Assessment Programme. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation (issued September 2006). Available at: http://www.hta.ac.uk/ fullmono/mon1031.pdf (accessed 13/06/08
9. van der Heijde D, et al. Etanercept Study 314 Investigators. Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis 2006; 65: 1572–7
10. Cantini F, et al. Switching from infliximab to once-weekly administration of 50 mg etanercept in resistant or intolerant patients with ankylosing spondylitis: results of a fifty-four-week study. Arthritis Rheum 2006; 55: 812–6
11. Woolacott NF, et al. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review. Clin Exp Rheumatol 2006; 24: 587–93
12. Braun J, et al. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford) 2007; 46: 999–1004
13. Romero-Maté A, et al. Efficacy and safety of etanercept in psoriasis/psoriatic arthritis: an updated review. Am J Clin Dermatol 2007; 8: 143–55
14. Frankel EH, et al. Etanercept improves psoriatic arthritis patient-reported outcomes: results from EDUCATE. Cutis 2007; 79: 322–6
15. McLeod C, et al. NHS Health Technology Assessment Programme. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Available at: http://www.hta.ac.uk/ fullmono/mon1128.pdf (accessed 13/06/08
16. Gottlieb AB, et al. Use of etanercept for psoriatic arthritis in the dermatology clinic: the Experience Diagnosing, Understanding Care, and Treatment with Etanercept (EDUCATE) study. J Dermatolog Treat 2006; 17: 343–52
17. Hoy SM, Scott LJ. Etanercept: a review of its use in the management of ankylosing spondylitis and psoriatic arthritis. Drugs 2007; 67: 2609–33.

Vasculitic syndromes.

For a preliminary report on the use of etanercept in Takayasu’s arteritis.

💊 Preparations

Proprietary Preparations

Arg.: Enbrel; Austral.: Enbrel; Belg.: Enbrel; Braz.: Enbrel; Canad.: Enbrel; Chile: Enbrel; Cz.: Enbrel; Denm.: Enbrel; Fin.: Enbrel; Fr.: Enbrel; Ger.: Enbrel; Gr.: Enbrel; Hong Kong: Enbrel; India: Enbrel; Indon.: Enbrel; Irl.: Enbrel; Israel: Enbrel; Ital.: Enbrel; Malaysia: Enbrel; Mex.: Enbrel; Neth.: Enbrel; Norw.: Enbrel; NZ: Enbrel; Philipp.: Enbrel; Pol.: Enbrel; Port.: Enbrel; S.Afr.: Enbrel; Singapore: Enbrel; Spain: Enbrel; Swed.: Enbrel; Switz.: Enbrel; Thai.: Enbrel; Turk.: Enbrel; UK: Enbrel; USA: Enbrel; Venez.: Enbrel. Multi-ingredient: Hung.: Enbrel.
Published January 04, 2019.