Coverage Policy Manual
Policy #: 1998168
Category: Pharmacy
Initiated: December 1998
Last Review: August 2018
  Etanercept (Enbrel)

Description:
Etanercept (Enbrel) is a recombinant version of soluble human Tumor Necrosis Factor receptor, which acts as an anti-TNF agent in rheumatoid arthritis.  TNF is one of the major cytokines responsible for the inflammation of rheumatoid arthritis.  Present in the synovium, it stimulates synoviocyte proliferation and production of inflammatory mediators, leading to recruitment of inflammatory cells, neo-angiogenesis, and joint destruction.  
 
Etanercept is given subcutaneously twice a week.  Injection site reactions have been common.  Patients treated with the drug have developed auto-antibody markers, but no autoimmune disease has occurred after one year.  Non-neutralizing anti-etanercept antibodies have been detected.
 
Etanercept has been shown in a small, single-center randomized trial to be effective for the treatment of ankylosing spondylitis.
 
On September 4, 2008, the FDA released an FDA Alert notifying healthcare professionals that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking tumor necrosis factor-α blockers (TNF blockers) certolizumab pegol (Cimzia), etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). This situation has resulted in delays in appropriate treatment, sometimes resulting in death. The FDA will require the makers of the tumor necrosis factor-α blockers (TNF blockers) to further highlight the information about the risk of invasive fungal infections, such as histoplasmosis, in the Boxed Warning and Warnings sections of the drugs’ prescribing information and the Medication Guide for patients. The FDA will also require that the makers of the TNF blockers educate prescribers about this risk. Subsequently, in August 2009, the FDA added another Boxed Warning indicating there is an increased risk of lymphoma and other cancers associated with the use of TNF blockers in children and adolescents. In November 2011, the FDA began requiring TNF blocker manufacturers to perform additional safety surveillance, consisting of in-depth follow-up of reports of malignancy cases and expedited reporting of malignancy to the FDA (within 15 days of becoming aware of the report) for pediatric and young adult patients. Annual summaries and assessments of malignancies and TNF blocker utilization data will also be required by the FDA from the manufacturers.
 

Policy/
Coverage:
Effective October 2018
 
The use of Etanercept is not covered under medical benefits and is addressed under pharmacy benefits.  
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Etanercept meets primary coverage criteria for effectiveness for patients with active, moderate-to-severe rheumatoid arthritis, for reducing signs and symptoms and inhibiting progression of structural damage.  Treatment for more than 3 months is considered investigational unless there has been substantial (at least 20%, based on the American College of Rheumatology criteria) improvement in joint pain or substantial reduction in dose of corticosteroid.  Etanercept can be used in combination with methotrexate in patients who do not respond adequately to a 6-month trial of  methotrexate alone.
 
Effective August 1, 2000 etanercept meets primary coverage criteria for effectiveness for reducing signs and symptoms of active arthritis in patients  with psoriatic arthritis.   Etanercept can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
 
Etanercept meets primary coverage criteria for effectiveness for the treatment of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients 2 years of age or older who have had an inadequate response to one or more  disease-modifying antirheumatic drugs.
 
Etanercept meets primary coverage criteria for effectiveness (at a dose of 25 mg twice weekly) for the treatment of ankylosing spondylitis that has failed therapy with nonsteroidal antiinflammatory agents, low dose corticosteroids, and/or methotrexate.
 
Etanercept meets primary coverage criteria for effectiveness for the treatment of moderate to severe chronic plaque psoriasis in adults 18 years of age or older when:
    • There is involvement of at least 10% of body surface area; and
    • The patient has failed previous therapy (phototherapy or other systemic medications such as methotrexate).
Therapy is covered for six months.  Additional coverage is available if the patient relapses.  Once disease control is achieved it may be possible to decrease the dose or change to an injection every one to two weeks.
 
Etanercept should be prescribed by a rheumatologist or a dermatologist.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
  
The use of etanercept in circumstances other than those noted above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of Etanercept in circumstances other than the above would be considered investigational. Investigational services are an exclusion of the member certificate of coverage.

Rationale:
This policy was initially developed in response to the FDA approval of etanercept (Enbrel™) on 11/02/1998.  
Enbrel was initially approved by the FDA for reduction in signs and symptoms of moderately severe active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).
 
Since the initial approval the indication for Enbrel™ has been expanded to include the following:
 
    • Reducing signs and symptoms of moderate to severe active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.
    • Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis.
    • Reducing signs and symptoms in patients with active ankylosing spondylitis.
    • Treatment of adult patients aged 18 years or older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
 
2009 Update
Studies are currently being conducted on the use of Enbrel for numerous indications.  However at this time, there are no new FDA approved indications.  The policy remains unchanged.
 
2016 Update
A literature search conducted through July 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Keystone and colleagues reported on an open-label non-inferiority trial to evaluate radiographic and clinical outcomes up to 24 months in patients with RA enrolled in the Canadian Methotrexate and Etanercept Outcome study (Keystone, 2016). Patients with inadequate response to MTX received etanercept plus MTX for 6 months and then were randomized to etanercept monotherapy or continued etanercept plus MTX until 24 months. Radiographic data were analyzed using the modified total Sharp score (mTSS), joint space narrowing and erosion scores. Secondary outcomes included the 28-joint DAS with ESR (DAS28-ESR), Simplified Disease Activity Index, Clinical Disease Activity Index, HAQ Disability Index (HAQ-DI) and safety. Two hundred five of 258 patients enrolled were randomized (98 etanercept, 107 etanercept plus MTX). At month 24, the mean increase from baseline to month 24 for the etanercept and etanercept plus MTX arms, respectively, for the mTSS were 0.4 (s.d. 1.9) and 0.0 (s.d. 1.4); for joint space narrowing, 0.1 (s.d. 0.6) and 0.0 (s.d. 0.7) and for erosion, 0.3 (s.d. 1.5) and 0.0 (s.d. 1.0). At month 24, the mean increase from month 6 mean scores/count increases for DAS28-ESR were 0.56 (s.d. 1.26) and 0.08 (s.d. 1.50); for Simplified Disease Activity Index, 4.7 (s.d. 13.1) and 0.9 (s.d. 12.5); for Clinical Disease Activity Index, 4.1 (s.d. 12.3) and 1.0 (s.d. 12.3) and for HAQ-DI, 0.20 (s.d. 0.45) and 0.02 (s.d. 0.54). Patients with DAS28-ESR low disease activity (LDA)/remission at month 6 had numerically better outcomes at month 24 than patients with moderate to high disease activity at month 6. In patients with LDA/remission at month 6, outcomes were similar at month 24 between etanercept monotherapy and etanercept plus MTX, whereas patients with moderate to high disease activity at month 6 had numerically better outcomes with etanercept plus MTX than etanercept at month 24. There were no new safety signals and serious adverse events were not different between groups.
 
2017 Update
A literature search conducted using the MEDLINE database through July 2017 did not reveal any new information that would prompt a change in the coverage statement.

CPT/HCPCS:
J1438Injection, etanercept, 25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)

References: Aalbers C, Gerlag D, Vos K, et al.(2015) Intra-articular etanercept treatment in inflammatory arthritis: A randomized double-blind placebo-controlled proof of mechanism clinical trial validating TNF as a potential therapeutic target for local treatment. Joint Bone Spine. 2015 Oct;82(5):338-44. doi: 10.1016/j.jbspin.2015.03.002. Epub 2015 Jul 15.

Callen JP, Krueger GG, et al.(2003) AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49:897-9.

Current Food and Drug Administration approved product labeling. Accessed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/103795s5359lbl.pdf. Last accessed on 7/13/09.

Dayer JM, Krane SM.(2002) Anti-TNF-alpha therapy for ankylosing spondylitis - a specific or nonspecific treatment? NEJM 2002; 346:1399-1400.

Firestein GS, Zvaifler NJ.(1997) Anticytokine Therapy in Rheumatoid Arthritis. NEJM 1997; 337:195-7.

Goldsmith DR, Wagstaff AJ.(2005) Etanercept: a review of its use in the management of plaque psoriasis and psoriatic arthritis. Am J Clin Dermatol 2005; 9:121-36.

Gorman JF, Sack KE, Davis JC.(2002) Treatment of ankylosing spondylitis by inhibition of Tumor Necrosis Factor alpha. NEJM 2002; 346:1349-57.

Keystone EC, Pope JE, Thorne JC, et al.(2016) Two-year radiographic and clinical outcomes from the Canadian Methotrexate and Etanercept Outcome study in patients with rheumatoid arthritis. Rheumatology (Oxford). 2016 Feb;55(2):327-34. doi: 10.1093/rheumatology/kev338. Epub 2015 Sep 11

Kipnis CD, Myers WA, et al.(2005) Biologic treatments for psoriasis. J Am Acad Dermatol 2005; 52:671-82.

Mease PJ, Goffe BS, Metz J, et al.(2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000; 356:385-390.

Moreland FW, Baumgartner SW, Schiff MH, et al.(1997) Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)-Fc Fusion Protein. NEJM 1997; 337:141-7.

Saripalli YV, Gaspari AA.(2004) Focus on: biologics that affect therapeutic agents in dermatology. J Drugs Dermatol 2004; 4:233-45.

Stern DK, Tripp JM, et al.(2005) The use of systemic Immune Moderators in dermatology: an update. Dermatol Clin 2005; 23:259-300.

Weinblatt ME, Kremer JM, Bankhurst AD, et al.(1998) Phase II/III Trial of the TNF Receptor P75 Fc Fusion Protein (TNFR:Fc, Enbrel) in Combination with Methotrexate (MTX) in RA Patients. Arthrit Rheum 1998; 41:S189.

Winterfield LS, Mentor A, et al.(2005) Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis 2005; 64 (suppl III):ii87-ii90.

Yamauchi PS, Gindi V, Lowe NJ.(2004) The treatment of psoriasis and psoriatic arthritis with etanercept: practical considerations on monotherapy, combination therapy, and safety. Dermatol Clin 2004; 22:449-459.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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