แนวทางเวชปฏิบัติการใช้ยากลุ่ม Anti- TNF Agents ใน โรคข้อกระดูกสันหลังอักเสบติดยึด AS รวมถึง โรคข้อสันหลังอักเสบที่จำแนกประเภทไม่ได้ Undifferentiated Spondyloarthropathy โดย สมาคมรูมาติสซั่มแห่งประเทศไทย

แนวทางเวชปฏิบัติการใช้ยากลุ่ม Anti- TNF Agents ใน โรคข้อกระดูกสันหลังอักเสบติดยึดรวมถึง Undifferentiated Spondyloarthropathy*

(Guideline for Anti-TNF Therapies in Ankylosing Spondylitis Including Undifferentiated Spondyloarthropathy)*

 สมาคมรูมาติสซั่มแห่งประเทศไทย

 

เป็นที่ยอมรับกันโดยทั่วไปว่ายาในกลุ่ม anti-TNF agents มีประสิทธิภาพดีทั้งในระยะสั้น และระยะยาวในการรักษาโรค ankylosing spondylitis (AS) ที่ไม่ตอบสนองต่อการรักษาด้วยยามาตรฐาน แต่เนื่องจากยากลุ่มนี้มีราคาแพงและต้องใช้ต่อเนื่องระยะยาว แม้จะมีข้อมูลสนับสนุน ด้านความคุ้มค่าของการใช้ยากลุ่มนี้ แต่เป็นการศึกษาในประเทศที่มีรายได้มวลรวมประชาชาติสูง ดังนั้นเพื่อให้เกิดความคุ้มค่าในการใช้ยากลุ่มนี้ในประเทศไทย จึงต้องใช้ยาให้เหมาะสมตามข้อบ่งชี้ มีกระบวนการติดตามเพื่อประเมินประสิทธิภาพและผลข้างเคียงของยาในระยะยาว

โรค AS เป็นโรคที่จัดอยู่ในกลุ่ม spondyloarthropathy (SpA) เกณฑ์การวินิจฉัยโรคใน ปัจจุบันยังมีปัญหาอยู่มาก เพราะ New York Criteria เป็นเกณฑ์การวินิจฉัยโรคที่ออกแบบเพื่อ คัดเลือกผู้ป่วยเข้ามาศึกษาในงานวิจัยเกณฑ์การวินิจฉัยโรคต้องอาศัยการเปลี่ยนแปลงภาพถ่ายรังสี ซึ่งในระยะแรกอาจยังตรวจไม่พบ และผู้ป่วยบางรายมีข้ออักเสบเป็นอาการเด่นกว่าอาการปวดหลัง ทำให้การวินิจฉัยโรคมักล่าช้าไป 5-10 ปี ส่งผลถึงผลการรักษาที่ไม่มีประสิทธิภาพเท่าที่ควร ดังนั้นสมาคมรูมาติสซั่มแห่งประเทศไทยจึงเห็นชอบให้ใช้เกณฑ์การวินิจฉัยโรค AS ของ The European Spondyloarthropathy Study Group ด้วยอีกเกณฑ์หนึ่งซึ่งจะทำให้ผู้ป่วย AS ในระยะแรก (early AS) อาจได้รับการวินิจฉัยว่าเป็น undifferentiated SpA (uSpA) ซึ่งจัดอยู่ในกลุ่มโรคเดียวกัน ทั้งนี้เพื่อไม่ให้ผู้ป่วยสูญเสียโอกาสในการรักษาโรคตั้งแต่ระยะแรกเนื่องจากการรักษาโรคในระยะแรกจะให้ผลลัพธ์ของโรคดีกว่ารักษาเมื่อมีอาการรุนแรงหรือเกิดภาวะทุพพลภาพเรียบร้อยแล้ว

 วัตถุประสงค์

1. เพื่อให้การรักษาผู้ป่วย AS และ  uSpA  ด้วยยากลุ่ม anti TNF  agents  เป็นไปในแนวทางเดียวกัน

2. เพื่อให้ผู้ป่วย AS และ uSpA ได้รับประโยชน์สูงสุดจากการใช้ anti TNF agents ทั้งด้าน ประสิทธิภาพ (efficacy) และความปลอดภัย (safety)

3. เพื่อให้ความคุ้มค่า (cost-effectiveness) จากการรักษาด้วยยา anti TNF agents

กลุ่มเป้าหมาย

1. สำหรับอายุแพทย์โรคข้อและรูมาติสซั่มและแพทย์ผู้เชี่ยวชาญในการรักษาโรค AS และ uSpA เพื่อให้การใช้ยากลุ่ม anti-TNF agents เป็นไปในแนวทางเดียวกัน

2. สำหรับแพทย์ทั่วไป พยาบาลวิชาชีพชำนาญการด้านการดูแลผู้ป่วยโรคข้อ และ บุคคลากรทางการแพทย์อื่นๆ ที่เกี่ยวข้อง เพื่อเป็นแนวทางในการเฝ้าติดตามผลข้างเคียงจากการใช้ยา กลุ่มนี้

แนวทางปฏิบัติการใช้anti-TNF agents ในโรคข้อกระดูกสันหลังอักเสบติดยึด(ankylosing spondylitis) รวมถึงundifferentiated spondyloarthropathy*

 1.  ข้อบ่งชี้ (indication) (ตารางที่1)

ตารางที่ 1 แผนผังแสดงการใช้ยากลุ่ม Anti- TNF Agents  ใน AS และ USpA

ตารางที่ 1 แผนผังแสดงการใช้ยากลุ่ม Anti- TNF Agents ใน AS และ USpA

 ผู้ป่วยจะต้องมีคุณสมบัติครบเกณฑ์ทุกข้อดังต่อไปนี้

  •  ได้รับการวินิจฉัยโรค AS ครบถ้วนตามเกณฑ์ของ Modified New York criteria (ภาคผนวกที่14) หรือ The European Spondyloarthropathy Study Group Criteria (ภาคผนวกที่15)
  •  ได้รับการวินิจฉัยโรค undifferentiated SpA (uSpA) ครบถ้วนตามเกณฑ์ของ ESSG (ภาคผนวกที่16)
  •  อยู่ในระยะกำเริบโดยมี Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > 4 หน่วย(ภาคผนวกที่12) และมีค่า physician global assessment > 2 (ภาคผนวกที่ 10)
  • ไม่ตอบสนองต่อการรักษาด้วยยามาตรฐาน

               ในกรณีเป็น peripheral joint involvement ต้องไม่ตอบสนองต่อ NSAIDs อย่างน้อย 2 ชนิดภายใน ระยะเวลา 3 เดือน และ ไม่ตอบสนองต่อการใช้ยา DMARDs ≥ 2 ชนิด โดยแต่ละชนิดต้องใช้ใน ขนาดมาตรฐานอย่างน้อย 3 เดือน (ภาคผนวกที่17) และ ในกรณีที่เป็น oligoarthritis หรือ enthesitis จะต้องไม่ตอบสนองต่อการรักษาด้วย local steroid injection อย่างน้อย 2 ครั้ง(ถ้าไม่มีข้อห้าม) ในช่วงเวลาที่เหมาะสม และมีผลกระทบต่อคุณภาพชีวิตของผู้ป่วย (functional class III หรือIV) (ภาคผนวกที่11)

                กรณีเป็น axial involvement

  •  ไม่ตอบสนองต่อ NSAIDs ³  2 ชนิด (โดยใช้ทีละชนิดและแต่ละชนิดใช้ในขนาดรักษา) เป็นเวลาอย่างน้อย 3 เดือน
  •  ไม่ตอบสนองต่อยา DMARDs ³  2  ชนิด(sulphasalazine,  methotrexate,  azathioprine  –ตามข้อแนะนำของผู้เชี่ยวชาญ)เป็นเวลาอย่างน้อย 3 เดือน

 

                                                            ภาคผนวก 13

ขนาดยา DMARDs ที่ควรใช้ในการรักษาโรค AS ก่อนให้ Anti-TNF agents

Sulphasalazine    ขนาดเต็มที่    40 มก/กก/วัน แบ่งให้ 2-3 เวลา สูงสุดไม่เกิน 3 กรัม/วัน

Azathioprine    ขนาดเต็มที่    2 มก/กก/วัน แบ่งให้ 2 เวลา

Methotrexate    ขนาดเต็มที่    0.3 มก/กก/สัปดาห์  สูงสุดไม่เกิน 20 มก./สัปดาห์

Leflunomide    ขนาดเต็มที่    20 มก/วัน

 

 

2.  ข้อห้าม (contraindication) (ภาคผนวกที่4)

 

3.  การประเมินก่อนให้ยา(pretreatment screening)  (ภาคผนวกที่5 และ 6)

 

 

4.  ขนาดและวิธีการบริหารยา (dosage and administration)

  1. Etanercept (25, 50 มก./ขวด) 25 มก. ฉีดเข้าใต้ผิวหนังสัปดาห์ละ 2 ครั้ง หรือ 50 มก. ฉีด เข้าใต้ผิวหนังสัปดาห์ละ หรือให้ร่วมกับ methotrexate
  2. Infliximab (100 มก./ขวด) เริ่มให้ในขนาด 5 มก/กก./ครั้งเจือจางใน 0.9% NSS 250 มล. หยดเข้าหลอดเลือดดำช้าๆ ในเวลาไม่น้อยกว่า 2 ชั่วโมง สัปดาห์ที่ 0, 2, 6 และต่อด้วยทุก 8 สัปดาห์ หรือให้ร่วมกับ methotrexate หากการตอบสนองไม่เป็นที่น่าพอใจหลังจากรักษา ไปนาน 3 เดือน อาจพิจารณาเพิ่มขนาดยาเป็น 10 มก./กก./ครั้งหยดเข้าหลอดเลือดทุก 8 สัปดาห์

  

5.   การประเมินผลตอบสนองต่อการรักษา (evaluation of effectiveness)

 ประเมินผลในสัปดาห์ที่ 12 นับจากวันที่เริ่มให้ยา anti-TNF agents

  •                  ผู้ที่ตอบสนองต่อการรักษา(responder) หมายถึง ผู้ป่วยมีอาการดีขึ้นโดยบรรลุเกณฑ์ การประเมินดังนี้

 สำหรับผู้ป่วย peripheral involvement ถือว่าผู้ป่วยมีการตอบสนอง (responder) เมื่อบรรลุเกณฑ์ 2/3 ข้อ โดยต้องมี 5.1 หรือ 5.2 ร่วมด้วยอย่างน้อย 1 ข้อ

                 5.1  Tender joint count ลดลงร้อยละ ≥ 30

                 5.2  Swollen joint count ลดลงร้อยละ ≥ 30

                 5.3  Physician global assessment มีการเปลี่ยนแปลงดีขึ้น ≥1หน่วย

สำหรับผู้ป่วยaxial  joint  involvement  ถือว่าผู้ป่วยมีการตอบสนอง(responder)  เมื่อค่า BASDAI ลดลง ≥ 2 หน่วย  และphysician global assessment ดีขึ้น ≥ 1 หน่วย

  •                  ผลการเปลี่ยนแปลงทางรังสี: ควรส่งตรวจภาพรังสีมือ ข้อมือ และ เท้า ทุกปีอาจให้ คะแนนโดยใช้ modified total Sharp score

 

6. การให้ยาซ้ำและระยะเวลาของการให้ยา (Repeated treatment and treatment duration)

 ปัจจุบันยังไม่มีข้อมูลเกี่ยวกับระยะเวลาในการให้ยา anti-TNF agents ในการรักษา ankylosing spondylitis ว่าควรให้ยานานเท่าใด แต่มีข้อเสนอแนะว่าเพื่อลดความเสี่ยงในการเกิด อาการข้างเคียงจากยาในระยะยาว ในรายที่ตอบสนองดีต่อการรักษาด้วย anti-TNF agents ให้พิจารณาปรับลดขนาดยาลงหรือหยุดยาตามความเหมาะสม โดยพิจารณาให้ยา DMARDs ต่อเนื่องระยาวเพื่อป้องกันโรคกำเริบ

7.     เกณฑ์การถอนตัวจากการรักษา (drug withdrawal criteria)

  • ให้หยุดยากลุ่ม anti-TNF agents ในกรณีต่อไปนี้
  • โรคมะเร็ง
  • เกิดผลข้างเคียงหรือพิษจากยาอย่างรุนแรง
  • ตั้งครรภ์ (ถอนตัวชั่วคราว)
  • การติดเชื้อรุนแรง (ถอนตัวชั่วคราว)
  • การผ่าตัด (ถอนตัวชั่วคราว) กรณีผ่าตัดไม่เร่งด่วนควรหยุด etanercept ล่วงหน้า 2 สัปดาห์และหยุด infliximab ล่วงหน้า8 สัปดาห์
  • ผู้ป่วยที่ไม่ตอบสนองต่อการรักษา (non-responder) หมายถึง ผู้ป่วยที่มีอาการไม่ดีขึ้น โดยไม่บรรลุตามเกณฑ์การตอบสนองต่อการรักษา (ดังที่ระบุไว้ในข้อ 5) หลังใช้ยานาน 12 สัปดาห์

8.   ผลข้างเคียง (adverse events) (ภาคผนวกที่7)

 

9.   ข้อควรปฏิบัติและการเฝ้าติดตามผลข้างเคียงระหว่างการให้ยา biologic (adverse events)

(ภาคผนวกที่8)

 

10. ระยะเวลาของการให้ยา (treatment duration)

 ปัจจุบันยังไม่มีข้อมูลเกี่ยวกับระยะเวลาในการให้ยา anti-TNF agents ส าหรับผู้ป่วย AS ว่า ควรให้ยานานเท่าใดแต่มีข้อเสนอแนะว่าเพื่อลดความเสี่ยงในการเกิดอาการข้างเคียงจากยาในระยะยาว ในรายที่ตอบสนองดีต่อการรักษาด้วย anti-TNF agents ให้พิจารณาปรับลดขนาดยาลงหรือหยุด ยาตามความเหมาะสม โดยพิจารณาให้ยา DMARDs ต่อเนื่องระยาวเพื่อป้องกันโรคกำเริบ

 

10. ระบบเฝ้าติดตามผลการรักษาและผลข้างเคียง (effectiveness and side effect monitoring)

 เพื่อความคุ้มค่า แพทย์ผู้รักษาควรทำการประเมินประสิทธิภาพและผลข้างเคียงจากการใช้ยาทุก 3 เดือนเพื่อปรับแผนการรักษาให้เหมาะสมกับสภาวะของโรคและอาจพิจารณาหยุดยาถ้าเป็นไปได้

อ่านข้อมูลทั้งหมดได้ที่ สมาคมรูมาติซั่มแห่งประเทศไทย

แนวทางเวชปฏิบัติการใช้สารชีวภาพในการรักษาโรครูมาติก (Guideline for Biologic Therapy in Rheumatic Diseases)

 

 

 

Study Comparing Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis

 

Study Comparing Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis

Register: ClinicalTrials.gov
Last refreshed on: 3 June 2010
Main ID:  NCT00422227
Date of registration: 11/01/2007
Primary sponsor: Wyeth
Public title: Study Comparing Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis
Scientific title: A Randomized, Open-Label Study in the Asia-Pacific Region Comparing the Safety and Efficacy of Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis
Date of first enrolment: June 2007
Target sample size: 300
Recruitment status: Completed
URL:  http://clinicaltrials.gov/show/NCT00422227
Study type:  Interventional
Study design:  Allocation: Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment  
Countries of recruitment
Hong Kong India Korea, Republic of Malaysia Philippines Singapore Taiwan Thailand
Contacts
Name:   Trial Manager
Address:   
Telephone:  
Email:  
Affiliation:  For Hong Kong: medinfo@wyeth.com
Name:   Trial Manager
Address:   
Telephone:  
Email:  
Affiliation:  For Taiwan: medinfo@wyeth.com
Name:   Medical Monitor
Address:   
Telephone:  
Email:  
Affiliation:  Wyeth
Key inclusion & exclusion criteria
Inclusion Criteria: – Diagnosis of RA – Currently receiving an adequate dose of methotrexate (MTX) for treatment of RA – Active RA at time of screening and baseline Exclusion Criteria: – Previous or current treatment with etanercept (ETN), other tumor necrosis factor-alpha inhibitors, or other biologic agents – Concurrent treatment with a DMARD, other than MTX, at screening – Receipt of any DMARD, other than MTX, within 3 months before screening

Age minimum: 18 Years
Age maximum: 70 Years
Gender: Both

Health Condition(s) or Problem(s) studied
Rheumatoid Arthritis
Intervention(s)
Drug: Etanercept , Methotrexate
Drug: Methotrexate; sulfasalazine; hydroxychloroquine;leflunomide
Primary Outcome(s)
American College of Rheumatology (ACR) response [Time Frame: 16 weeks]
Secondary Outcome(s)
Secondary ID(s)
0881A1-408
Source(s) of Monetary Support
Please refer to primary and secondary sponsors
Secondary Sponsor(s)

 

Data From: http://apps.who.int/trialsearch/trial.aspx?TrialID=NCT00422227

Information specific to: Enbrel 25mg powder and solvent for solution for injection vials when used in Ankylosing spondylitis

Information specific to: Enbrel 25mg powder and solvent for solution for injection vials when used in Ankylosing spondylitis

Enbrel (En-brell) is a medicine which is used in ankylosing spondylitis, cervical spondylitis and ankylosing spondylitis when prevention of NSAID-induced gastric and duodenal ulceration is needed. Enbrel contains etanercept. It is supplied by Wyeth Pharmaceuticals.

The information in this Medicine Guide for Enbrel varies according to the condition being treated and the particular preparation used.

Your medicine

Enbrel is an immunosuppressive medicine. It helps to suppress overactivity of the immune system in arthritic conditions and in plaque psoriasis. It can help to reduce pain and swelling by limiting inflammation. Enbrel is usually used with the medicinemethotrexate when treating rheumatoid arthritis.

Due to its effects on the immune system, people who have Enbrel are prone to getting infections. This includes serious infections such as sepsis. It is for this reason that people who have Enbrel are monitored for infections. People who have Enbrel must be careful to avoid exposure to chicken poxinfections whenever possible. If you have been exposed to chickenpox during treatment with Enbrel you must get immediate medical advice.

Other information about Enbrel:

  • in certain circumstances, such as when you are going to have your medicine regularly over a long period of time, you may be shown how to inject the medicine yourself
  • people taking this medicine should be given an alert card. You should keep it with you at all times as it can alert anyone involved in your medical care that you are having Enbrel. If you have any concerns or questions about having Enbrel you should discuss them with your prescriber
  • if possible, children should be brought up to date with all immunisation before initiating Enbrel therapy

Enbrel needs to be injected. Your prescriber will show you how to inject this medicine yourself.

There should also be instructions on how to inject this medicine in the Patient Information Leaflet that comes with this medicine or on the pharmacy label.

The pharmacy label on your medicine tells you how much medicine you should have. It also tells you how often you should have your medicine. This is the dose that you and your prescriber have agreed you should have. You should not change the dose of your medicine unless you are told to do so by your prescriber.

Do not share your medicine with other people. It may not be suitable for them and may harm them.

If you feel that the medicine is making you unwell or you do not think it is working, then talk to your prescriber.

Whether this medicine is suitable for you

Enbrel is not suitable for everyone and some people should never use it. Other people should only use it with special care. It is important that the person prescribing this medicine knows your full medical history.

Your prescriber may only prescribe this medicine with special care or may not prescribe it at all if you:

  • are allergic or sensitive to or have had a reaction to any of the ingredients in the medicine
  • are taking or have recently taken immunosuppressants
  • have a weakened immune system or are prone to infections
  • have alcoholicliver disease
  • have been in close contact with somebody with tuberculosis
  • have certain types of vasculitis
  • have come into contact with someone who has an infection
  • have diabetes
  • have had blood problems
  • have had PUVA treatment for a long time
  • have heart problems
  • have hepatitis Binfection or are at risk of having hepatitis Binfection
  • have kidney problems
  • have liver problems
  • have or have had cancer
  • have or have had demyelinating disorders
  • have or have had hepatitis Cinfection
  • have or have had infections
  • have or have had tuberculosis
  • have psoriasis
  • have recently been, or are going to be, vaccinated with live vaccines. For more information about vaccines, ask your prescriber, nurse or pharmacist
  • have risk factors for skin cancer

Furthermore the prescriber may only prescribe this medicine with special care or may not prescribe it at all for a child under eight years of age.

As part of the process of assessing suitability to take this medicine a prescriber may also arrange tests:

  • to check that this medicine is not having any undesired effects

Over time it is possible that Enbrel can become unsuitable for some people, or they may become unsuitable for it. If at any time it appears that Enbrel has become unsuitable, it is important that the prescriber is contacted immediately.

Alcohol

Alcohol can interact with certain medicines.

In the case of Enbrel:

  • there are no known interactions between alcohol and Enbrel

Diet

Medicines can interact with certain foods. In some cases, this may be harmful and your prescriber may advise you to avoid certain foods.

In the case of Enbrel:

  • there are no specific foods that you must exclude from your diet when having Enbrel

Driving and operating machinery

When taking any medicine you should be aware that it might interfere with your ability to drive or operate machinery safely.

Like all medicinesEnbrel can cause side effects. You should see how this medicine affects you and then judge if you are safe to drive or operate machinery. If you are in any doubt, talk to your prescriber.

Family planning and pregnancy

Most medicines, in some way, can affect the development of a baby in the womb. The effect on the baby differs between medicines and also depends on the stage of pregnancy that you have reached when you take the medicine.

In the case of Enbrel:

  • the use of this medicine during pregnancy is not recommended. If you could become pregnant, you must use effective contraception or abstain from penetrative sex. You must contact your prescriber if you become pregnant, or think you have become pregnant, while having Enbrel

You should discuss your personal circumstances with your doctor if you are pregnant or want to become pregnant. This is so that together you can make a decision about what treatment you may need during your pregnancy.

You should discuss whether there are any other medicines which you could take during pregnancy which would treat your condition.

Breast-feeding

Certain medicines can pass into breast milk and may reach your baby through breast-feeding.

In the case of Enbrel:

  • you should only have this medicine while breast-feeding if your doctor thinks you need it

Before you have your baby you should discuss breast-feeding with your doctor or midwife. They will help you decide what is best for you and your baby based on the benefits and risks associated with this medicine. You should only breast-feed your baby while taking this medicine on the advice of your doctor or midwife.

Taking other medicines

If you are taking more than one medicine they may interact with each other. At times your prescriber may decide to use medicines that interact, in other cases this may not be appropriate.

The decision to use medicines that interact depends on your specific circumstances. Your prescriber may decide to use medicines that interact, if it is believed that the benefits of taking the medicines together outweigh the risks. In such cases, it may be necessary to alter your dose or monitor you more closely.

Tell your prescriber the names of all the medicines that you are taking so that they can consider all possible interactions. This includes all the medicines which have been prescribed by your GP, hospital doctor, dentist, nurse, health visitor, midwife or pharmacist. You must also tell your prescriber about medicines which you have bought over the counter without prescriptions.

The following medicines may interact with Enbrel:

  • abatacept
  • anakinra
  • methotrexate
  • sulfasalazine

The following types of medicine may interact with Enbrel:

  • antidiabetics
  • live vaccines

If you are taking Enbrel and one of the above medicines or types of medicines, make sure your prescriber knows about it.

Complementary preparations and vitamins

Medicines can interact with complementary preparations and vitamins. In general, there is not much information available about interactions between medicines and complementary preparations or vitamins.

If you are planning to take or are already taking any complementary preparations and vitamins you should ask your prescriber whether there are any known interactions with Enbrel.

Your prescriber can advise whether it is appropriate for you to take combinations that are known to interact. They can also discuss with you the possible effect that the complementary preparations and vitamins may have on your condition.

If you experience any unusual effects while taking this medicine in combination with complementary preparations and vitamins, you should tell your prescriber.

Ingredients of your medicine

Medicines contain active ingredients. They may also contain other, additional ingredients that help ensure the stability, safety and effectiveness of the medicine. Some may be used to prolong the life of the medicine.

Enbrel contains:

  • etanercept
  • mannitol (E421)
  • sucrose
  • trometamol
  • water for injections

If you are not able to take any of the ingredients in your medicine, talk to your prescriber or pharmacist to see if they can suggest an alternative medicine. If you have reacted badly to Enbrel before, do not have Enbrel. Talk to your prescriber, pharmacist or nurse as soon as possible.

How to take your medicine

This medicine needs to be injected. Your medical team will train you how to inject the medicine yourself. For more information see the Patient Information Leaflet or contact one of your medical team.

In the case of Enbrel:

  • detailed advice on how to have Enbrel can be found in the Patient Information Leaflet that comes with this medicine

If you have any concerns about this medicine or about the process of having it you should talk to someone who is involved in your medical care.

When to take your medicine

Some medicines work best if they are taken at a specific time of day. If someone is giving you this injection, the person with responsibility for giving you your medicine will make sure that you have your medicine at the prescribed times.

If you are injecting this medicine yourself, make sure that you find out from your prescriber the best time to have Enbrel.

Taking too much of your medicine

Taking extra doses of some medicines can be harmful. In some cases even one extra dose can cause you problems.

The person who is responsible for giving you your medicine will make sure that you are given the correct dose of your medicine. If you inject the medicine yourself, make sure that you do not take any extra doses as this could cause you problems. If you take extra doses of your medicine, you must get medical advice immediately. You may need a test to assess the effect of taking extra doses. This is because the effects of taking too much medicine are very complex so it is very important that you seek medical advice.

Contact your prescriber, pharmacist, specialist clinic or NHS Direct on 0845 46 47 for advice.

Make sure you take all of your medicinecontainers with you if you are advised to go to hospital.

Stopping your medicine

Suddenly stopping your medicine may cause your original condition to return. The person in charge of your care will make the decision about whether you should stop this medicine. If you experience any problems while having this medicine talk to someone who is involved in your care. If you are injecting this medicine yourself, and are not having any problems with the medicine, do not stop having it, even if you feel better, unless advised to do so by your prescriber.

If you are in any doubt, contact your prescriber, pharmacist, specialist clinic or NHS Direct on 0845 46 47.

Looking after your medicine

If you are injecting this medicine yourself, read the pharmacy label to find out how you should look after your medicine. It is a good idea to keep your medicine in the original container. This will help to keep your medicine in the best condition and also allow you to check the instructions.

Do not use the medicine if the packaging appears to have been tampered with or if the medicine shows any signs of damage. Specific information about how to look after Enbrel can be found in the Patient Information Leaflet that comes with this medicine. Make sure that the medicine is out of the sight and reach of children.

In the case of Enbrel:

  • store in a fridge at temperatures between 2-8°C
  • you must not freeze this medicine
  • use this medicine immediately after you have made it up. If you need to store it after it has been made up, keep it in the fridge between 2-8°C and use it within 6 hours. Discard the medicine if you have not used it within 6 hours

Do not use the medicine after the expiry date shown on the packaging. If you have any unused medicine, return it to your pharmacist who will dispose of it safely.

Side-effects

A medicine is only made available to the public if the clinical trials have shown that the benefits of taking the medicine outweigh the risks.

Once a medicine has been licensed, information on the medicine’s effects, both intended and unintended, is continuously recorded and updated.

Some side-effects may be serious while others may only be a mild inconvenience.

Everyone’s reaction to a medicine is different. It is difficult to predict which side-effects you will have from taking a particular medicine, or whether you will have any side-effects at all. The important thing is to tell your prescriber or pharmacist if you are having problems with your medicine.

Very common: More than 1 in 10 people who have Enbrel

  • infections – some of the infections caused by Enbrel may be fatal. You must immediately seek medical advice if you get any symptoms of an infection such as a persistent fever while having Enbrel
  • injection site problems such as bleeding, bruising, redness, itching, pain or swelling

Common: More than 1 in 100 people who have Enbrel

  • fever – you must immediately seek medical advice if you develop a fever because this could be a sign of infection
  • hypersensitivity reactions or allergic reactions including anaphylactic type reactions – if you develop symptoms such angioedema or bronchospasm, stop having Enbrel and seek medical advice immediately
  • itching
  • production of antibodies to Enbrel

Uncommon: More than 1 in 1000 people who have Enbrel

  • blood or bone marrow problems – some of the blood problems caused by Enbrel may be fatal. You or your carer should seek medical advice if any of these occur: fever, sore throat, bruising, bleeding or paleness
  • cellulitis
  • eye or eyesight problems including irritation or inflammation of the eye
  • lung problems such as pneumonitis and pulmonary fibrosis which may be fatal
  • psoriasis or psoriasis-like rash; worsening of psoriasis
  • skin cancers
  • skin rash or rashes
  • urticaria

Rare: More than 1 in 10,000 people who have Enbrel

  • abnormal laboratory test results
  • brain or central nervous system problems
  • erythema multiforme
  • lupus or lupus-like problem
  • lymphoma
  • seizures
  • Stevens-Johnson syndrome
  • tuberculosis – some of the tuberculosisinfections caused by Enbrel may be fatal. You must seek medical advice if you get a persistent cough, fever or weight loss
  • vasculitis
  • worsening of heart problems

Very rare: Fewer than 1 in 10,000 people who have Enbrel

  • demyelinating polyneuropathies including Guillain-Barré syndrome, chronic inflammatory polyneuropathy and multifocal motor neuropathy or worsening of existing demyelinating problems
  • toxic epidermal necrolysis

The frequency of these side-effects is unknown

  • abscess
  • appendicitis
  • autoimmune problems
  • bowel problems
  • diabetes
  • diarrhoea
  • ear or hearing problems
  • gallbladder problems
  • gastritis
  • gastrointestinal problems
  • joint problems
  • leg ulcers
  • muscle problems
  • reactivation of hepatitis B
  • recall injection site reactions
  • sinusitis
  • skin ulcers
  • tumours including breast or lung malignancies
  • worsening of hepatitis C

If you feel unwell or if you have concerns about a side-effect, you will need to seek advice. If you feel very ill, get medical help straight away. Contact your prescriber, pharmacist, nurse or call NHS Direct on 0845 46 47.

Content provided by Datapharm

Yellow Card scheme

The Yellow card Scheme is vital in helping the MHRA monitor the safety of the medicines and vaccines that are on the market.

Before a medicine is granted a licence so that it can be made available in the United Kingdom, it must pass strict tests and checks to ensure that it is acceptably safe and effective. All effective medicines however, can cause side effects.

 

This medicine is also available as:

Printable guides available for this medicine:

Data from: http://www.nhs.uk/Conditions/Ankylosing-spondylitis/Pages/MedicineOverview.aspx?condition=Ankylosing spondylitis&medicine=Enbrel&preparation=Enbrel 25mg powder and solvent for solution for injection vials

==Etanercept (Enbrel®)== BCBSF medical coverage guideline

Subject: Etanercept (Enbrel®)

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

Position Statement Dosage/ Administration Billing/Coding Reimbursement Program Exceptions Definitions
Related Guidelines Other References Updates    

DESCRIPTION:

Etanercept (Enbrel®) binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), and ankylosing spondylitis and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.

Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. Etanercept inhibits binding of both TNFα and TNFβ (lymphotoxin alpha [LTα]) to cell surface TNFRs, rendering TNF biologically inactive. Cells expressing transmembrane TNF that bind ENBREL® are not lysed in vitro in the presence or absence of complement.

POSITION STATEMENT:

REQUIRED: Certificate of Medical Necessity

NOTE: The attached Certificate of Medical Necessity should be completed and submitted with the request for etanercept, in order to facilitate medical review. To access the certificate of medical necessity, click on the link below, complete the required fields, and print.

Etanercept meets the definition of medical necessity when administered for the following conditions (see TABLE 1 for specific criteria):

  1. Moderately to Severely Active Rheumatoid Arthritis
  2. Moderately to Severely Active Polyarticular Juvenile Rheumatoid Arthritis
  3. Active Ankylosing Spondylitis
  4. Psoriatic Arthritis
  5. Chronic Moderate to Severe Plaque Psoriasis.

Table 1:

SPECIFIC CRITERIA FOR ETANERCEPT (ENBREL®) THERAPY

 

Condition Criteria
  1. Moderately to Severely Active Rheumatoid Arthritis
  • Patient has a history of beneficial clinical response to etanercept therapy for moderately to severely active rheumatoid arthritis and the dosage does not exceed 50 mg per week OR
  • Patient is 18 years of age or older AND
  • Patient has had an inadequate response to one or more disease modifying antirheumatic drugs (DMARDS, see Table 2). AND
  • Dose does not exceed 50 mg per week given as one injection.
  1. Moderately to Severely Active Polyarticular Juvenile Rheumatoid Arthritis
  • Patient has a history of beneficial clinical response to etanercept therapy for moderately to severely active polyarticular juvenile rheumatoid arthritis and the dosage does not exceed 50 mg per week OR
  • Patient is 2 years of age or older AND
  • Patient has had an inadequate response to one or more DMARDS. AND
  • Dose does not exceed 0.8 mg/kg per week (up to a maximum of 50 mg per week) given as one or two injections (25 mg per injection).
  1. Active Ankylosing Spondylitis
  • Patient has a history of beneficial clinical response to etanercept therapy for active ankylosing spondylitis and the dosage does not exceed 50 mg per week OR
  • Etanercept is being used for reducing signs and symptoms. AND
  • Dose does not exceed 50 mg per week given as one injection.
  1. Psoriatic Arthritis
  • Patient has a history of beneficial clinical response to etanercept therapy for psoriatic arthritis and the dosage does not exceed 50 mg per week OR
  • Etanercept is to be used for improving physical function in patients with psoriatic arthritis
  • Etanercept can be used in combination with methotrexate. AND
  • Dose does not exceed 50 mg per week given as one injection.
  • Patient has a history of beneficial clinical response to etanercept therapy for chronic moderate to severe plaque psoriasis and the dosage does not exceed 50 mg per week OR
  • Patient 18 years of age or older AND
  • Patient must have failed to adequately respond to or is intolerant to one of the following phototherapies (unless contraindicated):
  1. Psoralens (methoxsalen, trioxsalen) with UVA light (PUVA); OR
  2. UVB with coal tar or dithranol;OR
  3. UVB (standard or narrow-band); AND
  4. Dose does not exceed 50 mg twice weekly for 3 months, then 50 mg weekly as a maintenance dose.

Etanercept is considered experimental or investigationalfor all other indications, as there is insufficient clinical evidence to support its use.

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING IT’S USAGE.

Moderate to Severe Rheumatoid Arthritis:

Patients over the age or 18, 50 mg per week given as one subcutaneous (SQ) injection.

Juvenile rheumatoid arthritis (JRA):

Pediatric patients ages 4 to 17 years with active polyarticular-course JRA with inadequate response to 1 or more DMARD (see Table 2 under OTHER) the dose is 0.8 mg/kg per week (up to a maximum of 50 mg per week subcutaneously (SQ)) given as one or two injections (maximum 25 mg per injection subcutaneously (SQ)).

Active Ankylosing Spondylitis:

50mg per week given as one subcutaneous (SQ) injection.

Psoriatic Arthritis:

50mg per week given as one subcutaneous (SQ) injection.

Chronic Moderate to Severe Plaque Psoriasis:

50 mg twice weekly subcutaneously (SQ), given 3 to 4 days apart for 3 months, then 50 mg weekly subcutaneously (SQ) as maintenance therapy.

PRECAUTIONS:

 

WARNING
RISK OF SERIOUS INFECTIONS

Patients treated with etanercept are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Etanercept should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before etanercept use and during therapy. Treatment for latent infection should be initiated prior to etanercept use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral and other infections due to opportunistic pathogens.

The risks and benefits of treatment with etanercept should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Etanercept, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES

Lymphona and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including etanercept.

Serious infections: Serious and sometimes fatal infections caused by bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving TNF-blocking agents. Among opportunistic infections, TB, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported. Patients have frequently presented with disseminated rather than localized disease, and are often taking concomitant immunosuppressants, such as methotrexate or corticosteroids, with etanercept.

Do not initiate treatment with etanercept in patients with an active infection, including clinically important localized infections. Consider the risks and benefits of treatment prior to initiating therapy in patients with chronic or recurrent infection; who have been exposed to TB; who have resided or traveled in areas of endemic TB or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with an underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes.

Cases of reactivation of TB or new TB infections have been observed in patients receiving etanercept, including patients who have previously received treatment for latent or active TB. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent TB infection is lower with etanercept than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of TB reactivation have been reported for TNF blockers, including etanercept. Evaluate patients for TB risk factors and test for latent infection prior to initiating etanercept and periodically during therapy.

Treatment of latent TB infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of TB reactivation during therapy. Induration of 5 mm or more with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent TB is needed prior to initiating etanercept, even for patients previously vaccinated with Bacille Calmette-Guérin.

Consider anti-TB therapy prior to initiation of etanercept in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. Consultation with a health care provider with expertise in the treatment of TB is recommended to aid in the decision whether initiating anti-TB therapy is appropriate for an individual patient.

Strongly consider TB in patients who develop a new infection during etanercept treatment, especially in patients who have previously or recently traveled to countries with a higher prevalence of TB, or who have had close contact with a person with active TB.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with etanercept, including the development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Tests for latent TB infection may be falsely negative while on therapy with etanercept.

Discontinue etanercept if a patient develops a serious infection or sepsis. Closely monitor a patient who develops a new infection during treatment with etanercept and have the patient undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Postmarketing cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including etanercept. For patients who reside or travel in regions where mycoses are endemic, suspect invasive fungal infection if they develop a serious systemic illness. Consider appropriate empiric antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, make a decision to administer empiric antifungal therapy in these patients in consultation with a health care provider with expertise in the diagnosis and treatment of invasive fungal infections, and take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Neurologic effects: Treatment with etanercept and other agents that inhibit TNF has been associated with rare cases of new-onset or exacerbation of CNS-demyelinating disorders, some presenting with mental status changes and some associated with permanent disability. Cases of transverse myelitis, optic neuritis, multiple sclerosis, and new-onset or exacerbation of seizure disorders have been observed in association with etanercept therapy. The causal relationship to etanercept therapy remains unclear. While no clinical trials have been performed evaluating etanercept therapy in patients with multiple sclerosis, other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity. Exercise caution in considering the use of etanercept in patients with preexisting or recent-onset CNS-demyelinating disorders.

Hematologic effects: Rare reports of pancytopenia, including aplastic anemia, some with a fatal outcome, have been reported in patients treated with etanercept. The causal relationship to etanercept therapy remains unclear. Although no high-risk group has been identified, exercise caution in patients being treated with etanercept who have a history of significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., bleeding, bruising, pallor, persistent fever) while on etanercept. Consider discontinuation of etanercept therapy in patients with confirmed significant hematologic abnormalities.

Malignancies: In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving the TNF blocker compared with control patients. During the controlled portions of etanercept trials, 3 lymphomas were observed among 4,509 etanercept-treated patients versus 0 among 2,040 control patients (mean duration of controlled treatment ranged from 3 to 24 months). In the controlled and open-label portions of clinical trials of etanercept, 9 lymphomas were observed in 5,723 patients over approximately 11,201 patient-years of therapy. This is 3-fold higher than that expected in the general population. While patients with RA or psoriasis, particularly those with highly active disease, may be at a higher risk (up to several-fold) for the development of lymphoma, the potential role of TNF-blocking therapy in the development of malignancies is not known.

In a randomized, placebo-controlled study of 180 patients with Wegener granulomatosis in which etanercept was added to standard treatment (including cyclophosphamide, methotrexate, and corticosteroids), the patients receiving etanercept experienced more noncutaneous solid malignancies than patients receiving placebo. The addition of etanercept to standard treatment was not associated with improved clinical outcomes when compared with standard therapy alone. The use of etanercept in patients with Wegener granulomatosis receiving immunosuppressive agents is not recommended. The use of etanercept in patients receiving concurrent cyclophosphamide therapy is not recommended.

Hepatitis B virus reactivation: Use of TNF blockers, including etanercept, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Prior to initiating TNF-blocker therapy, evaluate patients at risk for HBV infection for prior evidence of HBV infection. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Closely monitor patients who are carriers of HBV and require treatment with etanercept for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consider stopping etanercept and initiating antiviral therapy with appropriate supportive treatment. The safety of resuming etanercept therapy after HBV reactivation is controlled is not known. Therefore, weigh the risks and benefits when considering resumption of therapy in this situation.

Heart failure: Two large clinical trials evaluating the use of etanercept in the treatment of heart failure were terminated early because of lack of efficacy. Results of one study suggested higher mortality in patients treated with etanercept compared with placebo. Results of the second study did not corroborate these observations. Analyses did not identify specific factors associated with increased risk of adverse outcomes in patients with heart failure treated with etanercept. There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking etanercept. There have also been rare reports of new-onset CHF, including CHF in patients without known preexisting cardiovascular disease. Some of these patients have been younger than 50 years of age. Exercise caution when using etanercept in patients who also have heart failure, and monitor patients carefully.

Immunosuppression: Anti-TNF therapies, including etanercept, affect host defenses against infections and malignancies because TNF mediates inflammation and modulates cellular immune responses. In a study of 49 patients with RA treated with etanercept, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. The impact of treatment with etanercept on the development and course of malignancies, as well as active or chronic infections, is not fully understood. The safety and efficacy of etanercept in patients with immunosuppression or chronic infections have not been evaluated.

Immunizations: Most patients with psoriatic arthritis receiving etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower, and fewer patients had 2-fold rises in titers compared with patients not receiving etanercept. The clinical significance of this is unknown. Patients receiving etanercept may receive concurrent vaccinations, except for live vaccine. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept.

It is recommended that patients with juvenile idiopathic arthritis, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating etanercept therapy. Temporarily discontinue etanercept therapy in patients with a significant exposure to varicella virus and consider prophylactic treatment with varicella-zoster immune globulin.

Autoimmunity: Treatment with etanercept may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis that may resolve following withdrawal of etanercept. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with etanercept, discontinue treatment and carefully evaluate the patient.

Elderly: Because there is a higher incidence of infections in the elderly population in general, use caution in treating elderly patients.

Monitoring: Closely monitor patients for the development of signs and symptoms of infection during and after treatment with etanercept, including the development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Closely monitor a patient who develops a new infection during treatment with etanercept and have the patient undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. Closely monitor patients who develop a new infection while undergoing treatment with etanercept. Discontinue administration of etanercept if a patient develops a serious infection or sepsis. Do not initiate treatment with etanercept in patients with active infections, including chronic or localized infections. Exercise caution when considering the use of etanercept in patients with a history of recurring infections or with underlying conditions that may predispose patients to infections, such as advanced or poorly controlled diabetes. Evaluate patients for TB risk factors and test for latent infection prior to initiating etanercept and periodically during therapy. Closely monitor patients who are carriers of HBV and require treatment with etanercept for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.

BILLING/CODING INFORMATION:

The following codes may be used to report Etanercept (Enbrel®).

CPT Coding:

 

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS Coding:

 

J1438 injection, etanercept, 25 mg

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

696.0 Psoriatic arthropathy
696.1 Other psoriasis
711 – 711.99 Arthropathy associated with infections – unspecified infective arthritis (multiple sites)
713.0 – 713.8 Arthropathy associated with other endocrine and metabolic disorders – arthropathy associated with other conditions classifiable elsewhere
714.0 – 714.9 Rheumatoid arthritis – unspecified inflammatory polyarthropathy
716.20 – 716.29 Allergic arthritis (site unspecified) – allergic arthritis (multiple sites)
720.0 Ankylosing spondylitis
720.81 – 720.9 Other inflammatory spondylopathies (site unspecified) – unspecified inflammatory spondylopathy

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/13)

 

L40.54 Psoriatic juvenile arthropathy
L40.59 Other psoriatic arthropathy
L40.8 Other
M00.019 –
M00.9
Arthropathy associated with infections – pyrogenic
M01.x0 – M01.x9 Arthropathy, site unspecified, associated with other bacterial diseases
M02.00 Arthropathy following intestinal bypass, unspecified site
M02.10 – M0219 Postdysenteric arthropathy, unspecified site
M02.20 Postimmunization arthropathy, unspecified site
M02.9 Reactive arthropathy, unspecified
M05.00 Felty’s syndrome, unspecified site
M05.10 Rheumatoid lung disease with rheumatoid arthritis of unspecified site
M05.30 Rheumatoid heart disease with rheumatoid arthritis of unspecified site
M05.60 Rheumatoid arthritis of unspecified site with involvement of other organs and systems
M06.1 Adult-onset Still’s disease
M06.4 Inflammatory polyarthropathy
M06.9 Rheumatoid arthritis, unspecified
M08.00 Unspecified juvenile rheumatoid arthritis of unspecified site
M08.3 Juvenile rheumatoid polyarthritis (seronegative)
M08.40 Pauciarticular juvenile rheumatoid arthritis, unspecified site
M12.00 Chronic postrheumatic arthropathy [Jaccoud], unspecified site
M12.80 Other specific arthropathies, not elsewhere classified, unspecified site
M13.80 – M13.89 Allergic arthritis, site unspecified
M14.60 Charcot’s joint, unspecified site
M14.80 Arthropathies in other specified diseases classified elsewhere, unspecified site
M14.80 Arthropathies in other specified diseases classified elsewhere, unspecified site
M26.3 Arthropathy in other blood disorders
M35.2 Arthropathy in Behçet’s syndrome, site unspecified
M36.2 Hemophilic arthropathy
M36.4 Arthropathy in hypersensitivity reactions classified elsewhere
M45.9 Ankylosing spondylitis of unspecified sites in spine
M46.80 Other specified inflammatoryspondylopathies, site unspecified
M46.90 Unspecified inflammatory spondylopathy, site unspecified
M49.80 Spondylopathy in diseases classified elsewhere, site unspecified

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

DEFINITIONS:

Ankylosing spondylitis: is a type of inflammatory arthritis that most often affects the spinal joints. As the disease progresses, the affected bones fuse together, resulting in a stiff (“bamboo”) spine.

DMARDs: An acronym for disease-modifying antirheumatic drugs.

Juvenile arthritis: A term used to refer to the types of arthritis that affect children. Juvenile rheumatoid arthritis is the most common type.

Moderate Plaque Psoriasis: Three to 10% of body surface area involved.

Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches.

Psoriatic arthritis: Joint inflammation that occurs in about 5% to 10% of people with psoriasis (a common skin disorder).

Psoriatic athropathy: associated with inflammatory arthritis; often involves interphalangeal joints.

Rheumatic: A term referring to a disorder or condition that causes pain or stiffness in the joints, muscles, or bone.

Rheumatoid arthritis: An inflammatory disease of the synovium, or lining of the joint that result in pain stiffness, swelling, deformity, and loss of function in the joints.

Severe Plaque Psoriasis: More than 10% of body surface area (BSA) involved.

RELATED GUIDELINES:

Infliximab (Remicade®), 09-J0000-39
Anakinra (Kineret®), 09-J0000-45

Adalimumab (Humira®), 09-J0000-46

Rituximab (Rituxan®), 09-J0000-59

Abatacept (Orencia®), 09-J0000-67

Certolizumab Pegol (Cimzia®), 09-J0000-77

Golimumab (Simponi™), 09-J1000-11

Alefacept (Amevive®) IV, 09-J0000-78

Ustekinumab (Stelara™), 09-J1000-16
Tocilizumab (Actemra®), 09-J1000-21

OTHER:

Table 2: DMARDs

 

DMARD Generic Name DMARD Brand Name
Auranofin (oral gold) Ridaura
Azathioprine Imuran
Cyclophosphamide Cytoxan
Cyclosporine Neoral, Sandimmune
Gold sodium thiomalate (injectable gold) Myochrysine
Hydroxychloroquine sulfate Plaquenil
Leflunomide Arava
Methotrexate Rheumatrex, Trexall
Minocycline Minocin
Penicillamine Cuprimine, Depen
Sulfasalazine Azulfidine, Azulfidine EN-Tabs

REFERENCES:

  1. American Medical Association CPT Coding, 2009 professional edition.
  2. Berends MA, Driessen RJ, Langewouters AM, Boezeman JB, Van De Kerkhof PC, De Jong EM. Etanercept and efalizumab treatment for high-need psoriasis. Effects and side effects in a prospective cohort study in outpatient clinical practice. J Dermatolog Treat. 2007; 18(2): 76-83.
  3. Blumenauer B, Judd M, Cranney A, Burls A, Coyle D. Hochberg M, Tugwell P, Wells G. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004545. DOI: 10.1002/14651858.CD004525.
  4. Butler DM, Feldmann M, Di Padova F, et al. p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. Eur Cytokine Netw 1994; 5: 441-448.
  5. CRI. Anti-TNF Therapy for Rheumatoid Arthritis. Custom Hotline Response, updated 09/08/06.
  6. Dhillon S, Lyseng-Williamson KA, Scott LJ. Etanercept: a review of its use in the management of rheumatoid arthritis. Drugs. 2007; 67(8): 1211-41.
  7. DRUGDEX®. Accessed 06/16/10.
  8. Enbrel Prescribing Information. Revised 06/20/10.
  9. Facts & Comparisons® E Answers. Accessed 06/16/10.
  10. Guidelines for the Management of Rheumatoid Arthritis, American College of Rheumatology, 2005 – 2002 Update.
  11. HAYES, Inc. Etanercept for Ankylosing Spondylitis. Lansdale, PA: HAYES, Inc., 08/28/06.
  12. HAYES, Inc. Etanercept for Rheumatoid Arthritis. Lansdale, PA: HAYES, Inc., 03/10/06.
  13. HAYES, Inc. Etanercept for Treatment of Psoriasis and Psoriatic Arthritis. Lansdale, PA: HAYES, Inc., 06/06/06.
  14. HAYES, Inc. FDA Announces Ongoing Safety Review of Possible Association Between TNF Blockers and Cancer. Lansdale, PA: HAYES, Inc., 08/08/08.
  15. HIPAA Space, HCPCS Codes Lookup, Copyright® 2004 – 2010. Accessed 07/19/10.
  16. ICD-9 Data.com. Accessed 07/19/10.
  17. Lipsky PE. Rheumatoid arthritis. In: Isselbacher KJ, Braunwald E. Wilson JD, et al, eds. Harrison’s principles of internal medicine. 13th ed. McGraw-Hill, Inc; 1994: 1648-1655.
  18. Managed Prior Authorization Program, 2000 Merck-Medco Managed Care, LLC.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 08/11/10.

GUIDELINE UPDATE INFORMATION:

 

04/15/01 New Medical Coverage Guideline.
05/15/03 Annual review.
10/15/03 Added active ankylosing spondylitis to the When Services Are Covered section.
01/01/05 Revised psoriasis language in the When Services Are Covered Section.
02/15/06 Updated when services are covered added statement: For reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. Deleted warnings and contraindications, added DMARD table under Other.
12/15/06 Reviewed; reformatted, added CPT-4 and ICD-9 coding, related guidelines, and updated links and references. MCG revised to include Medicare Part D as a program exception.
08/15/07 Reviewed: reformatted, maintained current coverage and limitations, updated related guidelines, updated internet links and updated references.
10/15/07 Revision; consisting of updating ICD-9 coding.
05/15/08 Revision; consisting of adding a black box warning under “PRECAUTIONS”.
10/15/08 Review and revision consisting of; updating description section, reformatted and updated references.
01/01/09 Annual HCPCS coding update: deleted code 90772; added code 96372.
10/15/09 Review and revision consisting of updating precautions, related guidelines and reference sections.
04/15/10 Revision; consisting of adding specific continuation criteria.
09/15/10 Review and revision; consisting of updating precautions and references.
01/15/11 Revision; consisting of adding ICD-10 codes.
04/01/11 Revision; consisting of adding dosage limitations.

 

Data from: http://mcgs.bcbsfl.com/index.cfm

Clinical Policy Bulletin:Enbrel (Etanercept)

Policy

  1. Aetna considers Enbrel (etanercept) medically necessary for any of the following indications:
    1. Adult Rheumatoid Arthritis:

      Etanercept is considered medically necessary for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. 

    2. Juvenile Rheumatoid Arthritis:

      Entanercept is considered medically necessary for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.

    3. Active Psoriatic Arthritis:

      Etanercept is considered medically necessary for members with active psoriatic arthritis who have had a failure of two or more nonbiologic disease-modifying antirheumatic drugs (DMARDs) (methotrexate, sulfasalazine, cyclosporine, leflunomide, gold compounds, or antimalarials).

    4. Ankylosing Spondylitis:

      Etanercept is considered medically necessary for members with moderate to severe ankylosing spondylitis who have failed treatment with two or more non-steroidal anti-inflammatory drugs (NSAIDS).

    5. Reactive Arthritis:

      Etanercept is considered medically necessary for members with refractory reactive arthritis who have failed non-steroidal anti-inflammatory drugs, sulfasalazine, steroids and methotrexate.

    6. Behcet’s disease:

      Etanercept is considered medically necessary for treatment of mucocutaneous manifestations (oral ulcers, nodular skin lesions) of Behcet’s disease refractory to glucocorticoids and azathioprine.

    7. Chronic Moderate to Severe Psoriasis

      For medical necessity criteria, see CPB 658 – Psoriasis: Biological Therapies.

  2. Aetna considers Enbrel (etanercept) experimental and investigational for all other indications, including any of the following (not an all inclusive list):
    1. Asthma
    2. Chronic heart failure
    3. Churg-Strauss syndrome
    4. Graft-versus-host disease
    5. Hidradenitis suppurativa
    6. Idiopathic pulmonary fibrosis
    7. Inclusion-body myositis
    8. Inflammatory bowel disease (e.g., Crohn’s disease) arthritis
    9. Lupus erythematosus
    10. Sarcoidosis
    11. Sjogren’s syndrome
    12. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as Hibernian fever
    13. Wegener’s granulomatosis.

See also CPB 205 – Phototherapy and Photochemotherapy (PUVA) for Skin ConditionsCPB 341 – Remicade (infliximab)CPB 577 – Psoriasis: Laser TreatmentCPB 595 – Kineret (Anakinra), and CPB 655 – Adalimumab (Humira).

BackgroundThe patient selection criteria were adapted from the FDA-approved labeling of Enbrel, off-label indications for etanercept accepted by the U.S. Pharmacopoeial Convention, and from published studies of etanercept’s effectiveness.  Although there is evidence of the effectiveness of both tumor necrosis factor inhibitors etanercept and infliximab (Remicade) in Crohn’s disease arthritis, only infliximab has been shown to also improve the underlying Crohn’s disease.

Guidelines on rheumatoid arthritis (RA) from the American College of Rheumatology (Saag, et al., 2008) state that patients with early RA with low or moderate disease activity (in study) were not considered candidates for biologic therapy. The use of anti-TNF agents in combination with methotrexate was recommended if high disease activity was present for less than three months with features of a poor prognosis.

The FDA-approved labeling for Enbrel includes black-box warnings about the risk of infections with etanercept. The labeling states that, in post-marketing reports, serious infections and sepsis, including fatalities, have been reported with the use of etanercept. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections. The labeling states that rare cases of tuberculosis (TB) have been observed in patients treated with tumor necrosis factor (TNF) antagonists, including etanercept. The labeling recommends that patients who develop a new infection while undergoing treatment with etanercept should be monitored closely. Administration of etanercept should be discontinued if a patient develops a serious infection or sepsis. The labeling states that treatment with etanercept should not be initiated in patients with active infections including chronic or localized infections. The labeling recommends that physicians should exercise caution when considering the use of etanercept in patients with a history of recurring infections or with underlying conditions which may predispose patients to infections, such as advanced or poorly controlled diabetes. The labeling notes that, in a 24-week study of concurrent etanercept and anakinra therapy, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of etanercept and anakinra did not result in higher ACR response rates compared to etanercept alone. The labeling states that concurrent therapy with etancerpt and anakinra is not recommended.

In a Cochrane review, Jessop et al (2009) evluated the effects of drugs for discoid lupus erythematosus. In June 2009, these investigators updated their searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2009), MEDLINE, EMBASE, LILACS, and online ongoing trials registers. The reference lists of relevant reviews were searched. Index Medicus (1956 to 1966) was hand-searched and authors were approached for information about unpublished trials. These researchers included all randomized trials of drugs to treat people with discoid lupus erythematosus. Drugs included in the search were azathioprine, chloroquine, clofazimine, corticosteroids, (oral and topical), dapsone, gold, interferon alpha-2a, methotrexate, phenytoin, retinoids, sulphasalazine, thalidomide, topical calcineurin blockers (pimecrolimus and tacrolimus), and biological agents (etanercept, efalizimab, infliximab, and rituximab). Two reviewers independently examined each retrieved study for eligibility. Two trials involving 136 participants were included. No new trials were included in this update. In a cross-over study of 12 weeks duration, fluocinonide 0.05 % cream (a potent topical corticosteroid), appeared to be better than hydrocortisone 1 % cream (a mild corticosteroid) when the first arm of the trial involving 78 participants was analyzed at 6 weeks. Clearing or excellent improvement was seen in 27 % of people using fluocinonide and in 10 % of those using hydrocortisone, giving a 17 % absolute benefit in favor of fluocinonide (95 % confidence interval [CI] 0.0 to 0.34, NNT (Number needed to treat) 6). In the second trial, acitretin (50 mg/day) was compared with hydroxychloroquine (400 mg/day) in 58 people in a parallel trial of 8 weeks duration. There was marked improvement or clearing in 46 % of people using acitretin and in 50 % of those on hydroxychloroquine, but there was no significant difference between the 2 interventions. The adverse effects were more frequent and more severe in the acitretin group. In this trial, clearing of erythema was measured and found to be better in the hydroxychloroquine group (RR 0.61, 95 % CI 0.36 to 1.06). The authors concluded that fluocinonide cream may be more effective than hydrocortisone in treating people with discoid lupus erythematosus. Hydroxychloroquine and acitretin appear to be of equal efficacy, although adverse effects are more frequent and more severe with acitretin. There is not enough reliable evidence about other drugs (including etanercept) used to treat discoid lupus erythematosus.

Schoindre and colleagues (2009) stated that TNF receptor-associated periodic syndrome (TRAPS) is a highly polymorphic auto-inflammatory syndrome related to mutations in the TNFRSF1A gene encoding the type 1 TNF receptor. Arthralgia and non-erosive synovitis are among the most common manifestations. These investigators reported the case of a 73-year-old woman who presented with chronic erosive joint disease that progressed by flare-ups. Moderate non-specific abdominal and cutaneous abnormalities were noted, suggesting TRAPS. This diagnosis was confirmed when genetic tests identified the R92Q mutation in the TNFRSF1A gene. Although steroid therapy was effective in alleviating the symptoms, combination therapy with methotrexate and etanercept neither decreased the frequency of the flare-ups nor slowed the pace of joint destruction. Treatment with anakinra is being considered. The authors noted that this is the first reported case of joint destruction related to TRAPS.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
20600 – 20610  
96401 – 96450  
HCPCS code covered if selection criteria are met:
J1438 Injection, etanercept, 25 mg
ICD-9 codes covered if selection criteria are met:
136.1 Behcet’s syndrome [mucocutaneous manifestations (oral ulcers, nodular skin lesions) of Behcet’s disease refractory to glucocorticoids and azathioprine]
696.0 Psoriatic arthropathy [active and failed two or more nonbiologic DMARDS]
696.1 Other psoriasis [chronic moderate to severe]
711.00 – 711.99 Arthropathy associated with infections [refractory reactive]
713.0 – 713.8 Arthropathy associated with other disorders classified elsewhere [refractory reactive]
714.0 – 714.9 Rheumatoid arthritis and other inflammatory polyarthropathies [moderate to severe active]
716.20 – 716.29 Allergic arthritis [refractory reactive]
720.0 Ankylosing spondylitis [moderate to severe and failed two or more NSAIDS]
720.81 – 720.9 Other and unspecified inflammatory spondylopathies [moderate to severe]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
135 Sarcoidosis
428.0 – 428.9 Heart failure [chronic]
446.4 Wegener’s granulomatosis [Churg-Strauss syndrome]
493.00 – 493.92 Asthma
515 Postinflammatory pulmonary fibrosis [idiopathic]
555.0 – 555.9 Regional enteritis
556.0 – 556.9 Ulcerative colitis [Crohn’s disease arthritis]
695.4 Lupus erythematosus
705.83 Hidradenitis [suppurativa]
710.2 Sicca syndrome [Sjogren’s syndrome]
729.1 Myalgia and myositis [inclusion body]
996.85 Complication of bone marrow transplant [graft-versus-host disease]
Other ICD-9 codes related to the CPB:
719.00 – 719.09 Effusion of joint [swollen joints]
719.40 – 719.49 Pain in joint [tender joints]

The above policy is based on the following references:

  1. Immunex Laboratories. Enbrel® (Etanercept) Product Information. Doc. No. 106662-10. Seattle, WA: Immunex; January 2002.  
  2. Moreland LW. Soluble tumor necrosis factor receptor (p75) fusion protein (ENBREL) as a therapy for rheumatoid arthritis. Rheum Dis Clin North Am. 1998;24(3):579-591. 
  3. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337:141-147.  
  4. Murray KM, Dahl SL. Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis. Ann Pharmacother. 1997;31(11):1335-1338. 
  5. Brower V. Enbrel’s phase III reinforces prospects in RA. Nat Biotechnol. 1997;15(12):1240.  
  6. McGahan L. Etanercept: Anti-tumor necrosis factor therapy for rheumatoid arthritis. Issues in Emerging Health Technologies Issue 8. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1999.
  7. Lovell DJ, Giannini EF, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342(11):763-769. 
  8. American College of Rheumatology. Guidelines for the management of rheumatoid arthritis: American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheuma. 1996;39(5):713-723.  
  9. Alberta Heritage Foundation for Medical Research (AHFMR). Etanercept (Enbrel). Emerging Technology Report. Edmonton, AB: AHFMR; 2000.
  10. Yazici Y, Erkan D, Lockshin MD. Etanercept in the treatment of severe, resistant psoriatic arthritis: Continued efficacy and changing patterns of use after two years. Clin Exp Rheumatol. 2002;20(1):115. 
  11. Yazici Y, Erkan D, Lockshin MD. A preliminary study of etanercept in the treatment of severe, resistant psoriatic arthritis. Clin Exp Rheumatol. 2000;18(6):732-734. 
  12. Aboulafia DM, Bundow D, Wilske K, et al. Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis. Mayo Clin Proc. 2000;75(10):1093-1098. 
  13. de Vries C. Effects of TNF-alpha antagonists in people with rheumatoid arthritis. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian Ltd., eds. London, UK: Wessex Institute for Health Research and Development, University of Southampton; 2001;1(19).
  14. Braun J, Breban M, Maksymowych WP. Therapy for ankylosing spondylitis: New treatment modalities. Best Pract Res Clin Rheumatol. 2002;16(4):631-651.
  15. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med. 2002;346(18):1349-1356.
  16. Brandt J, Khariouzov A, Listing J, et al. Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum.  2003;48(6):1667-1675.
  17. Taylor PC. Anti-TNFalpha therapy for rheumatoid arthritis: An update. Intern Med. 2003;42(1):15-20.
  18. Jobanputra P, Barton P, Bryan S, Burls A. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: A systematic review and economic evaluation. Health Technol Assess.  2002;6(21):1-110.
  19. National Horizon Scanning Centre (NHSC). Etanercept for ankylosing spondylitis – horizon scanning review. Birmingham, UK: NHSC; 2003.
  20. National Institute for Clinical Excellence (NICE). Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis. Technology Appraisal Guidance 36. London, UK: NICE; 2002.
  21. National Institute for Clinical Excellence (NICE). Guidance on the use of etanercept for the treatment of juvenile idiopathic arthritis. Technology Appraisal Guidance 35. London, UK: NICE; 2002.
  22. Meador R, Hsia E, Kitumnuaypong T, Schumacher HR. TNF involvement and anti-TNF therapy of reactive and unclassified arthritis. Clin Exp Rheumatol. 2002;20(6 Suppl 28):S130-S134.
  23. Wendling D, Claudepierre P, Lohse A, et al. Therapeutic use of anti-TNF-alpha agents in spondyloarthropathies. Presse Med. 2003;32(32):1517-1524.
  24. D’Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn’s disease: A single-center pilot trial. Am J Gastroenterol. 2001;96(9):2564-2568.
  25. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: A randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001;121(5):1088-1094.
  26. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease.  Gastroenterology. 2003;124(7):1774-1785.
  27. Agnholt J, Dahlerup JF, Kaltoft K. The effect of etanercept and infliximab on the production of tumour necrosis factor alpha, interferon-gamma and GM-CSF in in vivo activated intestinal T lymphocyte cultures. Cytokine. 2003;23(3):76-85.
  28. Sandborn WJ. Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease. Curr Gastroenterol Rep. 2003;5(6):501-505.
  29. Akobeng AK, Zachos M. Tumor necrosis factor-alpha antibody for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2004;(1):CD003574. 
  30. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet. 2000;356(9227):385-390.
  31. Mease PJ. Etanercept, a TNF antagonist for treatment for psoriatic arthritis and psoriasis. Skin Therapy Lett. 2003;8(1):1-4.
  32. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022.
  33. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-1632; discussion 1632.
  34. Cummins C, Connock M, Fry-Smith A, Burls A. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: Etanercept. Health Technol Assess. 2002;6(17):1-43.
  35. Hochberg MC, Tracy JK, Hawkins-Holt M, Flores RH. Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2003;62(Suppl  2):13-16.
  36. Blumenauer B, Judd M, Cranney A, et al. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev. 2003;(3):CD004525.
  37. Hellmich B, Gross WL. Recent progress in the pharmacotherapy of Churg-Strauss syndrome. Expert Opin Pharmacother. 2004;5(1):25-35.
  38. von Haehling S, Jankowska EA, Anker SD. Tumour necrosis factor-alpha and the failing heart–pathophysiology and therapeutic implications. Basic Res Cardiol. 2004;99(1):18-28.
  39. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109(13):1594-1602.
  40. Sankar V, Brennan MT, Kok MR, Etanercept in Sjogren’s syndrome: A twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 2004;50(7):2240-2245.
  41. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352(4):351-361.
  42. Naldi L, Rzany B. Psoriasis (Chronic Plaque). In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; July 2006.
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Data from: http://www.aetna.com/cpb/medical/data/300_399/0315.html