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)

 

 

 

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Information specific to: Infliximab 100mg powder for solution for infusion vials when used in Ankylosing spondylitis

Information specific to: Infliximab 100mg powder for solution for infusion vials when used in Ankylosing spondylitis.

Infliximab (In-flix-ee-mab) 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.

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

Your medicine

Infliximab is an immunosuppressant which may be given in combination with other medicines. It helps to suppress overactivity of the immune system in inflammatory conditions. It helps to reduce pain and swelling by limiting inflammation.

Due to its effects on the immune system, people who have Infliximab are prone to getting infections. This includes serious infections such as tuberculosis and sepsis. It is for this reason that people who have Infliximab are monitored for infections.

Infliximab stays in the body for up to six months, so the effects of this medicine will persist for some time after you have your last dose.

Other information about Infliximab:

  • while you are having Infliximab you may have an increased chance of getting an infection. You should speak to your prescriber for further information about how you can best avoid getting an infection
  • your prescriber will give you an alert card and a package leaflet. It contains important information about Infliximab. If you have any concerns or questions about having Infliximab you should discuss them with your prescriber
  • when changing from one biologic to another, you will be monitored continuously by your prescriber for any signs of infection

Infliximab is usually given to you by a healthcare professional. The person responsible for giving you your medicine will make sure that you get the right dose.

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

Whether this medicine is suitable for you

Infliximab 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 a carrier of hepatitis Binfection
  • are about to have surgery or have had an arthroplasty
  • are aged over 65 years
  • are allergic or sensitive to or have had a bad reaction to mouse proteins in the past
  • are allergic or sensitive to or have had a reaction to any of the ingredients in the medicine
  • are immunosuppressed
  • are or have been a heavy smoker
  • have been in close contact with somebody with tuberculosis
  • have come into contact with someone who has a fungalinfection
  • have demyelinating disorders
  • have had recurrent infections
  • have heart problems
  • have infections, abscesses or infected fistulas
  • have intestinal strictures due to Crohn’s disease
  • have kidney problems
  • have liver problems
  • have or have had cancer
  • have or have had tuberculosis
  • have primary sclerosing cholangitis
  • have psoriasis and have or have had PUVA treatment for a long time
  • have recently had a vaccination or are having a vaccination soon
  • have sepsis
  • have ulcerative colitis
  • were last given Infliximab for Crohn’s disease or rheumatoid arthritis more than sixteen weeks ago

Furthermore the prescriber may only prescribe this medicine with special care or may not prescribe it at all for someone under 18 years of age.

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

  • to determine whether or not the medicine is suitable and whether it must be prescribed with extra care
  • to check that this medicine is not having any undesired effects

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

Alcohol

Alcohol can interact with certain medicines.

In the case of Infliximab:

  • there are no known interactions between alcohol and Infliximab

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 Infliximab:

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

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.

In the case of Infliximab:

  • as this medicine is only normally used in hospitals, its impact on someone driving or operating machinery may not be relevant

You should see how this medicine affects you before you judge whether you are safe to drive or operate machinery. If you are in any doubt about whether you should drive or operate machinery, 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 Infliximab:

  • you must not become pregnant while you are having it and for at least six months after you have the last dose of Infliximab. 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 you think you may be pregnant, while having Infliximab
  • the use of this medicine during pregnancy is not recommended. You should only have this medicine during pregnancy if your doctor thinks that you need it

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 Infliximab:

  • do not breast-feed for at least six months after you have the last dose of Infliximab
  • women who are having Infliximab should not breast-feed

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. If you wish to breast-feed you should discuss with your prescriber whether there are any other medicines you could take which would also allow you to breast-feed. You should not stop this medicine without taking advice from your doctor.

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 Infliximab:

  • 6-mercaptopurine
  • abatacept
  • anakinra
  • azathioprine
  • methotrexate

The following types of medicine may interact with Infliximab:

  • immunomodulators
  • live vaccines
  • Tumour Necrosis Factor antagonists

If you are taking Infliximab 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 Infliximab.

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. They may also be used to prolong the life of the medicine.

This medicine contains infliximab.

We are unable to list all of the ingredients for your medicine here. For a full list, you should refer to the patient information leaflet that comes with this medicine or ask your prescriber. You should check that you are able to take the ingredients of your medicine, especially if you have any allergies.

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 Infliximab before, do not take Infliximab. Talk to your prescriber, pharmacist or nurse as soon as possible.

How to take your medicine

This medicine will be given to you as an injection. If you have any concerns about this medicine or how this will be given to you, talk to someone who is involved in your medical care.

When to take your medicine

The person with responsibility for giving you your medicine will make sure that you have your medicine at the prescribed times.

Taking too much of your medicine

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

In the case of Infliximab, the person who is responsible for giving you your medicine will make sure that you are given the correct dose.

Stopping your medicine

The person in charge of your care will make the decision about when you should stop this medicine. If you experience any problems while having this medicine, talk to someone who is involved in your medical care.

Looking after your medicine

As Infliximab will be given to you as an injection, it will usually be stored by the medical team.

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 Infliximab

  • production of antibodies to Infliximab

Common: More than 1 in 100 people who have Infliximab

  • abnormal laboratory test results
  • chest pain
  • diarrhoea
  • dry skin
  • feeling dizzy
  • fever
  • flushing
  • headaches
  • indigestion
  • infusion-related reactions such as difficulty in breathing, urticaria and headache
  • itching
  • nausea
  • respiratory tractinfection such as bronchitis or pneumonia
  • serum-sickness or serum-sickness like reaction
  • sinusitis
  • skin rash or rashes
  • stomachpain
  • sweating
  • tiredness
  • urticaria
  • vertigo

Uncommon: More than 1 in 1000 people who have Infliximab

  • abscess
  • allergic reactions
  • anaphylactic reactions such as laryngeal oedema, pharyngeal oedema, bronchospasm or seizures
  • apathy
  • autoimmune problems
  • bruising
  • cellulitis
  • chills
  • collection of blood under the skin
  • confusion
  • constipation
  • cyanosis
  • demyelinating problems such as multiple sclerosis and Guillain Barré syndrome or worsening of such existing disorders
  • depression
  • difficulty sleeping
  • eye or eyesight problems
  • fainting or brief loss of consciousness
  • feeling agitated
  • feeling nervous
  • gallbladder problems
  • gastro-oesophageal reflux
  • hair loss
  • healing problems
  • heart problems or worsening of heart problems – these may be fatal
  • hot flushes
  • inflammation or cracking of the lips
  • injection site problems
  • irregular heart rate
  • irritation or inflammation of the vagina
  • kidney problems
  • liver problems – some of these liver problems may be fatal. Seek immediate medical advice if you develop jaundice
  • lowered blood pressure
  • lung problems
  • lupus or lupus-like problem
  • lymphadenopathy
  • memory problems
  • musclepain or tenderness
  • nail problems
  • nose bleed
  • oedema
  • pain including back pain or jointpain
  • palpitations
  • petechiae
  • pulmonary oedema
  • raised blood pressure
  • sarcoid-like reaction
  • sepsis
  • skin problems such as skin colour changes, boils, eczema, seborrhea, rosacea, certain types of dermatitis or thickening of the outer layer of the skin
  • sleepiness
  • slower heart rate
  • swelling around the eyes
  • thrombophlebitis
  • tuberculosis – some of the tuberculosisinfections caused by Infliximab may be fatal. Seek immediate medical advice if you get a persistent cough, fever or weight loss
  • urinary tractinfection
  • vasospasm

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

  • circulation problems
  • faster heart rate
  • gastrointestinal problems such as gastrointestinal bleeding
  • granulomatous lesion
  • lymphoma – this may be fatal
  • meningitis

The frequency of these side-effects is unknown

  • anaphylacticshock
  • cancer
  • changes in vision – this may happen during or within two hours of infusion
  • delayed hypersensitivity reactions – seek immediate medical advice if you get any of the following: painful muscles and joints that occur with fever and rashes, itching, swelling of the face, swelling of the hands, or swelling of the lips, swallowing difficulties, urticaria, sore throat or headache
  • erythema multiforme
  • heart attack – this may happen during or within two hours of infusion
  • hiding symptoms of infection such as fever
  • hypoaesthesia
  • inflammation of the spinal cord
  • leukaemia
  • neuropathies
  • pancreatitis
  • paraesthesiae
  • psoriasis or psoriasis-like rash or worsening of psoriasis
  • reactivation of hepatitis B – this may be fatal. You must seek medical advice if your symptoms return or if they become worse
  • reduced resistance to infection
  • seizures
  • Stevens-Johnson syndrome
  • toxic epidermal necrolysis
  • unexplained or easy bruising of the skin or mucous membranes
  • vasculitis

The following side effects have also been reported in people who have Infliximab. The reported frequency of these side-effects varies so the frequency is not included here.

  • blood and bone marrow problems – seek immediate medical advice if you develop persistent fever, bleeding, bruising or paleness
  • hypersensitivity reactions
  • infections – some of the infections caused by Infliximab may be fatal. Seek immediate medical advice if you get any symptoms of an infection whilst you are having Infliximab

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.

Printable guides available for this medicine:

This medicine is also used for:

 

Data From: http://www.nhs.uk/Conditions/Ankylosing-spondylitis/Pages/MedicineOverview.aspx?condition=Ankylosing spondylitis&medicine=Infliximab&preparation=Infliximab 100mg powder for solution for infusion vials

==Infliximab (Remicade®)== BCBSF medical coverage guideline

Subject: Infliximab (Remicade®)

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:

Infliximab, also known as cA2, is the first monoclonal antibody to be approved for the treatment of Crohn’s disease. A single intravenous infusion of infliximab has been shown to induce a clinical response or remission in 65% of patients with moderate-to-severe treatment-resistant Crohn’s disease. The short-term benefits after a single infusion may persist for up to 12 weeks. Long-term maintenance therapy with Infliximab in Crohn’s Disease was evaluated in the ACCENT I trial (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen). The results through week 54 of the ACCENT I trial demonstrate that Remicade is safe and well tolerated as a maintenance regimen in patients with moderately to severely active Crohn’s disease. Infliximab has been shown to significantly decrease the number of draining fistulas in patients with Crohn’s disease as compared to placebo. In patients with rheumatoid arthritis, infliximab substantially improves clinical symptoms when given in combination with methotrexate. Infliximab was granted final FDA approval for the treatment of Crohn’s disease on August 24, 1998. The FDA approved infliximab for the treatment of rheumatoid arthritis in combination with methotrexate on November 11, 1999.

On September 20, 2005, the FDA approved infliximab for the treatment of moderate to severe ulcerative colitis in those whose symptoms are not controlled by conventional therapies. A total of 728 patients with moderate to severe ulcerative colitiswere enrolled in the ACT 1 and ACT 2 studies who had uncontrolled disease on aminosalicylates, steroids, and/or immunosuppressant therapies. In the ACT 1 study 20% of the infliximab vs. 10% of the placebo group were in clinical remission and able to discontinue corticosteroids at week 30. The ACT 2 study demonstrated similar effects with 23% infliximab response vs. 3% placebo. The Remicade response was similar in the 5mg/kg and 10mg/kg groups 16. Jarnerot et al. conducted a randomized double-blind trial of infliximab in severe to moderately severe ulcerative colitis not responding to conventional treatment. Forty-five patients were randomized to receive either infliximab 5mg/kg or placebo. There were double the amount of colectomies in the placebo group (7 infliximab vs 14 placebo colectomies, P=0.017, 95%CI) 9.

POSITION STATEMENT:

Infliximab (Remicade®) meets the definition of medical necessity when administered for the following indications (SEE TABLE 1 FOR SPECIFIC CRITERIA):

  • Crohn’s Disease
  • Fistulizing Crohn’s Disease
  • Rheumatoid Arthritis
  • Ankylosing Spondylitis
  • Psoriatic Arthritis
  • Ulcerative Colitis
  • Plaque Psoriasis.

Table 1

 

   
SPECIFIC CRITERIA FOR REMICADE® THERAPY
1. Crohn’s Disease
  • Patient has a history of beneficial clinical response to infliximab therapy for Crohn’s disease OR
  • Infliximab is being prescribed for the reduction of signs and symptoms and inducing and maintaining clinical remission in adults and pediatrics with moderately to severely active Crohn’s disease AND
  • Patient has had an inadequate response to conventional therapy (i.e., mesalamine substances, corticosteroids, or immunosupprssives agents). AND
  • Dosage does not exceed: Adults 10 mg/kg. Children – 5 mg/kg.
2. Fistulizing Crohn’s Disease
  • Patient has a history of beneficial clinical response to infliximab therapy for fistulizing Crohn’s disease OR
  • Infliximab is being prescribed for the reduction in the number of draining enterocutaneous fistulas and rectovaginal fistulas and maintaining fistula closure in adult patients. AND
  • Dosage does not exceed: Adults 10 mg/kg. Children – 5 mg/kg.
3. Rheumatoid Arthritis
  • Patient has a history of beneficial clinical reponse to infliximab therapy for rheumatoid arthritis OR
  • Infliximab is being prescribed for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active rheumatoid arthritis. AND
  • Dosage does not exceed: 10 mg/kg. AND
  • Remicade® may be used as a first-line agent.
4. Ankylosing Spondylitis
  • Patient has a history of beneficial clinical response to infliximab therapy for ankylosing spondylitis OR
  • Infliximab is being prescribed for reducing signs and symptoms in patients with ankylosing spondylitis. AND
  • Dosage does not exceed: 5 mg/kg.
5. Psoriatic Arthritis
  • Patient has a history of beneficial clinical response to infliximab therapy for psoriatic arthritis OR
  • Infliximab is being prescribed for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage and improving physical function in patients with psoratic arthritis. AND
  • Dosage does not exceed: 5 mg/kg.
6. Ulcerative Colitis
  • Patient has a history of beneficial clinical response to infliximab therapy for ulcerative colitis OR
  • Infliximab is being prescribed for the reduction of signs and symptoms, achieving clinical remission and mucosal healing and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. AND
  • Dosage does not exceed: 5 mg/kg.
7. Plaque Psoriasis
  • Patient has a history of beneficial clinical response to infliximab therapy for plaque psoriasis OR
  • Infliximab is being prescribed for the treatment of severe plaque-type psoriasis when the following criteria are met:
  • Patient is 18 years old or older AND
  • Patients has had moderate to severe chronic plaque psoriasis for more than 1 year AND
  • Patient has ten percent or more body surface affected by plaque psoriasis 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
  • Dosage does not exceed: 5 mg/kg.

Infliximab (Remicade®) is considered experimental or investigationalwhen administered for conditions other than those listed above, as there is insufficient clinical evidence to support its use.

DOSAGE AND 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.

Crohn’s disease or Fistulizing Crohn’s Disease: The recommended dose of infliximab is 5mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn’s disease or fistulizing Crohn’s disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10mg/kg. Patients who do not respond by week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue infliximab in these patients.

The recommended dose of infliximab for children with moderately to severely active Crohn’s disease is 5mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5mg/kg every 8 weeks.

Rheumatoid Arthtitis: The recommended dose of infliximab is 3mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. Infliximab should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10mg /kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.

Ankylosing Spondylitis: The recommended dose of infliximab is 5mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infustion, then every 6 weeks thereafter.

Psoriatic arthritis: The recommended dose of infliximab is 5mg/kg given as an intravenous infusion, followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. Remicade can be used with or without methotrexate.

Ulcerative colitis: The recommended dose of infliximab is 5mg/kg given as an induction regimen at 0, 2 and 6 weeks, followed by a maintenance regimen of 5mg/kg every 8 weeks thereafter for the treatment of moderately to severely active ulcerative colitis.

Plaque Psoriasis: The recommended dose of infliximab is 5mg/kg given as an intravenous infusion, followed by additional doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

PRECAUTIONS:

 

WARNINGS
Risk of serious infections:

Patients treated with infliximab are at an 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.

Discontinue infliximab if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before infliximab use and during therapy. Initiate treatment for latent infection prior to infliximab 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 antifungal therapy should be considered in patients who develop severe systemic illness.
  • Bacterial, viral, and other infections caused by opportunistic pathogens.

Carefully consider the risks and benefits of treatment with infliximab prior to initiating therapy in patients with long-term or recurrent infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with infliximab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Malignancy:

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab.

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab. These cases had a very aggressive disease course and have been fatal. All reported infliximab cases have occurred in patients with Crohn disease or ulcerative colitis, and the majority were in adolescent and young adult males. All of these patients received treatment with azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis.

Risk of 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 infliximab.

Treatment with infliximab should not be initiated 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 long-term 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 underlying conditions that may predispose them to infection.

Cases of reactivation of TB or new TB infections have been observed in patients receiving infliximab, including patients who have previously received treatment for latent or active TB. Evaluate patients for TB risk factors and test for latent infection prior to initiating infliximab 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 greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent TB is needed prior to initiating infliximab, even for patients previously vaccinated with Bacille Calmette-Guerin.

Also consider anti-TB therapy prior to initiation of infliximab 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 of whether initiating anti-TB therapy is appropriate for an individual patient.

Strongly consider TB in patients who develop a new infection during infliximab treatment, especially in patients who have previously or recently traveled to countries with a high 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 infliximab, including the development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Tests for latent TB infection may also be falsely negative while on therapy with infliximab.

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

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected 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, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a health care provider with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-alpha–blocking agent, etanercept, with no added clinical benefit compared with etanercept alone. Because of the nature of the adverse reactions seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-alpha–blocking agents. Therefore, the combination of infliximab and anakinra is not recommended.

Malignancies: Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy, 18 years of age or younger), including infliximab. Approximately half of these cases were lymphomas, including Hodgkin and non-Hodgkin lymphomas. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range, 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and were derived from a variety of sources, including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphomas, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab. These cases have had a very aggressive disease course and have been fatal. All reported infliximab cases have occurred in patients with Crohn disease or ulcerative colitis, and the majority were in adolescent and young adult males. All of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis. It is uncertain whether the occurrence of hepatosplenic T-cell lymphomas is related to infliximab or infliximab in combination with these other immunosuppressants.

In the controlled portions of clinical trials of some TNF-blocking agents, including infliximab, more malignancies (excluding lymphoma and nonmelanoma skin cancer) have been observed in patients receiving TNF blockers, compared with control patients. During the controlled portions of infliximab trials in patients with moderately to severely active RA, Crohn disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and nonmelanoma skin cancer) among 4,019 infliximab-treated patients versus 1 among 1,597 control patients (at a rate of 0.52 per 100 patient-years among infliximab-treated patients vs a rate of 0.11 per 100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population, whereas the rate in control patients was lower than expected.

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker, compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5,707 patients treated with infliximab (median duration of follow-up, 1 year) versus 0 lymphomas in 1,600 control patients (median duration of follow-up, 0.4 years). In patients with RA, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for RA, Crohn disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.1 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn disease, RA, or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several-fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in RA and other indications. Even in the absence of TNF blocker therapy, patients with RA may be at higher risk (approximately 2–fold) than the general population for the development of leukemia.

In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients, compared with control patients. All patients had a history of heavy smoking. Exercise caution when considering the use of infliximab in patients with moderate to severe COPD.

Monitor psoriasis patients for nonmelanoma skin cancers, particularly patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, nonmelanoma skin cancers were more common in patients with previous phototherapy.

The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared with rates in clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. Exercise caution in considering infliximab treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab.

Hepatitis B virus reactivation: Use of TNF blockers, including infliximab, 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 also may contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers, including infliximab, 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 TNF blockers 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, stop TNF blockers and initiate antiviral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of TNF blocker therapy in this situation, and monitor patients closely.

Hepatotoxicity: Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks and more than a year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Evaluate patients with symptoms or signs of liver function impairment for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, 5 times the upper limit of normal [ULN] or more) develop, discontinue infliximab and investigate the abnormality thoroughly. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab without progression to severe hepatic injury.

Heart failure: Infliximab has been associated with adverse outcomes in patients with heart failure and use in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (New York Heart Association [NYHA] functional class ΙΙΙ/ΙV) suggested higher mortality in patients who received infliximab 10 mg/kg and higher rates of cardiovascular adverse reactions at doses of 5 and 10 mg/kg. There have been postmarketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare postmarketing reports of new-onset heart failure, including heart failure in patients without known preexisting cardiovascular disease. Some of these patients were younger than 50 years of age. If a decision is made to administer infliximab to patients with heart failure, closely monitor them during therapy and discontinue infliximab if new or worsening symptoms of heart failure appear.

Hematologic effects: Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab. The causal relationship to infliximab therapy remains unclear. Although no high-risk group has been identified, exercise caution in patients being treated with infliximab who have ongoing or histories of significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever) while on infliximab. Consider discontinuation of infliximab therapy in patients who develop significant hematologic abnormalities.

CNS effects: Infliximab and other agents that inhibit TNF have been associated in rare cases with optic neuritis, seizure, and new onset or exacerbation of clinical symptoms and/or radiographic evidence of CNS-demyelinating disorders, including multiple sclerosis and CNS manifestations of systemic vasculitis and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering the use of infliximab in patients with preexisting or recent onset of CNS-demyelinating or seizure disorders. Consider discontinuation of infliximab in patients who develop significant CNS adverse reactions.

Autoimmunity: Treatment with infliximab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with infliximab, discontinue treatment.

Vaccinations: No data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines in patients receiving anti-TNF therapy. It is recommended that live vaccines not be given concurrently.

It is recommended that all children with Crohn disease be brought up to date with all vaccinations prior to initiating infliximab therapy. The interval between vaccination and initiation of infliximab therapy should be in accordance with current vaccination guidelines.

Immunogenicity: Treatment with infliximab can be associated with the development of antibodies to infliximab. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10%, as assessed through 1 to 2 years of infliximab treatment. A higher incidence of antibodies to infliximab was observed in patients with Crohn disease receiving infliximab after drug-free intervals greater than 16 weeks. In a study of psoriatic arthritis, in which 191 patients received 5 mg/kg with or without methotrexate, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody positive were more likely to have higher rates of clearance, and reduced efficacy, and to experience an infusion reaction than were patients who were antibody negative. Antibody development was lower among patients with RA and Crohn disease receiving immunosuppressive therapies, such as 6-mercaptopurine/azathioprine or methotrexate.

In the psoriasis study ΙΙ, which included both the 5 and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis study ΙΙΙ, which also included both the 5 and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2, and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in studies Ι and ΙΙ (in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year) and in study ΙΙΙ (in patients treated with 5 mg/kg induction [14.1% to 23%]) and serious infusion reaction rates (less than 1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients compared with patients with other diseases treated with infliximab long-term is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an enzyme-linked immunosorbent assay and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.

Hypersensitivity reactions: Infliximab has been associated with hypersensitivity reactions that varied in times of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, occurred during or within 2 hours of infliximab infusion.

However, in some cases, serum sickness–like reactions have been observed in patients after initial infliximab therapy (as early as after the second dose) and when infliximab therapy was reinstituted following an extended period without infliximab treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema, and/or dysphagia. These reactions were associated with marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.

For severe hypersensitivity reactions, discontinue infliximab. Have medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids, epinephrine) available for immediate use in the event of a reaction.

Fertility impairment: It is not known if infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.

Children: Infliximab has not been studied in children with Crohn disease younger than 6 years of age. The long-term (more than 1 year) safety and effectiveness of infliximab in children with Crohn disease have not been established in clinical trials.

Safety and efficacy of infliximab in children with ulcerative colitis and plaque psoriasis have not been established.

The safety and efficacy of infliximab in patients with juvenile RA were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension for a maximum of 44 weeks.

BILLING/CODING INFORMATION:

The following codes may be used to report these services:

CPT Coding:

 

96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366 Each additional hour (list separately in addition to code for primary)
96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
96415 Chemotherapy administration, intravenous infusion technique; each additional hour (list separately in addition to code for primary procedure)

HCPCS Coding:

 

J1745 Injection, infliximab, 10 mg
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

364.3 Unspecified iridocyclitis
555.0 Crohn’s disease, small intestine
555.1 Crohn’s disease, large intestine
555.2 Crohn’s disease, small intestine with large intestine
555.9 Crohn’s disease, unspecified site
556.0 Ulcerative (chronic) enterocolitis
556.1 Ulcerative (chronic) ileocolitis
556.2 Ulcerative (chronic) proctitis
556.3 Ulcerative (chronic) proctosigmoiditis
556.5 Left-sided ulcerative (chronic) colitis
556.6 Universal ulcerative (chronic) colitis
556.8 Other ulcerative colitis
556.9 Ulcerative colitis, unspecified
565.1 Anal fistula
569.81 Fistula of intestine, excluding rectum and anus
696.0 Psoriatic arthropathy
696.1 Other psoriasis
714.0 – 714.9 Rheumatoid arthritis
720.0 Ankylosing spondylitis

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

 

H20.9 Unspecified iridocyclitis Uveitis NOS
K50.00 Crohn’s disease of small intestine without complications
K50.10 Crohn’s disease of large intestine without complications
K50.80 Crohn’s disease of both small and large intestine without complications
K50.90 Crohn’s disease, unspecified, without complications
K51.80 Other ulcerative colitis without complications
K51.20 Ulcerative (chronic) proctitis without complications
K51.30 Ulcerative (chronic) rectosigmoiditis without complications
K51.50 Left sided colitis without complications
K51.00 Ulcerative (chronic) pancolitis without complications
K51.90 Ulcerative colitis, unspecified, without complications
K60.3 Anal fistula
K60.4 Rectal fistula
K60.5 Anorectal fistula
K63.2 Fistula of intestine
L40.54 Psoriatic juvenile arthropathy
L40.59 Other psoriatic arthropathy
L40.8 Other psoriasis
M06.9 Rheumatoid arthritis, unspecified
M05.00 Felty’s syndrome, 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
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
M05.10 Rheumatoid lung disease with rheumatoid arthritis of unspecified site
M06.4 Inflammatory polyarthropathy
M45.9 Ankylosing spondylitis of unspecified sites in spine

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: A type of arthritis that causes chronic inflammation of the spine.

Crohn’s Disease: is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder. Symptoms may include watery diarrhea and abdominal pain. The symptoms of Crohn’s Disease can be difficult to manage and diagnosis is often delayed.

Enterocutaneous fistula: a fistula between the intestine and skin of the abdomen.

Mild-Moderate Crohn’s Disease: Mild-moderate Crohn’s disease applies to ambulatory patients able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.

Moderate-Severe Crohn’s Disease: Moderate-severe disease applies to patients who have failed to respond to treatment for mild-moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.

Monoclonal antibody: derived from a single cell; pertaining to a single clone. Widely used to measure proteins and drugs in the serum, type tissue and blood, identify infectious agents, identify classification and follow-up therapy of leukemias and lymphomas, and identify tumor antibodies.

Plaque psoriasis: It is the most common form of psoriasis. It affects 80 to 90% of people with psoriasis. Plaque psoriasis typically appears as raised areas of inflamed skin covered with silvery white scaly skin. These areas are called plaques.

Psoriatic arthritis: Joint inflammation associated with psoriasis. Psoriatic arthritis is a potentially destructive and deforming form of arthritis that affects approximately 10% of persons with psoriasis.

Remission: Remission refers to patients who are asymptomatic or without inflammatory sequelae and includes patients who have responded to acute medical intervention or have undergone surgical resection without gross evidence of residual disease. Patients requiring steroids to maintain well-being are considered to be “steroid-dependent” and are usually not considered to be “in remission.”

Rheumatoid arthritis: usually strikes between ages 20 and 50. Inflammation begins in a joint, usually those of the fingers and hands, resulting in pain, swelling, redness, and eventually joint deformity. It is considered an autoimmune disease, which can affect the entire body, causing fatigue, weight loss, weakness, fever, and loss of appetite. It affects each person differently, with symptoms ranging from mild to debilitating. In many cases, it is difficult to control. In about one in six cases, rheumatoid arthritis becomes severely debilitating and can shorten the life of the person affected.

Severe-Fulminant Disease: Severe-fulminant disease refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, and evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.

Ulcerative colitis: a chronic inflammatory disease of the colon that is of unknown cause and is characterized by diarrhea with discharge of mucus and blood, cramping abdominal pain, and inflammation and edema of the mucous membrane with patches of ulceration.

RELATED GUIDELINES:

Etanercept (Enbrel®), 09-J0000-38
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

Natalizumab (Tysabri®) IV, 09-J0000-73

Alefacept (Amevive®), 09-J0000-78

Ustekinumab (Stelara™), 09-J1000-16

Tocilizumab (Actemra®) IV, 09-J1000-21

OTHER:

None applicable.

REFERENCES:

  1. American College of Rheumatology. Position Statement: Biologic Agents for Rheumatic Diseases. Approved: 03/03 and 08/09.
  2. American Gastroenterological Association. Position Statement: Perianal Crohn’s Disease. Gastroenterology 2003; 125: 1503-1507.
  3. American Medical Association CPT Coding, 2009 professional edition.
  4. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006893. DOI: 10.1002/14651858.CD006893.
  5. Data presented at the 2001 American College of Gastroenterology meeting: Las Vegas, NV; October 21-24, 2001.
  6. Data presented at the 2001 Digestive Disease Week Meeting; Atlanta, GA: May 20-23, 2001.
  7. DRUGDEX®. Accessed 07/21/10.
  8. Eidelwein AP, Cuffari C, Abadom V et al. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis. March 2005; 11(3): 213-8.
  9. Facts & Comparisons E Answers. Accessed 07/21/10.
  10. Garnett WR and Yunker N. Treatment of Crohn’s Disease with Infliximab. Am J Health-Sys Pharm 2001; 58 (4): 307-19.
  11. Guidelines for the Management of Rheumatoid Arthritis 2002 Update. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis & Rheumatism Vol. 46, No. 2, February 2002, pp 328-346.
  12. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance for Crohn’s disease; the ACCENT I randomized trial. Lancet 2002; 359: 1541-9.
  13. Harrison MJ, Dixon WG, Watson KD, King Y, Groves R, Hyricdh KL, Symmons DP. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-TNF (alpha) therapy. Results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2008 Apr 2.
  14. HAYES, Inc. FDA Approves Long-Term Remicade for Crohn’s Disease. Lansdale, PA: HAYES, Inc. July 2002.
  15. HAYES, Inc. FDA Approves Remicade® as First-Line Therapy in Patients WITH Moderate to Severe Rheumatoid Arthritis. Lansdale, PA: HAYES, Inc. October 2004.
  16. HAYES, Inc. Infliximab for Crohn’s Disease. Lansdale, PA: HAYES, Inc. May 2004.
  17. HAYES, Inc. Infliximab for Rheumatoid Arthritis. Lansdale, PA: HAYES, Inc. April 2004.
  18. HAYES, Inc. Infliximab Maintenance Therapy for Fistulizing Crohn’s Disease. Lansdale, PA: HAYES, Inc. March 2004.
  19. HAYES, Inc. Maintenance Infliximab Benefits Select Patients With Crohn’s Disease. Lansdale, PA: HAYES, Inc. May 2002.
  20. HAYES, Inc. Remicade® Now Indicated to Treat Ulcerative Colitis. Lansdale, PA: HAYES, Inc. September 2005
  21. HIPAA Space, HCPCS Codes Lookup, Copyright® 2004-2010. Accessed 07/21/10.
  22. ICD-9 Data.com. Accessed 07/21/10.
  23. Jarnerot G, Hertervig E, Friis-Liby I et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. June 2005.
  24. National Guideline Clearinghouse. Management of ulcerative colitis. Society of Surgery of the Alimentary Tract. Accessed October 2005.
  25. Remicade® (infliximab) Prescribing Information. Revised April 2010.
  26. The Merck Manual, 16th Edition.
  27. Wailoo AJ, Bansback N, Brennan A, Michaud K, Nixon RM, Wolfe F. Biologic drugs for rheumatoid arthritis in the medicare program: A cost-effectiveness analysis. Arthritis Rheum. 2008 Mar 27; 58(4): 939-946.

COMMITTEE APPROVAL:

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

GUIDELINE UPDATE INFORMATION:

 

04/25/01 Medical Coverage Guideline developed.
04/25/02 Reviewed, revised coverage for Crohn’s disease.
08/15/02 Revised coverage for Crohn’s disease.
04/01/05 Revised with updates: Added maintenance therapy to fistulizing crohn’s. Added coverage for psoriatic arthropathy and ankylosing spondylitis. Updated dosing.
11/15/05 Revised; added coverage for ulcerative colitis, updated dosage and administration, deleted warnings and contraindications section, updated references and Internet links.
01/01/06 CPT coding update: deleted expired codes 90780, 90781 and added new codes 90765, 90766.
11/15/06 Scheduled review: added psoriasis indication and ICD-9 code, updated code descriptions and updated references.
01/01/07 MCG revised to include Medicare Part D as a program exception.
02/15/07 Revised by adding CPT-4 codes 96413 & 96415.
06/15/07 Review and revision to guideline; consisting of reformatting, removed ICD-9 codes 557.0 and 619.1, added ICD-9 code 714.2, added statement saying Remicade® is a first line agent and updated references.
05/15/08 Review and revision to guideline; consisting of reformatting, added black box warning.
01/01/09 Annual HCPCS coding update: deleted 90765 and 90766; added 96365 and 96366.
05/15/09 Revision to guideline; consisting of adding maximum dose for each indication.
09/15/09 Review and revision to guideline; consisting of updating boxed warning, updating the references, and rewording dosing maximums within the position statement.
04/15/10 Revision to guideline; consisting of adding specific continuation criteria.
09/15/10 Review and revision to guideline; consisting of updating boxed warnings, precautions and references.
01/15/11 Revision to guideline; consisting of adding ICD-10 codes.

 

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

Clinical Policy Bulletin: Remicade (Infliximab)

Policy

  1. Aetna considers Remicade (infliximab) medically necessary for members with any of the following indications:
    1. Active Crohn’s Disease:
      1. Member has active Crohn’s disease, as manifested by any one of the following signs/symptoms:
        1. Abdominal pain;
        2. Bleeding;
        3. Diarrhea;
        4. Extra-intestinal manifestations: arthritis or spondylitis;
        5. Internal fistulae;
        6. Intestinal obstruction;
        7. Megacolon;
        8. Perianal disease; or
        9. Weight loss; and
      2. Crohn’s disease has remained active despite treatment with one of the following:
        1. 6-mercaptopurine/azathioprine; or   
        2. Corticosteroids.
    2. Fistulizing Crohn’s Disease:

      Member has fistulizing Crohn’s disease for at least 3 months.

    3. Rheumatoid Arthritis:

      Member has moderately to severely active rheumatoid arthritis.

    4. Juvenile Idiopatic Arthritis:

      Member has moderately to severely active polyarticular juvenile idiopathic arthritis, and has failed to adequately respond to etanercept (Enbrel), adalimumab (Humira), and abatacept (Orencia), unless contraindicated.

    5. Psoriasis:

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

    6. Psoriatic Arthritis:

      Members with active psoriatic arthritis who have had an inadequate response to two or more disease-modifying antirheumatic drugs (DMARDs) (sulfazalazine, methotrexate, azothioprine, cyclosporine, cyclophosphamide).

    7. Ankylosing Spondylitis and Other Spondyloarthropathies:

      Members with active ankylosing spondylitis or other active spondyloarthropathy with evidence of inflammatory disease who have an inadequate response to two or more NSAIDS (e.g., ibuprofen, diclofenac, naproxen, indomethacin, sulindac, celecoxib, meloxicam, valdecoxib). 

    8. Reactive Arthritis and Inflammatory Bowel Disease Arthritis:

      Members with refractory reactive arthritis or inflammatory bowel disease arthritis (enteropathic arthritis) who have failed or are intolerant to non-steroidal anti-inflammatory drugs, sulfasalazine, steroids and methotrexate.

    9. Ulcerative Colitis:

      Members with moderate to severe active ulcerative colitis refractory to one or more of the following standard therapies:

      1. 5-aminosalicylic acid agents (e.g., sulfasalazine, mesalamine, balsalazide)
      2. Corticosteroids (e.g., prednisone, methylprednisolone)
      3. Immunosuppressants (e.g., azathioprine, cyclosporine, 6-mercaptopurine).
    10. Chronic Pulmonary Sarcoidosis:

      Members with chronic pulmonary sarcoidosis who remain symptomatic despite treatment for three or more months with steroids (10 mg per day or more) and immunosuppressants (such as methotrexate, cyclophosphamide, or azathioprine).

    11. Pyoderma Gangrenosum:

      Aetna considers infliximab medically necessary for persons with refractory pyoderma gangrenosum.

  2. Aetna considers infliximab experimental and investigational for all other indications (e.g., asthma, Behcet’s disease, birdshot retinochoroidopathy, chronic obstructive pulmonary disease, Cogan’s syndrome, corneal ulcer, disc herniation-induced sciatica, discoid lupus erythematosus, eosinophilic fasciitis, granuloma annulare, granulomatous mastitis, hidradenitis suppurativa, multi-focal osteomyelitis, neurosarcoidosis, prevention of post-operative recurrence of Crohn’s disease, Reiter’s syndrome, rejection following small bowel transplantation, scleroderma, uveitis, Wegener’s granulomatosis/Wegener’s peripheral neuropathy, not an all inclusive list).
  3. Aetna considers measurements of serum levels of infliximab and antibodies to infliximab (human anti-chimeric antibodies (HACA)) experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.
  4. Aetna considers measurements of anti-histone antibodies for monitoring infliximab therapy experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.

See also CPB 249 – Inflammatory Bowel Disease: Serologic Markers and Pharmacogenomic and Metabolic Assessment of Thiopurine Therapy.

BackgroundInfliximab is a monoclonal antibody that binds to and inhibits tumor necrosis factor alpha, a cytokine that plays an important role in a variety of inflammatory processes, including induction of pro-inflammatory cytokines, enhancement of leukocyte migration, activation of neutrophil and eosinophil activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and chondrocytes.  Elevated concentrations of TNF alpha have been found in the joints of rheumatoid arthritis patients and the stools of Crohn’s disease patients, and correlate with elevated disease activity.  In Crohn’s disease, treatment with infliximab reduced infiltration of inflammatory cells and TNF alpha production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propia able to express  TNF alpha and interferon gamma.  In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction, and tissue degradation.

The patient selection criteria outlined above were derived from the FDA-approved prescribing information for Remicade, the studies that were presented to the FDA in support of the pre-market approval application, and studies in the peer-reviewed published medical literature.

Infliximab is an intravenous medication that is indicated for the reduction in the number of enterocutaneous fistulas in patients with fistulating Crohn’s disease.  The safety and efficacy of infliximab in fistulizing Crohn’s disease was demonstrated in a randomized, controlled study of patients with fistulizing Crohn’s disease of at least three months duration.  Initial therapy consists of three doses of infliximab (5mg/kg) given at 0, 2 and 6 weeks.  Retreatment with infliximab is covered.

Infliximab is also indicated for the reduction in signs and symptoms of active Crohn’s disease in patients who have had an inadequate response to conventional therapies (corticosteroids, sulfasalazine, mesalamine, olsalazine, or 6-mercaptopurine).  The safety and efficacy of infliximab for patients with active Crohn’s disease was demonstrated in a randomized controlled clinical trial.  In clinical studies of infliximab for active Crohn’s disease, all patients had experienced an inadequate response to prior conventional therapies, including corticosteroids, 5-aminosalicylates (5-ASA), and/or 6-mercaptupurine/ azathioprine (6-MP/AZA).  Initial therapy consists of a single infusion of infliximab (5mg/kg). In clinical studies, there was no evidence of a dose response; doses higher than 5 mg/kg did not result in a greater proportion of responders. Retreatment with infliximab may be necessary and is covered.  Although the optimal frequency of retreatment is uncertain, there is preliminary evidence to suggest that the optimal interval frequency of retreatments is 8-week intervals.

Consistent with FDA-approved product labeling, infliximab, in combination with methotrexate, is considered medically necessary for the reduction of signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate monotherapy.  The safety and efficacy of infliximab for rheumatoid arthritis was demonstrated in a 30-week-long, multicenter, randomized, controlled clinical study involving rheumatoid arthritis patients who had failed to adequately respond to 6 or more months of methotrexate monotherapy.  When used for treatment of rheumatoid arthritis, infliximab is administered intravenously in 3 mg/kg doses at zero, two and six weeks and then every eight weeks thereafter. Infliximab may be administered as frequently as every four weeks in patients with an inadequate response to less frequent dosing.  However, in clinical trials, higher doses and/or more frequent administrations did not result in higher response rates.

There are currently three biological response modifiers for rheumatoid arthritis currently on the market: infliximab (Remicade) and etanercept (Enbrel) act by inhibiting tumor-necrosis factor, and anakinra (Kineret) acts by blocking interleukin-1.  However, there are no published direct comparative studies of these drugs to determine whether any one is more safe or effective than another.  Although the three currently available biological response modifiers differ in structure, mechanism of action and pharmacokinetics, they each have proven effective in reducing the signs and symptoms of rheumatoid arthritis and in slowing and even arresting the progression of radiographic damage. Infliximab requires intravenous administration by a health care professional; by contrast, both etanercept and anakinra are self-administered by subcutaneous injection.

Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy.  Studies have shown that infliximab, improves clinical, endoscopic, and histologic outcomes in patients with severely active ulcerative colitis refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy.  This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade.  Two Phase III randomized, placebo-controlled clinical trials have demonstrated efficacy of infliximab in inducing and maintaining clinical response and remission of refractory moderate to severe ulcerative colitis (Rutgeerts, et al., 2005; Sandborn, et al., 2005).  In these clinical trials, subjects with moderate to severe ulcerative colitis that was refractory to at least one standard therapy were randomly assigned to infliximab in doses of 5 mg per kg or 10 mg per kg, or to placebo.  In one clinical trial involving 364 subjects with moderate to severe ulcerative colitis (Sandborn, et al., 2005), 62 percent of subjects in the 10 mg group and 69 percent of subjects in the 5 mg group had a clinical response at 8 weeks, compared to 37 percent of subjects in the placebo group (p < 0.001 for both).  At that time, 32 percent of subjects in the 10 mg group and 39 percent of subjects in the 5 mg group were in clinical remission, versus 15 percent of subjects in the placebo group. (p = 0.002 and p < 0.001, respectively).  By 30 weeks, 51 percent of the 10 mg group and 52 percent of the 5 mg group achieved clinical response versus 30 percent of placebo-treated subjects (p = 0.002 and p < 0.001).  At that time, 37 percent of the 10 mg group and 34 percent of the 5 mg group were in clinical remission, versus 16 percent of the placebo group (p < 0.001 and p = 0.001).

In a second clinical trial involving 364 subjects with moderate to severe ulcerative colitis (Sandborn, et al., 2005), 69 percent of subjects in the 10 mg group and 65 percent of subjects in the 5 mg group had a clinical response at 8 weeks, compared to 29 percent of subjects in the placebo group (p < 0.001 for both).  At that time, 28 percent of subject in the 10 mg group and 34 percent of subjects in the 5 mg group were in clinical remission, versus 6 percent of subjects in the placebo group (p < 0.001 for both).  By 30 weeks, 60 percent of subjects in the 10 mg group and 47 percent of subjects in the 5 mg group had a clinical response, compared to 26 percent of subjects receiving placebo (p < 0.001 for both).   At that time, 36 percent of subjects in the 10 mg group and 26 percent of subjects in the 5 mg group were in clinical remission, compared to 11 percent in the placebo group (p < 0.001 and p = 0.003).

Additional studies are needed to evaluate the optimal timing and duration of infliximab therapy, the utility of adjuvant medical treatments during infliximab therapy, and the long-term safety and comparative efficacy of the various treatments for ulcerative to better define the role of infliximab in the treatment of this condition.  Other TNF antagonists for ulcerative colitis in various phases of investigation include the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide.

Two published randomized controlled trials have reported on significant reductions in disease activity in patients with ankylosing spondylitis and other spondyloarthropathies who were treated with infliximab.  Spondyloarthropathy (literally arthritis of the spine) may be associated with ankylosing spondylitis, Reiter syndrome, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease, or may be idiopathic (undifferentiated spondyloarthropathy).  Van den Bosch, et al. (2002) reported on a 12-week long clinical study involving forty patients with active spondyloarthropathy who were randomly assigned to receive an intravenous loading dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or placebo.  Both patient and physician global assessments of disease activity on a visual analog scale improved significantly in the infliximab group compared with the baseline value, with no improvement in the placebo group.  As early as week 2 and sustained up to week 12, there was a highly statistically significant difference between the values for these two endpoints in the infliximab versus the placebo group.  In most of the other assessments of disease activity (laboratory measures, assessments of specific peripheral and/or axial disease), significant improvements were observed in the infliximab group compared with the baseline value and compared with placebo.  There was one severe drug-related adverse event, in which a patient developed disseminated tuberculosis.

Braun, et al. (2002) reported the results of a 12-week randomized placebo-controlled clinical trial involving 35 patients with active ankylosing spondylitis treated with intravenous 5mg/kg infliximab infusion (at weeks 0, 2 and 6) and 35 patients assigned to placebo.  Eighteen (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% CI 23-61], p<0.0001).  Function and quality of life also improved significantly on infliximab but not on placebo (p<0.0001 and p<0.0001, respectively).  The investigators reported that treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.

These randomized controlled trials confirm the findings of an open label study of infliximab in 21 patients with active spondyloarthropathy who received a maintenance regimen of 5 mg/kg infliximab every 14 weeks, 19 of whom were followed for one year (Kruithof, et al., 2002).  The investigators reported that, after each re-treatment a sustained significant decrease of all disease manifestations was observed.  Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48.  Twelve minor infectious episodes were observed in this cohort.

Based on limited evidence, the U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab.  A controlled clinical study (Chaudhari, et al., 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis.  In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of two doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo.  Nineteen of 22 patients assigned to infliximab achieved good or better physician’s overall assessments, compared with two of 11 patients assigned to placebo.  In initial studies, remissions seemed to be durable, with many patients improving for six months or longer.

Based on the evidence of efficacy of infliximab in a variety of spondyloarthropathies where tumor necrosis factor plays a role, the U.S. Pharmacopeial Convention (2003) has concluded that reactive arthritis and inflammatory bowel disease arthritis are accepted off-label indications for infliximab.

Evidence suggests that infliximab may be effective in juvenile rheumatoid arthritis. A randomized, controlled clinical study found a nonsignificant trend in favor of infliximab in polyarticular juvenile idiopathic arthritis (Ruperto, et al., 2007). In this multicenter, randomized, placebo-controlled study, 122 children with persistent polyarticular juvenile idiopathic arthritis despite prior methotrexate therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received methotrexate plus infliximab 3 mg/kg through week 44, or methotrexate plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. The investigators reported that a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), but the between-group difference in this primary efficacy end point was not statistically significant (p = 0.12). The investigators reported that, by week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients.

An open-label extension of this study of juvenile idiopathic arthritis concluded that infliximab was safe and effective in the long-term, but had a high discontinuation rate (Ruperto, et al., 2010). Seventy-eight of the 122 subjects (64%) entered this open-label extension study. Of these, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (8 patients) or patient/physician/sponsor requirement (8 patients). The authors reported that infliximab at a mean dose of 4.4 mg/kg per infusion was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At four years, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24%, and 13%, respectively.

There is limited evidence of infliximab’s effectiveness in persons with chronic pulmonary sarcoidosis who remain symptomatic despite treatment with steroids or immunosuppressants.  Baughman, et al. (2005) reported on a randomized controlled clinical trial comparing two doses of infliximab (3 or 5 mg/kg) to placebo in 138 patients with chronic (greater than 1 year duration) sarcoidosis who remain symptomatic (American Thoracic Society dyspnea score greater than 1) despite treatment with 3 or more months of prednisone (10 mg or more) or immunomodulator therapy or both, with evidence of parenchymal disease (Stage II or II) on chest x-ray, and a forced vital capacity (FVC) of > 50% to < 75% predicted.  The investigators reported significant (delta 2.5%, p = 0.038) improvement in the percent of predicted FVC at week 24, the primary study endpoint, in the combined infliximab groups.  The results did not differ significantly between infliximab doses.  The investigators reported that subgroup analysis demonstrated greater benefit in patients with more extensive sarcoidosis disease burden, duration, activity, and severity. 

Infliximab is under investigation as a treatment for uveitis.  Current evidence is limited to case reports and uncontrolled case series.  In the largest series of infliximab for uveitis published to date, Suhler and colleagues (2005) reported that at 10 weeks’ follow-up, 18 of 23 patients were considered successfully treated.  Those successfully treated for 1 year fell to 7 of 14 eligible patients, with 5 not completing the 1 year of treatment because of significant adverse effects.  An editorial by Robert Nussenblatt of the National Eye Institute (Nussenblatt, 2005) that accompanied this report noted, however, that only 4 of 23 patients demonstrated an improvement in their visual acuity of 2 lines or better. “Perhaps the most striking part of the report is the litany of adverse effects associated with the administration of this medication” (Nussenblatt, 2005).

Commenting on the available literature on infliximab for uveitis, Nussenblatt (2005) stated: “More than 60 publications have appeared in the literature to date describing the effects of infliximab in the treatment of uveitis.  This large number reflects a serious problem that needs to be addressed in this field.  While small, often single, case reports are important in generating hypotheses, these studies seem to produce not hypotheses but merely more of the same case reports.  Further, the reports use criteria that are not standardized, so comparing one study to another is difficult to do. This is the case for the present study as well.”

Well designed clinical studies are necessary for assessing the effectiveness and safety of infliximab in uveitis. It should also be noted that another tumor necrosis factor inhibitor, etanercept, showed apparently positive results in the treatment of uveitis in case reports and uncontrolled case series, but subsequently published controlled clinical trials demonstrated no significant benefit (Foster, et al., 2003; Smith, et al., 2005).

Kahn et al (2006) reported their experience in using infliximab for the treatment of childhood uveitis.  A total of 17 children (3 males, 14 females) with chronic uveitis were administered high-dose infliximab (10 to 20 mg/kg/dose).  Main outcome measure was the ability to eliminate all signs of intra-ocular inflammation.  All 17 patients showed a dramatic, rapid response, with no observed inflammation in 13 patients after the second infusion, and 4 patients requiring 3 to 7 infusions to achieve disease quiescence.  Additional immunosuppressives and topical glucocorticoids were tapered when patients achieved no intra-ocular inflammation.  The authors noted that in this series, high-dose infliximab was a rapidly effective, well-tolerated therapeutic agent for the treatment of chronic, medically refractory, non-infectious uveitis.  Moreover, they stated that larger, randomized, controlled studies will provide a better understanding of the dose, interval, and duration of treatment needed and will provide data on long-term safety.

A phase II clinical trial by Suhler and associates (2009) reported the 2-year follow-up data of patients with refractory uveitis treated with intravenous infliximab as part of a prospective clinical trial.  Their 1-year data, published in 2005 (Suhler, 2005) reported reasonable initial success, but an unexpectedly high incidence of adverse events.  Of their 23 patients, 7 developed serious adverse events, including 3 thromboses, 1 malignancy, 1 new onset of congestive heart failure, and 2 cases of drug-induced lupus.  Of patients who received at least 3 injections of infliximab, 75 % also developed elevated antinuclear antibody titers, although the significance of this is unknown.  The protocol initially permitted 1 year of therapy, but was extended to 2 years midway through the study.  Longer-term follow-up data were also collected for patients who continued with infliximab therapy after study completion.  Of the 31 patients who received infliximab in this study, approximately 75 % had an initial favorable response, and the drug was effective in select patients for 2 to 4 years.  Of 23 patients who demonstrated initial success at 10 weeks, 15 completed 1 year in the study and 8 completed 2 years of therapy, 7 in the study and 1 outside the study protocol prior to its extension to 2 years.  Three patients developed a drug-related lupus-like illness.  Two developed fatal solid malignancies, which were considered by the authors to have an unclear relation to the drug.  There were no further cases of congestive heart failure or venous thrombosis.  Unfortunately, 2 of the 7 patients who completed 2 years of the study were ultimately lost to follow-up, and another 2 patients who completed the 1-year protocol were also lost to follow-up.  It may be, in fact, that the risk of long-term adverse effects is even higher than reported in this article. The study by Suhler is difficult to interpret because of the small size, lack of comparision group, and substantial loss to followup.

In an accompanying editorial of theafore-mentioned article, Goldstein (2009) noted that Suhler et al (2009) are to be congratulated for adding to the literature on the use of TNF inhibitors in uveitis.  The editorialist stated that, while the trial is small and is neither randomized nor controlled, the data are collected in a prospective fashion, with at least 2 years of follow-up.  Although infliximab was not universally successful at controlling inflammation in this series, it was effective in selected patients, with 60 % of patients retained in the study per year.  This series also demonstrated that while infliximab is well-tolerated in terms of immediate treatment-limiting adverse effects, significant late toxicity may occur.  Furthermore, Goldstein noted that the rate of adverse events reported by Suhler et al (2009) is much higher than reported in retrospective uveitis series.  Because this is a prospective trial, its results may be more clinically relevant than those from retrospective series and may offer the clinician a more accurate estimate of the risks associated with the use of infliximab in patients with uveitis.  Clinical trials of infliximab for uveitis are currently ongoing.

A clinical trial has demonstrated that infliximab is superior to placebo in the treatment of pyoderma gangrenosum. Pyoderma gangrenosum is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. Pyoderma gangrenosum is treated by managing the underlying cause. Topical and oral steroids are used. If resistant, oral dapsone or minocycline, and occasionally cyclosporine is used. Brooklyn, et al. (2006) reported on the results of a randomized controlled trial of infliximab. Patients 18 years of age and older with pyoderma gangrenosum were randomized to receive infliximab at 5 mg per kilogram (n = 13) or placebo (n = 17). Patients were assessed two weeks later and, during the open label portion of the study, nonresponders were offered open labeled infliximab, and were reassessed four weeks later. At week 2, significantly more patients in the infliximab group had improved (46 percent (6/13) compared with the placebo group (6 percent (1/17) (p = 0.025). Overall, 29 patients received infliximab with 69 percent (20/29) demonstrating a clinical beneficial response. Remission rate at week 6 was 21 percent (6/29). There was no response in 31 percent (9/29) of patients. The authors concluded that infliximab is superior to placebo in the treatment of pyoderma gangrenosum. 

A systematic evidence review in BMJ Clinical Evidence found that the effectiveness of infliximab in treatment of herniated disc is unknown (Jordan, et al., 2008). The assessment identified one randomized controlled clinical trial of 41 people with acute or subacute sciatic pain, caused by herniated discs confirmed by magnetic resonance imaging, comparing infliximab, given as a single intravenous infusion) versus control (saline infusion over 2 hours) (Korhonen, et al., 2005).  The randomized controlled trial found no significant difference between infliximab and control in leg or back pain score improvements at 12 weeks or median reduction in back pain score at 12 weeks. The trial also found no significant difference between groups in reduction of Oswestry Disability Index scores, median cumulative sick leave, or the proportion of people undergoing discectomy.

There is insufficient scientific evidence regarding the clinical value of measurements of serum levels of infliximab and/or HACA for patients receiving infliximab therapy.

In a double-blind, placebo-controlled, phase III clinical trial, Maini and colleagues (1999) examined if infliximab would provide additional clinical benefit to patients who had active RA despite receiving methotrexate.  A total of 428 patients who had active RA and had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomized to placebo (n = 88) or one of four regimens of infliximab at weeks 0, 2, and 6.  Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for greater than or equal to 6 months, range 10 to 35 mg/wk).  Patients were assessed every 4 weeks for 30 weeks.  At 30 weeks, the American College of Rheumatology (ACR)-20 response criteria, representing a 20 % improvement from baseline, were achieved in 53, 50, 58, and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20 % of patients receiving placebo plus methotrexate (p < 0.001 for each of the four infliximab regimens versus placebo).  A 50 % improvement was achieved in 29, 27, 26, and 31 % of infliximab plus methotrexate in the same treatment groups, compared with 5 % of patients on placebo plus methotrexate (p < 0.001).  Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.  The authors concluded that during 30 weeks, treatment with infliximab plus methotrexate was more effective than methotrexate alone in patients with active RA not previously responding to methotrexate.

The protocol in the study by Maini et al (1999) pre-specified that pharmacokinetic data would be analyzed in the first 200 subjects.  However, the number of subjects with human anti-chimeric antibodies (HACA) formation was not stated.  Because of the murine component of the antibody, patients receiving infliximab can develop HACA that are associated with an increased rate of infusion reactions.  Pharmacokinetic measurements were actually performed in 197 patients and results were consistent with the previously defined half-life of 8 to 12 days.  It should be noted that HACA formation could not be measured in patients receiving infliximab since the drug interferes with the assay.  However, 27 patients who discontinued treatment before 30 weeks were tested for HACA formation, and 3 patients (11 %) tested positive for HACA (2 with a titer of 1/10 and 1 with a titer of 1/40).  The rate of HACA formation in patients with CD treated with infliximab is reported to be 13 %, but this rate appears to be less if a patient is on concurrent immunosuppressive therapy (Hanauer, 1999; Sanborn and Hanauer, 2002).  It is unclear whether serum infliximab levels may decline more rapidly in the presence of HACA resulting in reduced effectiveness of infliximab therapy. 

St Clair, et al. (2002) examined the relationship between serum concentrations of infliximab and clinical improvement from RA following infliximab treatment.  Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multi-center, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the safety and effectiveness of infliximab therapy.  Serum levels of infliximab were measured by enzyme-linked immunosorbent assay.  Dose-response trends were analyzed using generalized logistic regression techniques.  Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.  At week 54, 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (p < 0.001).  Increased magnitude of ACR response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR-20 criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (p < 0.001), as was less progression of radiographical joint damage (p = 0.004), providing support for a dose-response relationship.  Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.  The authors concluded that these results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

In the study by St. Clair, et al. (2002), the relatively low proportion of ACR-50 responders in patients receiving 3mg/kg every 8 weeks may be due to inadequate exposure to infliximab during the course of therapy.  The trough serum levels of infliximab at 54 weeks varied more than 100-fold in this group suggesting marked differences among patients in exposure to infliximab.  The basis for this individual variability is unclear, but HACA and/or metabolic differences may offer some explanations.  However, it is unlikely that HACA are the sole reason for the rapid clearance of serum infliximab in this group of patients.  After completion of the study, HACA were detected in 25 patients (8.5 %) with analyzable samples.  These antibodies were distributed across all infliximab-treated groups.  The appropriate serum samples were available for measuring HACA in 19 of 21 patients from the group that received 3mg/kg every 8 weeks; and this group of patients had undetectable trough levels of infliximab.  Of these 19 subjects, only 6 were HACA-positive, and 2 had inconclusive results.  Therefore, metabolic factors probably are responsible for the rapid clearance of infliximab in some patients.

The relationship between clinical improvement and trough serum levels of infliximab bears clinical implications.  Although there was a trend towards a slightly higher proportion of serious side effects in the group receiving 3mg/kg every 4 weeks compared with the group receiving 3mg/kg every 8 weeks (16 % versus 11 %), this incidence was no higher than that observed in the placebo-controlled group (21 %).  Presently, there is a lack of evidence to identify which patients might benefit from a dose increase based on any clinical, laboratory, or radiographical factors.  Additionally, the relationship between trough serum levels of infliximab and clinical improvement is imprecise.  At 54 weeks, 6 (21 %) of the 28 patients in the study attained ACR-50 or better despite trough serum infliximab levels of less than 0.1 ug/ml.  Thus, trough serum levels of infliximab are not, by themselves reliable predictors of treatment response.  St Clair, et al. (2002) stated that they would not advocate the routine measurement of serum infliximab levels for this reasons.  It should also be noted that poor or lack of response to infliximab therapy may be the result of a particular disease characteristics (e.g., joint inflammation not primarily driven by TNF-alpha) or other host factors that preclude an adequate response to treatment.

The clinical significance of HACA formation, if any, has yet to be established.  HACA is associated with an increased frequency of infusion reactions, although overall, the presence of HACA is poorly predictive of infusion reactions (Smith, et al., 2005).  Guidelines from the Canadian Consensus Group on the Use of Infliximab in Crohn’s Disease (Panaccione, 2001) note that most infusion reactions are easily dealt with by stopping the infusion and restarting at a decreased rate.  Furthermore, formation of antibodies to infliximab can be prevented by coadministration of infliximab with methotrexate or other immunosuppressants (Panaccione, 2004).  It should be noted that HACA-positive patients who received repeated treatment with infliximab have demonstrated sustained clinical benefit and have tolerated such treatment well even though they may be more likely to experience an infusion reaction to the administration of infliximab.

Measurement of anti-histone antibodies has been employed for monitoring of infliximab therapy.  However its clinical value has yet to be established.  Allanore et al (2004) examined autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab.  These investigators included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide.  They tested the sera of the patients for anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30.  Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after 3 infusions.  At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 % versus 42 %, p = 0.009).  At week 30, the frequency of patients with ANA had increased from 29 % to 69 % (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0 % to 3 % for IgG (NS) and from 0 % to 32 % for IgM (p < 0.001); the frequency of anti-histone IgG detection had increased from 22 % to 32 % (p = 0.04) and that of IgM detection, from 18 % to 79 % (p < 0.001).  No lupus-like syndrome was observed.  RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001).  No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy.  The authors concluded that Infliximab therapy lead to the selective and delayed induction of autoantibodies.  This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.

Elkayam and colleagues (2005) noted that therapy with TNFa blocking agents has been associated with increased rate of ANA and rare cases of lupus like syndromes.  The objective of this study was to prospectively analyze a wide array of autoantibodies in RA patients before and 14 weeks after starting infliximab.  In this study, 26 consecutive active RA patients participated.  All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and every 8 weeks, along with weekly low dose methotrexate.  Patients were evaluated at week 0 and 14.  Clinical assessment included the number of tender and swollen joints, duration of morning stiffness, adverse events (AE) (including SLE-like) and ESR.  Sera were collected before the 1st infusion of infliximab at week 0 and 14.  The autoantibodies studied were: fluorescent ANA, anti dsDNA, IgG and IgM anti-cardiolipin (ACA), anti-histone- H1 and C (H1, H2A, H2B, H3, H4), anti-SSA, -SSB, -ENA, -scleroderma 70, -thyroid peroxidase (TPO) and -neutrophilic cytoplasmatic (ANCA) antibodies.  Of 26 patients, 17 were women.  A significant decrease in duration of morning stiffness, number of tender and swollen joints and ESR were observed between week 0 and 14.  During follow-up (mean of 20.5 +/- 7.3 months), 9 patients stopped infliximab due to inefficacy or AE (most of them after the 4th infusion).  Two patients developed lupus-like phenomena.  ANA was found positive at baseline in 7 out of 26 patients.  In 5 of them, an increase in the titer of ANA was observed at week 14.  ANA negative turned positive for 8 patients.  A significant increase of anti-cardiolipin (ACA)-IgM levels was observed in 8 patients and of ACA-IgG in 6, in parallel with ANA seroconversion.  The mean level of anti dsDNA) -IgG significantly increased from 66 +/-3 3 to 93 +/- 68 IU/ml, in 4 patients to pathological levels.  Four patients demonstrated an increase in anti-histone H1.  Levels of ANCA, anti-ENA, -SSA, -SSB, -RNP, -scleroderma70 and -thyroid peroxidase (TPO) were negative in all patients and remained unchanged during the study.  Cessation of treatment with infliximab was found to be associated with the appearance of ANA.  The authors concluded that an increased titer or a new appearance of ANA was observed in 12 out of 26 patients.  The main autoantibodies found were anti dsDNA, ACA-IgM and -IgG and anti-histone.  The authors noted that in their cohort, the appearance of some autoantibodies seemed to predict late cessation of treatment.

The FDA-approved product labeling for Remicade includes a black box warning that patients treated with infliximab are at increased risk for infections, including progression to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections. The black box warning states that patients should be educated about the symptoms of infection, closely monitored for signs and symptoms of infection during and after treatment with infliximab, and should have access to appropriate medical care. The warning states that patients who develop an infection should be evaluated for appropriate antimicrobial therapy and for serious infections infliximab should be discontinued. The labeling states that tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving infliximab. The black box warning states that patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating infliximab and during therapy. The labeling recommends that treatment of latent tuberculosis infection should be initiated prior to therapy with infliximab. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving infliximab. The labeling notes that some patients who tested negative for latent tuberculosis prior to receiving infliximab have developed active tuberculosis. The black box warning states that physicians should monitor patients receiving infliximab for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.

The black box also warns that rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with infliximab have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.

The labeling for Remicade states that infliximab has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. The labeling states that there have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. The labeling recommends that, if a decision is made to administer infliximab to patients with heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear.

In a Cochrane review, Doherty et al (2009) examined the use of medical therapies for the prevention of post-operative recurrence of Crohn’s disease. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify relevant studies. References from selected papers and abstracts from Digestive Disease Week were also searched. Randomized controlled trials that compared medical therapy to placebo or other medical agents for the prevention of recurrence of intestinal Crohn’s disease were selected for inclusion. Two authors reviewed all abstracts containing search terms, and those meeting inclusion criteria were selected for full data abstraction. Dichotomous data were summarized using relative risk and 95 % confidence intervals (CI). A fixed-effects model was used, and sensitivity analysis performed. A total of 23 studies were identified for inclusion. Probiotics were not superior to placebo for any outcome measured. The use of nitroimidazole antibiotics appeared to reduce the risk of clinical (RR 0.23; 95 % CI 0.09 to 0.57, number needed to treat [NNT] = 4) and endoscopic (RR 0.44; 95 %CI 0.26 to 0.74, NNT = 4) recurrence relative to placebo. However, these agents were associated with higher risk of serious adverse events (RR 2.39, 95 % CI 1.5 to 3.7). Mesalamine therapy was associated with a significantly reduced risk of clinical recurrence (RR 0.76; 95 % CI 0.62 to 0.94, NNT = 12), and severe endoscopic recurrence (RR 0.50; 95 % CI 0.29 to 0.84, NNT = 8) when compared to placebo. Azathioprine/6MP was also associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95 % CI 0.38 to 0.92, NNT = 7), and severe endoscopic recurrence (RR 0.64; 95 % CI 0.44 to 0.92, NNT = 4), when compared to placebo. Neither agent had a higher risk than placebo of serious adverse events. When compared to azathioprine/6MP, mesalamine was associated with a higher risk of any endoscopic recurrence (RR 1.45, 95 % CI 1.03 to 2.06), but a lower risk of serious adverse events (RR 0.51; 95 % CI 0.30 to 0.89). There was no significant difference between mesalamine and azathioprine/6MP for any other outcome. The authors concluded that there are insufficient randomized controlled trials of infliximab, budesonide, tenovil and interleukin-10 to draw conclusions. Nitro-imidazole antibiotics, mesalamine and immunosuppressive therapy with azathioprine/6-MP or infliximab all appear to be superior to placebo for the prevention of post-operative recurrence of Crohn’s disease. The cost, toxicity and tolerability of these approaches require careful consideration to determine the optimal approach for post-operative prophylaxis.

In a review on standard and novel treatments to Behçet’s disease, Gul (2007) stated that multi-center, multi-disciplinary and long-term trials aiming to assess the effectiveness of interventions (including infliximab) in both the treatment of acute inflammatory attacks and the prevention of relapses are needed in order to provide more generalizable results that can lead to better management plans. Kobayashi et al (2007) stated that 5-aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçet’s disease. Moreover, infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy.

Moravan and Segal (2009) described the effects of infliximab, and the anti-proliferative immunosuppressant, mycophenolate mofetil, in refractory neurosarcoidosis. These researchers treated patients with biopsy-proven sarcoidosis and central nervous system (CNS) involvement, who had failed treatment with steroids, with infliximab (5 mg/kg on weeks 0, 2, and 6, and then every 6 to 8 weeks thereafter). Six out of seven patients were co-treated with mycophenolate mofetil (1,000 mg PO BID). Patients underwent a review of symptoms and complete neurological examination every 3 months and MRI scanning before and after 3 to 4 infusions of infliximab. All patients reported significant symptomatic improvement by the 4th infusion of infliximab, including relief of headache and neuropathic pain, reversal of motor, sensory, or coordination deficits, and control of seizure activity. Furthermore, infliximab therapy was universally associated with a decrease in lesion size or suppression of gadolinium enhancement as documented by MRI. A positive treatment response was attained irrespective of location or distribution of CNS involvement by sarcoidosis (dural/leptomeningeal based versus intra-parenchymal; cord versus brain; single lesion versus multi-focal). There were no serious adverse effects in a follow-up period spanning 6 to18 months. The authors concluded that combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis.

Sodhi and colleagues (2009) stated that CNS involvement is a severe manifestation of sarcoidosis that often requires aggressive immunosuppressive therapy. The most effective approach for refractory disease is unknown. These investigators reviewed the cases of 4 subjects who demonstrated active progression of neurosarcoidosis while under treatment with cyclophosphamide, and who were subsequently treated with infliximab. All 4 subjects demonstrated rapid and substantial reversal of their clinical course. Radiological findings were concordant with the clinical responses. There were no notable toxicities. Infliximab may be more effective than cyclophosphamide for refractory CNS sarcoidosis. The authors noted that a larger, prospective study is warranted.

In a Cochrane review, Jessop et al (2009) assessed the effects of drugs for discoid lupus erythematosus. 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 handsearched and we approached authors for information about unpublished trials. They 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 0.0 5% 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 subjects was analyzed at 6 weeks. Clearing or excellent improvement was seen in 27 % of individuals using fluocinonide and in 10 % of those using hydrocortisone, giving a 17 % absolute benefit in favor of fluocinonide (95 % CI 0.0 to 0.34, NNT = 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 used to treat discoid lupus erythematosus.

Appendix

Table 1: Infliximab Dosing

Indication Dose
Ankylosing spondylitis Induction: 5mg/kg IV at weeks 0, 2, and 6

Maintenance: 5 mg/kg IV every 6 weeks

Crohn’s disease, fistulizing Induction: 5 mg/kg IV at weeks 0, 2, and 6

Maintenance: 5 mg/kg IV every 8 weeks

For persons who respond and then lose their response, consideration may be given to treatment with 10 mg/kg IV every 8 weeks.

Crohn’s disease, moderate to severe Induction: 5 mg/kg IV at weeks 0, 2, and 6

Maintenance: 5 mg/kg IV every 8 weeks

For persons who respond and then lose their response, consideration may be given to treatment with 10 mg/kg IV every 8 weeks.

Plaque psoriasis, chronic (severe) Induction: 5 mg/kg IV at weeks 0, 2, and 6

Maintenance: 5 mg/kg IV every 8 weeks

Psoriasis with arthropathy Induction: 5 mg/kg at weeks 0, 2, and 6

Maintenance: 5 mg/kg IV every 8 weeks

Rheumatoid arthritis, moderate to severe Induction: 3 mg/kg IV at weeks 0, 2 and 6

Maintenance: 3 mg/kg IV every 8 weeks

Incomplete response: 10 mg/kg IV every 8 weeks; or

     3 mg/kg IV every 4 weeks

Ulcerative colitis Induction: 5 mg/kg IV at weeks 0, 2 and 6

Maintenance: 5 mg/Kg IV every 8 weeks

Pediatric Crohn’s disease Induction: 5 mg/kg IV at weeks 0, 2 and 6

Maintenance: 5 mg/kg IV every 8 weeks

Chronic pulmonary sarcoidosis Induction: 3 mg/kg IV at weeks 0, 2, and 6

Maintenance: 3 mg/kg IV every 6 weeks

Pyoderma gangrenosum 5 mg/kg IV every 6 to 8 weeks
Sources: Remicade prescribing information; Baughman, et al. (2006); Brooklyn, et al., 2006.

 

Table 2: Grading of Severity of Rheumatoid Arthritis

Severity Criteria
Mild Joint pain
Inflammation of at least three joints
No inflammation in tissues other than the joints
Usually, a negative result on a rheumatoid factor test
An elevated ESR or CRP level
No evidence of bone or cartilage damage on x-rays
Moderate Between 6 and 20 inflamed joints
Usually no inflammation in tissues other than the joints
An elevated ESR or CRP levels
A positive rheumatoid factor test or anti-cyclic citrullinated peptide (anti-CCP) antibodies
Evidence of inflammation but no evidence of bone damage on x-rays
Severe More than 20 persistently inflamed joints or a rapid loss of functional abilities
Elevated ESR or CRP levels
Anemia related to chronic illness
Low blood albumin level
A positive rheumatoid factor test, often with a high level
Evidence of bone and cartilage damage on x-ray
Inflammation in tissues other than joints

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes not covered for indications listed in the CPB:
83516  
83520  
86235  
Other CPT codes related to the CPB:
96910 – 96913  
HCPCS codes covered if selection criteria are met:
J1745 Injection, infliximab, 10 mg
S9359 Home infusion therapy, anti-tumor necrosis factor intravenous therapy; (e.g., Infliximab); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
Other HCPCS codes related to the CPB (examples of other drug therapies):
J0129 Injection, abatacept, 10 mg
J0135 Injection, adalimumab, 20 mg
J1020 Injection, methylprednisolone acetate, 20 mg
J1030 Injection, methylprednisolone acetate, 40 mg
J1040 Injection, methylprednisolone acetate, 80 mg
J1438 Injection, etanercept, 25 mg
J1600 Injection, gold sodium thiomalate, up to 50 mg
J2920 Injection, methylprednisolone sodium succinate, up to 40 mg [Solu-Medrol]
J2930 Injection, methylprednisolone sodium succinate, up to 125 mg [Solu-Medrol]
J7500 Azathioprine, oral, 50 mg
J7501 Azathioprine, parenteral, 100 mg
J7502 Cyclosporine, oral, 100 mg
J7506 Prednisone, oral, per 5 mg
J7509 Methylprednisolone, oral, per 4 mg
J7510 Prednisolone, oral, per 5 mg
J7515 Cyclosporine, oral, 25 mg
J7516 Cyclosporine, parenteral, 250 mg
J8530 Cyclophosphamide, oral, 25 mg
J8610 Methotrexate, oral, 2.5 mg
J9070 Cyclophosphamide, 100 mg
J9096 Cyclophosphamide, lyophilized, 1 g
J9097 Cyclophosphamide, lyophilized, 2 g
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg
S0108 Mercaptopurine, oral, 50 mg
ICD-9 codes covered if selection criteria are met:
135 Sarcoidosis [chronic pulmonary]
555.0 – 555.9 Crohn’s disease
556.0 – 556.9 Ulcerative colitis
565.1 Anal fistula
569.81 Fistula of intestine, excluding rectum and anus
686.01 Pyoderma gangrenosum
696.0 Psoriatic arthropathy [active and failed two or more nonbiologic DMARDS]
696.1 Other psoriasis
711.00 – 711.99 Arthropathy associated with infections
713.00 – 714.2, 714.4 – 714.9 Arthropathy associated with other disorders classified elsewhere and rheumatoid arthritis and other inflammatory polyarthropathies
714.30 – 714.33 Juvenile chronic polyarthritis
716.20 – 716.29 Allergic arthritis
720.0 Ankylosing spondylitis [moderate to severe and failed two or more NSAIDS]
720.8 – 720.9 Other and unspecified inflammatory spondylopathies
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
099.3 Reiter’s disease
130.2 Chorioretinitis due to toxoplasmosis
136.1 Behcet’s syndrome
264.3 Vitamin A deficiency with corneal ulceration and xerosis
360.11 Sympathetic uveitis
363.13 Disseminated choroiditis and chorioretinitis, generalized
363.20 Chorioretinitis, unspecified [birdshot retinochoroidopathy]
364.00 – 364.05 Disorders of iris and ciliary body
364.10 – 364.11 Chronic iridocyclitis
364.21 Fuch’s heterochromic cyclitis
364.23 Lens-induced iridocyclitis
364.3 Unspecified iridocyclitis [uveitis]
370.00 – 370.06 Corneal ulcer
370.52 Diffuse interstitial keratitis [Cogan’s syndrome]
446.4 Wegener’s granulomatosis
493.00 – 493.92 Asthma
496 Chronic airway obstruction, not elsewhere classified
611.0 Inflammatory disease of breast [granulomatous mastitis]
695.4 Lupus erythematosus [discoid]
695.89 Other specified erythematous conditions [granuloma annulare]
701.0 Circumscribed scleroderma [scleroderma, circumscribed or localized]
705.83 Hiradenitis
710.1 Systemic sclerosis [scleroderma]
722.10 Displacement of lumbar intervertebral disc without myelopathy [disc-herniation-induced sciatica]
728.89 Other disorders of muscle, ligament, and fascia [eosinophilic fasciitis]
730.00 – 730.99 Osteomyelitis [multi-focal]
996.87 Complications of transplanted intestine [rejection]

The above policy is based on the following references:

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Data from: http://www.aetna.com/cpb/medical/data/300_399/0341.html