A Study of the Safety and Efficacy of Golimumab in Subjects With Rheumatoid Arthritis That Are Methotrexate-naive

A Study of the Safety and Efficacy of Golimumab in Subjects With Rheumatoid Arthritis That Are Methotrexate-naive

Register: ClinicalTrials.gov
Last refreshed on: 22 March 2011
Main ID:  NCT00264537
Date of registration: 11/12/2005
Primary sponsor: Centocor, Inc.
Public title: A Study of the Safety and Efficacy of Golimumab in Subjects With Rheumatoid Arthritis That Are Methotrexate-naive
Scientific title: A Multicenter, Randomized, Double-blind, Placebo-controlledTrial of Golimumab, a Fully Human Anti-TNFa MonoclonalAntibody, Administered Subcutaneously, in Methotrexate-naïve Subjects With Active Rheumatoid Arthritis
Date of first enrolment: November 2005
Target sample size: 637
Recruitment status: Active, not recruiting
URL:  http://clinicaltrials.gov/show/NCT00264537
Study type:  Interventional
Study design:  Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment  
Countries of recruitment
Argentina Australia Austria Belgium Brazil Canada Chile Hungary
India Korea, Republic of Malaysia Mexico New Zealand Philippines Poland Russian Federation
Singapore Spain Taiwan Thailand Turkey Ukraine United Kingdom United States
Contacts
Name:   Centocor, Inc. Clinical Trial
Address:   
Telephone:  
Email:  
Affiliation:  Centocor, Inc.
   
Key inclusion & exclusion criteria
Inclusion Criteria: – Have a diagnosis of rheumatoid arthritis (RA) (according to the revised 1987 criteria of the ACR) for at least 3 months prior to first administration of study agent – Are methotrexate (MTX)-naïve (ie, have not received more than 3 weekly doses of MTX for RA at any time) – Have active RA as defined by persistent disease activity with at least 4 swollen and 4 tender joints, at the time of screening and baseline, and at least 2 of the following 4 criteria: a) C-reactive protein (CRP) >=1.5 mg/dL at screening or erythrocyte sedimentation rate (ESR) by Westergren method of >= 28 mm in the first hour at screening or baseline, b)Morning stiffness of >= 30 minutes at screening and baseline, c)Bone erosion by x-ray and/or MRI prior to first administration of study agent, d)Anti-cyclic citrullinated peptide (anti-CCP) antibody-positive or rheumatoid factor (RF) positive at screening – If using oral corticosteroids, must be on a stable dose equivalent to <= 10 mg of prednisone/day for at least 2 weeks prior to first administration of study agent Exclusion Criteria: – Can not have inflammatory diseases other than RA that might confound the evaluation of the benefit of golimumab therapy – No treatment with disease-modifying anti-rheumatic drugs (DMARDs)/systemic immunosuppressives during the 4 weeks prior to the first administration of study agent – No prior treatment with biologic anti-TNF drugs (infliximab, etanercept, adalimumab) – No history of, or ongoing, chronic or recurrent infectious disease – No serious infection within 2 months prior to first administration of study agentAge minimum: 18 Years
Age maximum: N/A
Gender: Both
Health Condition(s) or Problem(s) studied
Rheumatoid Arthritis
Intervention(s)
Biological: golimumab
Drug: golimumab; methotrexate
Drug: placebo; methotrexate
Primary Outcome(s)
American College of Rheumatology 50 Response at Week 24 [Time Frame: Week 24]
Secondary Outcome(s)
American College of Rheumatology 20 Response at Week 24 [Time Frame: Week 24]
American College of Rheumatology 50 Response at Week 24 in Patients With Abnormal C-reactive Protein at Baseline [Time Frame: Week 24]
Secondary ID(s)
C0524T05
CR006331
GO-BEFORE
Source(s) of Monetary Support
Please refer to primary and secondary sponsors
Secondary Sponsor(s)
Schering-Plough

Information specific to: Humira 40mg/0.8ml solution for injection pre-filled syringes when used in Ankylosing spondylitis

Information specific to: Humira 40mg/0.8ml solution for injection pre-filled syringes when used in Ankylosing spondylitis.

Humira (Hew-meer-rah) 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. Humira contains adalimumab. It is supplied by Abbott Laboratories Limited.

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

Your medicine

Humira is an immunosuppressive medicine. It helps to suppress overactivity of the immune system in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn’s disease. It can help to reduce pain and swelling by limiting inflammation.

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

Humira stays in the body for several months so the effects of this medicine will persist for some time after you have your last dose.

Other information about Humira:

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

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

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

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

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

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

Whether this medicine is suitable for you

Humira 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 about to have surgery
  • are aged over 65 years
  • are allergic or sensitive to or have had a bad reaction to latex in the past
  • are allergic or sensitive to or have had a reaction to any of the ingredients in the medicine
  • are taking or have recently taken immunosuppressants
  • have a weakened immune system or are prone to infections
  • have been a heavy smoker
  • have been in close contact with somebody with tuberculosis
  • have been or are going to be vaccinated with live vaccines. For more information about vaccines, ask your prescriber, nurse or pharmacist for more advice
  • have chronic obstructive pulmonary disease
  • have demyelinating disorders
  • have heart problems
  • have hepatitis Binfection or are at risk of having hepatitis Binfection
  • have kidney problems
  • have liver problems
  • have or have had cancer
  • have or have had infections
  • have or have had lung problems
  • have or have had tuberculosis
  • have recently traveled in areas of high risk of tuberculosis or endemic mycoses

Furthermore the prescriber may only prescribe this medicine with special care or may not prescribe it at all for someone under 13 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 Humira can become unsuitable for some people, or they may become unsuitable for it. If at any time it appears that Humira has become unsuitable, it is important that the prescriber is contacted immediately.

Alcohol

Alcohol can interact with certain medicines.

In the case of Humira:

  • there are no known interactions between alcohol and Humira

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 Humira:

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

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 Humira:

  • this medicine could affect your ability to drive or operate machinery

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 Humira:

  • the use of this medicine during pregnancy is not recommended
  • you must not become pregnant while you are having this medicine, and for at least five months after you stop having this medicine. If you could become pregnant, you must use effective contraception or abstain from penetrative sex. You must contact your prescriber if you become pregnant, or think you have become pregnant, while having Humira

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 Humira:

  • women who are breast-feeding must not have this medicine
  • do not breast-feed for at least five months after you have the last dose of Humira

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 Humira:

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

The following types of medicine may interact with Humira:

  • Tumour Necrosis Factor antagonists
  • vaccines

If you are taking Humira 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 Humira.

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

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

Ingredients of your medicine

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

Humira contains:

  • adalimumab
  • citric acid monohydrate
  • disodium phosphate dihydrate
  • mannitol
  • polysorbate 80
  • sodium chloride
  • sodium dihydrogen phosphate dihydrate
  • sodium hydroxide
  • sodiumcitrate
  • water for injections

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

How to take your medicine

This medicine needs to be injected. Your prescriber may give you your injections or you may be shown how to inject the medicine yourself. If you are injecting this medicine yourself, follow the instructions from your prescriber and the information on the pharmacy label. There should also be further information in the Patient Information Leaflet that comes with this medicine.

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

When to take your medicine

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

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

Taking too much of your medicine

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

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

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

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

Stopping your medicine

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

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

Looking after your medicine

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

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

In the case of Humira:

  • store in a fridge at temperatures between 2-8°C
  • you must not freeze this medicine
  • store the pre-filled pens or pre-filled syringes in the outer carton

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

Side-effects

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

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

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

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

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

  • abnormal laboratory test results
  • blood and bone marrow problems – seek immediate medical advice if you get a persistent fever, become pale or have any type of bleeding or bruising
  • headaches
  • high levels of lipids in the blood
  • infections – some of the infections caused by Humira may be fatal. Seek immediate medical advice if you get any symptoms of an infection such as persistent fever; general feeling of being unwell; increased sweating; cough; or breathing problems while having Humira
  • inflammation of the nose and throat
  • injection site problems such as redness, inflammation, bleeding, itching, swelling or pain
  • muscle, bone or jointpain
  • nausea
  • pharyngitis
  • pneumonia
  • sinusitis
  • skin rash or rashes
  • stomachpain
  • vomiting

Common: More than 1 in 100 people who have Humira

  • asthma
  • autoimmune problems
  • benign tumour
  • bleeding problems
  • blood in the urine
  • breathing difficulties – seek immediate medical advice if you have difficulty breathing because this may be a sign of infection
  • changes in blood clotting time
  • chest pain
  • collection of blood under the skin
  • depression
  • dermatitis
  • difficulty sleeping
  • eczema
  • eye or eyesight problems including irritation or inflammation of the eye
  • faster heart rate
  • feeling anxious
  • flushing
  • gastrointestinal bleeding
  • gastro-oesophageal reflux
  • healing problems
  • hypersensitivity reactions or allergic reactions including anaphylactic type reactions – if these happen to you, stop having Humira and seek medical advice immediately
  • hypoaesthesia
  • increased blood sugar levels
  • indigestion
  • itching
  • kidney problems
  • metabolic problems
  • migraine
  • mood changes
  • muscle spasm
  • nail problems
  • oedema
  • paraesthesiae
  • raised blood pressure
  • sciatica
  • seasonal allergies
  • Sjögren’s syndrome
  • skin cancers
  • unexplained or easy bruising of the skin or mucous membranes
  • urticaria
  • vertigo

Uncommon: More than 1 in 1000 people who have Humira

  • breast cancer
  • deafness
  • dehydration
  • double vision
  • erectile dysfunction
  • facialoedema
  • gallbladder problems
  • heart or circulation problems
  • irregular heart rate
  • liver problems
  • lung or thyroidtumours
  • lung problems
  • lymphoma – this may be fatal
  • neurological problems
  • night sweats
  • pancreatitis
  • reactivation of infections including tuberculosis which may be fatal – seek immediate medical advice if you get a persistent cough, fever or weight loss
  • rhabdomyolysis
  • scar formation
  • swallowing difficulties
  • tinnitus
  • tremors
  • urinating more often at night
  • viral meningitis

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

  • cardiac arrest
  • circulation problems
  • lupus or lupus-like problem
  • multiple sclerosis
  • thrombophlebitis

The frequency of these side-effects is unknown

  • angioedema
  • cancer
  • collection of fluid around the lungs
  • demyelinating problems or worsening of existing demyelinating problems
  • erythema multiforme
  • feeling dizzy
  • gastrointestinal problems
  • Guillain Barré syndrome
  • hair loss
  • psoriasis or psoriasis-like rash or worsening of psoriasis
  • pulmonary embolism
  • reactivation of hepatitis B – this could be fatal
  • sarcoidosis
  • Stevens-Johnson syndrome
  • stroke
  • tiredness
  • vasculitis of the skin
  • worsening of heart problems

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.

This medicine is also available as:

This medicine is also used for:

Data From: http://www.nhs.uk/Conditions/Ankylosing-spondylitis/Pages/MedicineOverview.aspx?condition=Ankylosing spondylitis&medicine=Humira&preparation=Humira 40mg/0.8ml solution for injection pre-filled syringes

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

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

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

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

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

Your medicine

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

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

Other information about Enbrel:

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

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

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

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

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

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

Whether this medicine is suitable for you

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

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

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

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

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

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

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

Alcohol

Alcohol can interact with certain medicines.

In the case of Enbrel:

  • there are no known interactions between alcohol and Enbrel

Diet

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

In the case of Enbrel:

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

Driving and operating machinery

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

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

Family planning and pregnancy

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

In the case of Enbrel:

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

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

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

Breast-feeding

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

In the case of Enbrel:

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

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

Taking other medicines

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

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

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

The following medicines may interact with Enbrel:

  • abatacept
  • anakinra
  • methotrexate
  • sulfasalazine

The following types of medicine may interact with Enbrel:

  • antidiabetics
  • live vaccines

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

Complementary preparations and vitamins

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

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

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

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

Ingredients of your medicine

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

Enbrel contains:

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

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

How to take your medicine

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

In the case of Enbrel:

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

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

When to take your medicine

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

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

Taking too much of your medicine

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

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

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

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

Stopping your medicine

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

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

Looking after your medicine

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

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

In the case of Enbrel:

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

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

Side-effects

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

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

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

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

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

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

Common: More than 1 in 100 people who have Enbrel

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

Uncommon: More than 1 in 1000 people who have Enbrel

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

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

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

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

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

The frequency of these side-effects is unknown

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

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

Content provided by Datapharm

Yellow Card scheme

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

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

 

This medicine is also available as:

Printable guides available for this medicine:

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

Medicines for Ankylosing spondylitis

Medicines for Ankylosing spondylitis

Over-the-counter medicineOver-the-counter medicine. Medicine can be bought without a prescription.

K

L

M

N

P

R

S

T

V

Data From: http://www.nhs.uk/Conditions/Ankylosing-spondylitis/Pages/MedicineGuidePage.aspx

First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis.

First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis.

Abstract

OBJECTIVE:

To update the international recommendations for use of anti-tumour necrosis factor (TNF) agents in the treatment of ankylosing spondylitis.

METHODS:

The published recommendations on anti-TNF treatment in ankylosing spondylitis formed the basis of the update. A questionnaire was sent to the ASAS (assessment in ankylosing spondylitis) members before the final decisions were agreed upon at an international meeting of the ASAS working group.

RESULTS:

Only minor changes to the original consensus statement were required. For the initiation of anti-TNF treatment, there should be: a diagnosis of definitive ankylosing spondylitis (normally based on modified New York criteria); active disease for at least four weeks, as defined by a sustained Bath ankylosing spondylitis disease activity index (BASDAI) of > or =4 on a 0-10 scale and expert opinion based on clinical findings; refractory disease, defined by failure of at least two non-steroidal anti-inflammatory drugs during a three month period, failure of intra-articular steroids (if indicated), and failure of sulfasalazine in patients with predominantly peripheral arthritis; and application of the usual precautions and contraindications for biological treatment. For monitoring anti-TNF treatment: both the ASAS core set for clinical practice and the BASDAI should be followed after the initiation of treatment. Discontinuation of anti-TNF treatment in non-responders should be considered after 6-12 weeks. Response is defined by improvement of at least 50% or 2 units (on a 0-10 scale) of the BASDAI.

CONCLUSIONS:

This updated consensus statement is recommended in guiding clinical practice and as a basis for developing national guidelines. Evaluation and regular update of this consensus statement is subject to further research by the ASAS group.

Data from: http://www.ncbi.nlm.nih.gov/pubmed/16096329?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

==Adalimumab (Humira®)== BCBSF medical coverage guideline

Subject: Adalimumab (Humira®)

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.

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

DESCRIPTION:

Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Humira® was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgF1:k constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surfact TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients and play an in important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In plaque psoriasis, treatment with Humira® may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism by which adalimumab exerts its clinical effects is unknown.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte mitration.

POSITION STATEMENT:

REQUIRED: Certificate of Medical Necessity

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

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

  • Rheumatoid Arthritis
  • Juvenile Idiopathic Arthritis
  • Psoriatic Arthritis
  • Ankylosing Spondylitis
  • Crohn’s Disease
  • Plaque Psoriasis.

Table 1:

 

   
SPECIFIC CRITERIA FOR HUMIRA® (ADALIMUMAB) THERAPY
1. Rheumatoid Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for rheumatoid arthritis and dosage does not exceed 40 mg every other week if methotrexate is used concomitantly or dosage does not exceed 40 mg weekly if methotrexate is not being used OR
  • Patient is 18 years old or older AND
  • Patient has had an inadequate response to one or more DMARDs (disease modifying antirheumatic drugs). Adalimumab may be used alone OR in combination with methoxate or other DMARDs (Refer to Table 2 under OTHER) AND
  • If methotrexate is used concomitantly, dosage does not exceed 40 mg every other week OR
  • If methrotrexate is not used concomitantly, dosage does not exceed 40 mg weekly.
2. Juvenile Idiopathic Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for juvelile idiopathic arthritis and dosage does not exceed 20 mg every other week if patient weighs less than 30 kg or does not exceed 40 mg every other week if patient weighs more than 30 kg OR
  • Adalimimab is prescribed for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) AND
  • Patient is 4 years of age or older AND
  • Patient has had an inadequate response to one or more DMARDs AND
  • For patients weighing between 15 kg (33 lbs) to <30 kg (66 lbs, dosage does not exceed 20 mg every other week OR
  • For patients weighing >30 kg (66 lbs), dosage does not exceed 40 mg every other week.
3. Psoriatic Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for psoriatic arthritis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimab is prescribed to reduce the signs and symptoms of psoriatic arthritis as single therapy or in combination with a DMARD AND
  • Dosage does not exceed 40 mg every other week.
4. Ankylosing Spondylitis
  • Patient has a history of beneficial clinical response to adalimumab therapy for ankylosing spondylitis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for reducing signs and symptoms of ankylosing spondylitis in patients when conventional treatment options (e.g., nonsteroidal anti-inflammatory drugs, sulfasalazine, methotrexate) have failed or not indicated AND
  • Dosage does not exceed 40 mg every other week.
5. Crohn’s Disease
  • Patient has a history of beneficial clinical response to adalimumab therapy for Crohn’s disease and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for reducing signs and symptoms of moderately to severely active Crohn’s disease and inducing and maintaining clinical remission in adult patients AND
  • Patient has had an inadequate response to conventional therapy or have lost response to or are intolerant to infliximab AND
  • Initial dosing does not exceed 160 mg at week 0, and 80 mg at week 2 AND
  • Maintenance dose does not exceed 40 mg every other week.
6. Plaque Psoriasis
  • Patient has a history of beneficial clinical response to adalimumab therapy for plaque psoriasis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for adult patients with moderate to severe chronic 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
  4. Initial dose does not exceed 80 mg at week 0 AND
  5. Maintenance dose does not exceed 40 mg every other week starting at week 1.

NOTE: concomitant use of adalimumab and anakinra is NOTrecommended since serious infections have been seen in clinical studies with concurrent use of anakinra and another TNF-blocking agent with no added benefit.

NOTE: Safety and efficacy of adalimumab in pediatric patients for uses other than juvenile arthritis have not been established.

Adalimumab is considered experimental or investigationalfor all other indications since safety and effectiveness have not been established.

DOSAGE/ADMINISTRATION:

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

Rheumatoid Arthrtitis

The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection. Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics OR other DMARDsmay be continued during treatment with adalimumab. The dose of adalimumab can be increased to 40 mg per week if methotrexate is not used concomitantly.

Juvenile Idiopathic Arthritis

The recommended dose of adalimumab for patients weighing between 15 kg (33 lbs) to <30 kg (66 lbs) is 20 mg every other week and those weighing >30 kg (66 lbs) the dose is 40mg every other week.

Psoriatic Arthritis

The recommended dose of adalimumab for adult patients with psoriatic arthritis is 40 mg subcutaneously every other week alone or in combination with other disease-modifying anti-rheumaticdrugs.

Ankylosing Spondylitis

The recommended dose of adalimumab for adult patients with ankylosing spondylitis is 40 mg subcutaneously every other week alone or in combination with NSAIDS, glucocorticoids, methotrexate or other DMARDs.

Crohn’s Disease

The recommended dose of adalimumab for adult patients with Crohn’s disease is 160 mg initially at week 0, 80 mg at week 2, followed by a maintenance dose of 40 mg every other week beginning at week 4. Initial dose may be given as 4 injections on 1 day, or divided over 2 days.

Plaque Psoriasis

The recommended dose of adalimumab for adult patients with plaque psoriasis is 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

PRECAUTIONS:

 

WARNINGS:
SERIOUS INFECTIONS

Patients treated with adalimumab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued 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. Patients should be tested for latent TB before adalimumab use and during therapy. Treatment for latent infection should be initiated prior to adalimumab use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral and other infections due to opportunistic pathogens.

The risks and benefits of treatment with adalimumab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, 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 TNF blockers, of which adalimumab is a member.

Hepatitis B virus reactivation: Use of TNF blockers, including adalimumab, may increase the risk of reactivation of 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 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 infections throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop adalimumab and initiate effective 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 adalimumab therapy in this situation and monitor patients closely.

Neurologic effects: Use of TNF-blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset CNS demyelinating disorders.

Hematologic effects: Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, thrombocytopenia), have been reported infrequently with adalimumab. The causal relationship of these reports to adalimumab remains unclear. Advise patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., bleeding, bruising, pallor, persistent fever) while on adalimumab. Consider discontinuation of adalimumab therapy in patients with confirmed significant hematologic abnormalities.

Congestive heart failure: Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. Adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using adalimumab in patients who have heart failure and monitor them carefully.

Autoimmunity: Treatment with adalimumab 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 adalimumab, discontinue treatment.

Immunizations: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were coadministered with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown.

Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating adalimumab therapy.

Immunosuppression: The possibility exists for TNF-blocking agents, including adalimumab, to affect host defenses against infections and malignancies because TNF mediates inflammation and modulates cellular immune responses.

In a study of 64 patients with RA treated with adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T and B cells and NK cells, monocyte/macrophages, and neutrophils. The impact of treatment with adalimumab on the development and course of malignancies as well as active and/or chronic infections is not fully understood. The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated.

Immunogenicity: Patients in studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58/1,062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% vs. 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every-other-week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the American College of Rheumatology (ACR) 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.

In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of adalimumab-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared with 26% receiving adalimumab monotherapy.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable with patients with RA. In patients with psoriatic arthritis, the rate of antibody development in patients receiving adalimumab monotherapy was comparable with patients with RA; however, in patients receiving concomitant methotrexate, the rate was 7% compared with 1% in RA. In patients with Crohn disease, the rate of antibody development was 2.6%. The immunogenicity rate was 8% for plaque psoriasis patients who were treated with adalimumab monotherapy.

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

Latex allergy: The needle cover of the prefilled syringe contains dry rubber (latex), which should not be handled by people sensitive to this substance.

Hypersensitivity reactions: In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, discontinue administration of adalimumab immediately and institute appropriate therapy. In adults in clinical trials of adalimumab, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, nonspecified drug reaction, urticaria) have been observed in approximately 1% of patients.

Carcinogenesis: Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential.

Mutagenesis: No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.

Fertility impairment: Long-term animal studies of adalimumab have not been conducted to evaluate its effect on fertility.

Children: Safety and effectiveness of adalimumab in children for uses other than juvenile idiopathic arthritis have not been established.

In the juvenile idiopathic arthritis study, adalimumab was shown to reduce signs and symptoms of active polyarticular juvenile idiopathic arthritis in patients 4 to 17 years of age.

Adalimumab has not been studied in children younger than 4 years of age, and there are limited data on adalimumab treatment in children weighing less than 15 kg.

Safety of adalimumab in children was generally similar to that observed in adults, with certain exceptions.

Elderly: A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through RA-IV. No overall difference in effectiveness was observed between these subjects and younger subjects.

The frequency of serious infection and malignancy among adalimumab-treated subjects older than 65 years of age was higher than for those younger than 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, use caution when treating elderly patients.

Monitoring: Closely monitor patients who develop a new infection while undergoing treatment with adalimumab. Monitor patients for signs and symptoms of active TB, including patients who had a negative tuberculin skin test. Monitor heart failure patients carefully. Closely monitor patients who are carriers of HBV and require treatment with TNF blockers for clinical and laboratory signs of active HBV infections throughout therapy and for several months following termination of therapy.

BILLING/CODING INFORMATION:

CPT Coding:

 

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

HCPCS Coding:

 

J0135 Adalimumab (Humira®) Injection 20 mg

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

555.0 – 555.9 Crohn’s disease
696.0 Psoriatic arthropathy
696.1 Other psoriasis
714.0 – 714.2 Rheumatoid arthritis
714.30 – 714.33 Juvenile chronic polyarthritis
714.4 Chronic postrheumatic arthropathy
714.81 Other specified inflammatory polyarhtropathies
714.89 Other
714.9 Unspecified inflammatory polyarthropathy
720.0 Ankylosing spondylitis

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

 

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
L40.54 Psoriatic juvenile arthropathy
L40.59 Other psoriatic arthropathy
L40.8 Other psoriasis
M05.00 Felty’s syndrome, unspecified site
M05.10 Rheumatoid lung disease with rheumatoid arthritis of unspecified site
M05.30 Rheumatoid heart disease with rheumatoid arthritis of unspecified site
M05.60 Rheumatoid arthritis of unspecified site with involvement of other organs and systems
M06.1 Adult-onset Still’s disease
M06.4 Inflammatory polyarthropathy
M06.9 Rheumatoid arthritis, unspecified
M08.00 Unspecified juvenile rheumatoid arthritis of unspecified site
M08.3 Juvenile rheumatoid polyarthritis (seronegative
M08.40 Pauciarticular juvenile rheumatoid arthritis, unspecified site
M12.00 Chronic postrheumatic arthropathy [Jaccoud], unspecified site
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: Immobility and consolidation of a vertebral joint caused by inflammation.

Antirheumatic: An agent that relieves or prevents musculoskeletal pain.

Crohn’s diseasse: A chronic granulomatous inflammatory disease of unknown etiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall.

DMARDs: An acronym for disease-modifying antirheumatic drugs.

Psoriatic arthritis: a severe form of arthritis accompanied by inflammation, psoriasis of the skin or nails, and a negative test for rheumatoid factor.

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

Rheumatoid arthritis: An inflammatory disease of the synovium, or lining of the joint, that results in pain, stiffness, and swelling of multiple joints. The inflammation may extend to other joints and cause bone and cartilage erosion, joint deformities, movement problems, and activity limitations.

RELATED GUIDELINES:

Etanercept (Enbrel®), 09-J0000-38
Infliximab (Remicade®), 09-J0000-39

Anakinra (Kineret®), 09-J0000-45

Rituximab (Rituxan®), 09-J0000-59

Abatacept (Orencia®), 09-J0000-67

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

Alefacept (Amevive®), 09-J0000-78

Rilonacept (Arcalyst™), 09-J0000-89

Golimumab (Simponi™), 09-J1000-11

Canakinumab (Ilaris®) Injection, 09-J1000-14

Ustekinumab (Stelara™), 09-J1000-16

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

OTHER:

Table 2: DMARDs

 

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

REFERENCES:

  1. Abbott Laboratories. Letter, “IMPORTANT DRUG WARNING” dated 11/05/04.
  2. Abbott Laboratories. Press Release. Abbott Seeks U.S. and E.U. Regulatory Approval for Humira® (adalimumab) in Psoriasis. 04/02/07.
  3. American Journal of Respiratory and Critical Care Medicine (2003; 167:603-62).
  4. American Medical Association CPT Coding, 2009 professional edition.
  5. 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.
  6. Clinical Pharmacology, copyright® 2009.
  7. Cush JJ, Biologic Treatments for Rheumatoid Arthritis. American College of Rheumatology 2006.
  8. DRUGDEX®, accessed 06/24/10.
  9. eHealth MD: Autoimmune Disorders, 2005.
  10. Facts & Comparisons, 4.0, accessed 06/24/10.
  11. Food and Drug Administration (FDA). Orphan designations and approvals list. 2005.
  12. Gordon KB et. al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis. J Am Acad Dermatol 10.1016/j, haad. 05/27/06.
  13. 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.
  14. HAYES, Inc. New Drug for Crohn’s Disease Approved. Lansdale, PA: HAYES, Inc. 03/06/07.
  15. HIPAA Space, HCPCS Codes Lookup, Copyright® 2004 – 2010. Accessed 06/29/10.
  16. Humira® Prescribing Information, November 2009.
  17. ICD-9 Data.com. Accessed 06/29/10.
  18. Mease PJ, Gladman DD, Ritchlin CT et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005 Oct; 52(10): 3279-89.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 07/14/10.

GUIDELINE UPDATE INFORMATION:

 

01/01/05 New Medical Coverage Guideline.
08/15/05 Revised and Updated: Updated description, dosage/administration. Deleted precautions, updated when services are not covered, billing/coding information, and definitions, table 1, references.
11/15/05 Updated when services are covered for psoriatic arthritis, updated ICD-9 codes, definitions, and references.
11/15/06 Scheduled review: added indication of ankylosing spondylitis, added ICD-9 code, corrected CPT-4 coding and updated references.
01/01/07 MCG revised to include Medicare Part D as program exception.
04/15/07 Revision; consisting of adding Crohn’s disease indication and ICD-9 code, related guidelines and definitions.
06/15/07 Review and revision; consisting of reformatting, updating related guidelines and references.
03/15/08 Revision; consisting of adding plaque psoriasis and juvenile idiopathic arthritis (JIA) as covered indications, rewording coverage criteria for Crohn’s disease, updated dosage and administration section, added ICD-9 codes and updated references.
05/15/08 Review and revision; consisting of reformatting, adding a black box warning under “PRECAUTIONS”, adding related guideline and updating references.
09/15/08 Revision of guideline; consisting of adding 3 ICD-9 codes.
01/01/09 Annual HCPCS coding update: deleted code 90772; added code 96372.
09/15/09 Review and revision; consisting of updating references, boxed warning and ICD-9 coding.
04/15/10 Revision; consisting of adding specific continuation criteria.
08/15/10 Review and revision; consisting of adding age criteria to all indications, updated precautions and references.
01/15/11 Revision; consisting of adding ICD-10 codes.
04/01/11 Revision; consisting of adding dosage limitations.

 

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

==Golimumab (Simponi™)== BCBSF medical coverage guideline

Subject: Golimumab (Simponi™)

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.

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

DESCRIPTION:

Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells.

Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF).

POSITION STATEMENT:

Golimumab meets the definition of medical necessitywhen administered for the following conditions:

  1. Rheumatoid arthritis when the following criteria are met:
  • Patient has a history of beneficial clinical response to golimumab therapy for rheumatoid arthritis and the dose does not exceed 50 mg per month OR
  • Patient is 18 years old or older AND
  • Patient has moderately to severely active rheumatoid arthritis AND
  • Patient is also taking methotrexate AND
  • Patient must has had an inadequate response to one or more DMARDs, AND
  • Dose does not exceed 50 mg per month.
  1. Active psoriatic arthritis when the following criteria are met:
  • Patient has a history of beneficial clinical response to golimumab therapy for active psoriatic arthritis the dose does not exceed 50 mg per month OR
  • Patient is 18 years old or older AND
  • Patient must has had an inadequate response to one or more DMARDs, AND
  • Dose does not exceed 50 mg per month.
  1. Active ankylosing spondylitis when the following criteria are met:
  • Patient has a history of beneficial clinical response to golimumab therapy for active ankylosing spondylitis the dose does not exceed 50 mg per month OR
  • Patient is 18 years old or older AND
  • Patient must has had an inadequate response to one or more DMARDs, AND
  • Dose does not exceed 50 mg per month.

NOTE: Patient with psoriatic arthritis (PsA) or ankylosing spondylitis (AS), golimumab may be given with or without methotrexate or other non-biologic DMARDs. Corticosteroids, non-biologic DMARDs and/or NSAIDsmay be continued during treatment with golimumab for RA, PsA or AS.

DOSAGE/ADMINISTRATION:

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

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are all dosed at 50 mg subcutaneously once a month.

PRECAUTIONS:

 

WARNINGS
SERIOUS INFECTIONS

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

Golimumab should be discontinued if a patient develops a serious infection.

Reported infections include:

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

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

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

MALIGNANCY

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which golimumab is a member.

Serious infections: Serious and sometimes fatal infections caused by bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers, including golimumab. Among opportunistic infections, TB, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated, rather than localized, disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of golimumab and these biologic products is not recommended.

Do not initiate treatment with golimumab in patients with an active infection, including clinically important localized infections. Consider the risks and benefits of treatment prior to initiating golimumab in patients with chronic or recurrent infection; patients who have been exposed to TB; patients with a history of an opportunistic infection; patients who have resided or traveled in areas of endemic TB or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or patients with underlying conditions that may predispose them to infection. See Monitoring for more information.

Tuberculosis: Cases of reactivation of TB or new TB infections have been observed in patients receiving TNF-blockers, 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 golimumab and periodically during therapy.

Treatment of latent TB infection prior to therapy with TNF-blockers has been shown to reduce the risk of TB reactivation during therapy. Consider induration of 5 mm or more with tuberculin skin testing a positive test result when assessing if treatment for latent TB is needed prior to initiating golimumab, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).

Also consider anti-TB therapy prior to initiation of golimumab 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.

Closely monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

TB should be strongly considered in patients who develop a new infection during golimumab 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.

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

Hepatitis B virus reactivation: The use of TNF-blockers, including golimumab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (ie, surface-antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF-blocker therapy. Consider the risks and benefits of treatment prior to prescribing TNF-blockers, including golimumab, to patients who are carriers of HBV. Adequate data are not available on whether antiviral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. 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 antiviral therapy and initiate appropriate supportive treatment. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, exercise caution when considering resumption of TNF-blockers in this situation, and monitor patients closely.

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 and younger), of which golimumab is a member. Approximately half the cases were lymphomas, including Hodgkin and non-Hodgkin lymphoma. 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 are derived from a variety of sources, including registries and spontaneous postmarketing reports.

Consider the risks and benefits of TNF-blocker treatment, including golimumab, prior to initiating therapy in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer or when considering continuing a TNF-blocker in patients who develop a malignancy.

In the controlled portions of clinical trials of TNF-blockers, including golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the phase 2 trials in RA and the phase 3 trials in RA, psoriatic arthritis, and ankylosing spondylitis, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI, 0.03 to 0.77) in the combined golimumab group compared with an incidence of 0 (95% CI, 0 to 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2,347 golimumab-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general US population according to the Surveillance, Epidemiology and End Results (SEER) database (adjusted for age, gender, and race). Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at 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 a higher risk (approximately 2-fold) than the general population for the development of leukemia.

During the controlled portions of the phase 2 trial in RA and the phase 3 trials in RA, psoriatic arthritis, and ankylosing spondylitis, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined golimumab group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in golimumab-treated patients was similar to that expected in the general United States population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with chronic obstructive pulmonary disease, patients with Wegener granulomatosis treated with concomitant cyclophosphamide), a greater portion of malignancies occurred in the TNF-blocker group compared with the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100, and 200 mg of golimumab in 309 patients with severe persistent asthma, 6 patients developed malignancies other than nonmelanoma skin cancer in the golimumab groups compared with none in the control group. Three of the 6 patients were in the golimumab 200 mg group.

Congestive heart failure: Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF-blockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker–treated patients who had CHF exacerbations requiring hospitalization or increased mortality. Golimumab has not been studied in patients with a history of CHF; use with caution in patients with CHF. If a decision is made to administer golimumab to patients with CHF, closely monitor these patients during therapy, and discontinue golimumab if new or worsening symptoms of CHF appear.

Demyelinating disorders: Use of TNF-blockers has been associated with cases of new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating golimumab in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, exercise caution in considering the use of TNF-blockers, including golimumab, in patients with CNS demyelinating disorders, including MS.

Immunogenicity: Antibodies to golimumab were detected in 4% of golimumab-treated patients across the phase 3 RA, psoriatic arthritis, and ankylosing spondylitis trials through week 24. Similar rates were observed in each of the 3 indications. Patients who received golimumab with concomitant methotrexate had a lower proportion of antibodies to golimumab than patients who received golimumab without methotrexate (approximately 2% vs. 7%, respectively). Of the patients with a positive antibody response to golimumab in the phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to golimumab limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures.

The previous data reflect the percentage of patients whose test results were considered positive for antibodies to golimumab in an enzyme-linked immunosorbent assay (ELISA) 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 medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to golimumab with the incidence of antibodies to other products may be misleading.

Hematologic effects: There have been postmarketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although there were no cases of severe cytopenias seen in the golimumab clinical trials, exercise caution when using TNF-blockers, including golimumab, in patients who have significant cytopenias.

Vaccinations: Patients treated with golimumab may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination, the risk of infection, or the transmission of infection after the administration of live vaccines to patients receiving golimumab. In the phase 3 psoriatic arthritis study, after pneumococcal vaccination, a similar proportion of golimumab- and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both golimumab- and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving methotrexate compared with patients not receiving methotrexate. The data suggest that golimumab does not suppress the humoral immune response to the pneumococcal vaccine.

Children: Safety and effectiveness of golimumab in children younger than 18 years of age have not been established.

Monitoring: Closely monitor patients for the development of signs and symptoms of infection during and after treatment with golimumab. Discontinue golimumab if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with golimumab should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Closely monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Closely monitor patients with CHF and discontinue treatment if new or worsening symptoms of CHF appear.

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.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

CPT Coding:

 

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

HCPCS Coding:

 

J3590 Unclassified biologicals

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

696.0 Psoriatic arthropathy
714 – 714.2 Rheumatoid arthritis
720.0 Ankylosing spondylitis

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

 

L40.59 Other psoriatic arthropathy
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
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.

DEFINITIONS:

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

DMARDs: an acronym for disease-modifying antirheumatic drugs.

NSAIDs: non steroidal anti-inflammatory drugs.

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

Rheumatoid Arthritis: an inflammatory disease of the synovium, or lining of the joint, that results in pain, stiffness, swelling, deformity, and loss of function in the joints.

RELATED GUIDELINES:

Abatacept (Orencia®), 09-J0000-67
Adalimumab (Humira®), 09-J0000-46

Anakinra (Kineret®), 09-J0000-45

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

Etanercept (Enbrel®), 09-J0000-38
Infliximab (Remicade®), 09-J0000-39

Rituximab (Rituxan®), 09-J0000-59

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

OTHER:

Table 1: DMARDs

 

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

REFERENCES:

  1. American Medical Association CPT Coding, 2009 professional edition.
  2. DRUGDEX®. Accessed 07/20/10.
  3. Facts & Comparisons® E Answers. Accessed 07/20/10.
  4. HIPAA Space, HCPCS Codes Lookup, Copyright® 2004 – 2010. Accessed 07/20/10.
  5. ICD-9 Data.com. Accessed 07/20/10.
  6. Oldfield V, Plosker GL. Golimumab: in the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. BioDrugs. 2009; 23(2): 125-35.
  7. Saag KG, Teng GG, et. al. American College of Rheumatology 2008 Recommendation for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis & Rheumatism, Vol. 59, No. 6, June 15, 2008, pp 762 – 784.
  8. Simponi® Prescribing Information. Revised 11/09.

COMMITTEE APPROVAL:

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

GUIDELINE UPDATE INFORMATION:

 

08/15/09 New Medical Coverage Guideline.
04/15/10 Revision; consisting of adding specific continuation criteria.
09/15/10 Review and revision; consisting of Updating boxed warning, precautions section and references.
01/15/11 Revision; consisting of adding ICD-10 codes.
04/01/11 Revision; consisting of adding dosage limits.

 

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

==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

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

Subject: Etanercept (Enbrel®)

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

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

DESCRIPTION:

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

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

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

POSITION STATEMENT:

REQUIRED: Certificate of Medical Necessity

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

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

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

Table 1:

SPECIFIC CRITERIA FOR ETANERCEPT (ENBREL®) THERAPY

 

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

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

DOSAGE/ADMINISTRATION:

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

Moderate to Severe Rheumatoid Arthritis:

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

Juvenile rheumatoid arthritis (JRA):

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

Active Ankylosing Spondylitis:

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

Psoriatic Arthritis:

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

Chronic Moderate to Severe Plaque Psoriasis:

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

PRECAUTIONS:

 

WARNING
RISK OF SERIOUS INFECTIONS

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

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

Reported infections include:

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

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

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

MALIGNANCIES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BILLING/CODING INFORMATION:

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

CPT Coding:

 

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

HCPCS Coding:

 

J1438 injection, etanercept, 25 mg

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

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

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

 

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

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

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

DEFINITIONS:

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

DMARDs: An acronym for disease-modifying antirheumatic drugs.

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

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

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

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

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

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

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

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

RELATED GUIDELINES:

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

Adalimumab (Humira®), 09-J0000-46

Rituximab (Rituxan®), 09-J0000-59

Abatacept (Orencia®), 09-J0000-67

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

Golimumab (Simponi™), 09-J1000-11

Alefacept (Amevive®) IV, 09-J0000-78

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

OTHER:

Table 2: DMARDs

 

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

REFERENCES:

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

COMMITTEE APPROVAL:

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

GUIDELINE UPDATE INFORMATION:

 

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

 

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