Model Biologics Indications

AMERICAN COLLEGE OF RHEUMATOLOGY
Position Statement
SUBJECT:
Model Biologics Indications
PRESENTED BY:
Committee on Rheumatologic Care
FOR DISTRIBUTION TO:
Members of the American College of Rheumatology

Medical Societies
Members of Congress
Health Care Organizations/Third Party Carriers
Managed Care Entities
This policy addresses the indications for the class of drugs known as biologics. These biologics include
disease modifying anti-rheumatic drugs (DMARDs) used to treat many types of rheumatic conditions.
Each of these molecules has been approved by the FDA for specific rheumatic diseases based on the
available peer-reviewed evidence . In addition, off label use of biologics for certain rheumatic
diseases are widely accepted and are included in this statement. ACR promotes early, equal
access to the following biologic therapies:
Adalimumab (Humira), certolizumab pegol (Cimzia ), etanercept (Enbrel), golimumab (Simponi ),
and infliximab (Remicade) inhibit the cytokine Tumor Necrosis Factor (TNF)-.
Anakinra (Kineret), rilonacept (Arcalyst) and canakinumab (Ilaris) work as antagonists to the
cytokine IL-1.
Abatacept (Orencia) inhibits T-cell co-stimulation.
Rituximab (Rituxan) is a B-cell depleting therapy, whereas belimumab (Benlysta) is a B-lymphocyte
stimulator (BLyS)-specific inhibitor.
Tocilizumab (Actemra) is an interleukin-6 receptor inhibitor.
Denosumab (Prolia) is a RANK ligand inhibitor.
Pegloticase (KrystexxaTM) is a modified urate oxidase enzyme specific toward uric acid.
AMA CPT Copyright Statement

CPT codes, descriptions and other data only are copyright 2010 American Medical Association
(or such other date of publication of CPT). All Rights Reserved.
Region Applicable:
All Regions as applicable
Indications and Limitations of Coverage and/or Medical Necessity
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A. Coverage for medication is based on the patients condition, the appropriateness of the dose and
route of administration, based on the clinical condition and the standard of medical practice
regarding the effectiveness of the drug for the diagnosis and condition.
B. The following established ICD-9, CPT and drugs will be allowed for therapy and service when
criteria are met as indicated: The following codes for treatments and procedures applicable to
this policy are included below for informational purposes. Inclusion or exclusion of a
procedure, diagnosis or device code(s) does not constitute or imply member coverage or
provider reimbursement policy. Please refer to the members contract benefits in effect at the
time of service to determine coverage or non-coverage of these services as it applies to an
individual member.
When services may be Medically Necessary when criteria are met:
HCPCS
J0129
J0135
J0718
J1438
J1745
J9310
J3262
J0638
J2793
J0490
J0897
J2507
J3590*no
specific
code
abatacept, 10 mg (Orencia)
adalimumab, 20 mg (Humira)
certolizumab pegol, 1 mg (Cimzia)
etanercept, 25 mg, administered under the direct supervision of a physician (not for use
when drug is self-administered) (Enbrel)
infliximab, 10 mg (Remicade)
rituximab, 100 mg(Rituxan)
tocilizumab (Actemra)
canakinumab (Ilaris)
rilonacept (Arcalyst)
belimumab (Benlysta)
denosumab (Prolia)
pegloticase (Krystexxa)
anakinra (Kineret)
CPT Codes
96372
96374
96401
96413
+96415
Therapeutic, prophylactic, or diagnostic injection (specify substance or drug);

subcutaneous or intramuscular (Humira, Enbrel, Cimzia, Simponi, Orencia SQ)
Therapeutic, prophylactic, or diagnostic; intravenous push (Boniva)
Chemotherapy, antineoplastic; subcutaneous or intramuscular (Prolia)
Chemotherapy administration, intravenous infusion technique; up to 1
hour, single or initial substance/drug
- each additional hour (list separately in addition to code for primary
procedure)
ICD-9 Diagnosis
099.3
135
136.1
274.00
274.01
Reactive Arthritis
Sarcoidosis
Behcets syndrome
Gouty arthropathy, unspecified
Acute gouty arthropathy
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274.02
Chronic gouty arthropathy without mention of tophus (tophi)
274.03
Chronic gouty arthrocopy with tophus (tophi)
277.31
Familial Mediterranean Fever (Periodic Fever (CAPS, Muckle-Wells syndrome, FCAS)
359.79
Inflammatory myopathy NOS
361.19
Pseudocyst retina
364.3
Uveitis NOS
370.52
Cogans syndrome
379.00
Scleritis and episcleritis
379.05
Scleritis with corneal involvement
446.4
Granulomatosis with polyangiitis (GPA)
446.5
Temporal arteritis
555.9
Crohns disease NOS
556.9
Ulcerative colitis, unspecified
696.0
Psoriatic arthropathy
696.1
Psoriasis NOS
705.83
Hidradenitis suppurativa
710.0
Systemic Lupus Erythematosus
710.1
Scleroderma
710.2
Sjogrens syndrome
710.3
Dermatomyositis
710.4
Polymyositis
714.0-714.2
Rheumatoid arthritis
714.30 or 714.89uvenile idiopathic arthritis
714.31
Polyarticular juvenile rheumatoid arthritis acute
714.9
Unspecified inflammatory polyarthritis
716.59
Unlisted polyarthropathy or polyarthritis
720.0-720.9
Ankylosing spondylitis
725
Polymyalgia rheumatica
733.01
Senial Osteoporosis (post-menopausal osteoporosis)
733.09
Steroid-induced Osteoporosis
When services are Investigational/Not Medically Necessary:
For the procedure codes listed above, when criteria are not met and for all other diagnosis not listed
above; or when the code describes a procedure indicated in the Policy section as Investigational/Not
Medically Necessary.
Policy Statement
I.
Abatacept (Orencia)
A.
Abatacept is medically necessary and has an FDA-approved indication for the treatment
of:
1.
Adult Rheumatoid Arthritis: reducing signs and symptoms, inducing major

clinical response, inhibiting progression of structural damage, and improving
physical function in adult patients with moderately to severely active RA.
Abatacept may be used as monotherapy or concomitantly with DMARDs other
than TNF antagonists.
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2.
B.
C.
D.
Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms in pediatric

patients 6 years of age and older with moderately to severely active polyarticular
JIA. Abatacept may be used as monotherapy or concomitantly with methotrexate.
Special considerations for abatacept:

1.
Patients should be tested for latent tuberculosis before and during therapy.
Treatment for latent tuberculosis infection should be initiated prior to therapy.
2.
Concomitant use with TNF antagonists increases the risk of infection.
3.
Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,

Human Papilloma and Herpes Zoster vaccines are recommended.
4.
During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and Human

Papilloma are recommended vaccines. Live attenuated vaccines such as Herpes
Zoster vaccines are not recommended during therapy.
Off-label use of abatacept may include but is not limited to:

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.

Sjogrens Syndrome
Vasculitides
Psoriatic Arthritis
Ankylosing Spondylitis
JIA all ages and all subtypes
Autoinflammatory Diseases
Undifferentiated Polyarthritis
Undifferentiated Spondyloarthritis
Reactive Arthritis
Ankylosing Spondylitis
12.
12. Uveitis
Dosage and administration (IV administration):

1.
2.
3.
4.
5.
6.
Abatacept is administered as an intravenous infusion. Following the initial

administration, Orencia should be given at 2 and 4 weeks after the first
infusion, then every 4 weeks thereafter.
A dose of 500 mg per infusion is recommended for adults with a body weight of
<60 kg.
60 to 100 kg.
>100 kg.
For children > 6 years old and < 75 kg, recommended dose is 10 mg/kg per
infusion.
For children > 6 years old and > 75 kg, dosage is according to body weight as
follows:
75-100 kg: dose is 750 mg
>100 kg: dose is 1,000 mg
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E.
II.
Dosage and administration (SQ administration):

1.
Abatacept may be administered by subcutaneous injection instead of infusion.
2.
The recommended dose is 125mg by subcutaneous injection weekly.
Adalimumab (Humira)
A.
B.
Adalimumab is medically necessary and has an FDA-approved indication for the

treatment of:
1.
Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing major

clinical response, inhibiting the progression of structural damage, and improving
physical function in adult patients with moderately to severely active disease.
2.
Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately

to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of
age and older.
3.
Psoriatic Arthritis (PsA): reducing signs and symptoms of active arthritis,

inhibiting the progression of structural damage, and improving physical function.
4.
Ankylosing Spondylitis (AS): reducing signs and symptoms in patients with

active disease.
5.
Crohns Disease: reducing signs and symptoms and inducing and maintaining
clinical remission in adult patients with moderately to severely active Crohns
disease who have had inadequate response to conventional therapy. Reducing
signs and symptoms and inducing clinical remission in these patients if they have
also lost response to or are intolerant to infliximab.
6.
Plaque Psoriasis: the treatment of adult patients with moderate to severe chronic
plaque psoriasis who are candidates for systemic therapy or phototherapy, and
when other systemic therapies are less appropriate.
Special considerations with adalimumab:

1.
2.
Monitor HBV carriers during and several months after therapy. If reactivation
occurs then stop drug and begin anti-viral therapy.
3.
Concomitant use of anti-TNF- therapy with anakinra and abatacept increases

the risk of infection.
5|Page
C.
4.

5.

6.
Treatment not recommended in patients with NYHA class III/IV with ejection
fraction 50% or less.
Off-label use of adalimumab may include but is not limited to the following conditions:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
D.
Dosage and administration:

1.
2.
3.
4.
5.
6.
III.
Undifferentiated Spondyloarthropathy
Sarcoidosis
Myositis
Behets Disease
Uveitis
Adult-Onset Stills Disease
Reactive Arthritis
Adalimumab is administered by subcutaneous injection.

In RA, PsA, and AS the recommended dose is 40 mg every other week.
In RA, some patients not taking concomitant methotrexate may derive additional
benefit from increasing the dosing frequency of adalimumab to 40 mg every
week.
In Crohns Disease, the recommended initial dosage is 160 mg, then 80 mg 2
weeks later, and then 40 mg every other week.
In Plaque Psoriasis, the recommended initial dosage in 80 mg, then 40 mg every
other week.
For children with JIA who weigh 15 kg to <30 kg, recommended dose is 20 mg
every other week. For children who weigh > 30 mg, recommended dose is 40 mg
every other week.
Anakinra (Kineret)
A.
Anakinra is medically necessary and has an FDA-approved indication for the treatment
of:
1.
B.
Rheumatoid Arthritis (RA): reducing signs and symptoms and slowing the
progression of structural damage in moderately to severely active RA, in patients
18 years of age or older who have failed one or more disease modifying
antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination
with DMARDs other than TNF blocking agents.
Special considerations with anakinra:
6|Page
1.
C.
Off-label use of anakinra may include but is not limited to:

1.
2.
3.
4.
5.
D.
2.
Belimumab is medically-necessary and has an FDA-approved indication for the

treatment of:
1.
B.
D.
Systemic Lupus Erythematosus (SLE): adult patients with active, autoantibodypositive, SLE who are receiving standard therapy.
Special Considerations for belimumab:

1.
Live vaccines should not be given concurrently with belimumab

1.
2.
3.
Belimumab is an intravenous infusion delivered over 1 hour.

Belimumab must be reconstituted and diluted prior to administration.
For SLE the dosing is 10mg/kg at 2-week intervals for the first 3 doses and at 4week intervals thereafter.
Canakinumab (Ilaris)
A.
B.
Canakinumab is medically necessary and has an FDA-approved indication for the

treatment of Cryopryin-Associated Periodic Syndromes (CAPS), in adults and children 4
years of age and older including:
1.
Familial Cold Autoinflammatory Syndrome
2.
Muckle-Wells Syndrome
Special considerations with canakinumab:

1.
C.
In RA the recommended dose of anakinra is 100 mg/day administered by

subcutaneous injection.
In RA patients who have severe renal insufficiency (creatinine clearance < 30
ml/min) a dose of 100 mg every other day should be considered.
Belimumab (Benlysta)
A.
V.

Periodic Febrile Syndromes
Gout
Juvenile Idiopathic Arthritis

1.
IV.
Concomitant use with TNF antagonists increases the risk of infection.
Live vaccines should not be given concurrently with canakinumab.
Off-label use of canakinumab may include but is not limited to:
7|Page
1. Systemic Juvenile Idiopathic Arthritis

D.

2.
3.
4.
5.
VI.
Canakinumab is administered by subcutaneous injection every 8 weeks.

For CAPS patients with body weight greater than 40 kg, the recommended dose
is 150 mg.
For CAPS patients with body weight between 15 kg and 40 kg, the recommended
dose is 2 mg/kg.
For children 15 to 40 kg with an inadequate response, the dose can be increased
to 3 mg/kg.
Certolizumab pegol (Cimzia )

A.
B.
C.
Certolizumab pegol is medically necessary and has an FDA-approved indication for the
treatment of:
1.
Rheumatoid Arthritis (RA): moderately to severely active RA.
2.
Crohns Disease: reducing signs and symptoms of Crohns disease and

maintaining clinical response in adult patients with moderately to severely active
disease who have had an inadequate response to conventional therapies.
Special considerations with certolizumab pegol:

1.
2.
3.

4.

5.

6.
Off-label use of certolizumab pegol may include but is not limited to the following
conditions:
1.
2.
3.
4.
Sarcoidosis
Myositis
8|Page
5.
6.
7.
8.
9.
10.
D.

1.
2.
3.
4.
VII.
Certolizumab pegol is administered by subcutaneous injection.

In RA the recommended dose is 400 mg initially and at weeks 2 and 4, followed
by 200 mg every other week.
In RA, for maintenance dosing, 400 mg every 4 weeks can be considered.
In Crohns Disease, the recommended initial dosage is 400 mg, then repeated in
2 weeks. Maintenance dosage is 400 mg every 4 weeks.
Denosumab (Prolia)
A.
Denosumab is medically necessary and has an FDA-approved indication for the

treatment of:
1.
B.
C.
Hypocalcemia must be corrected prior to initiating denosumab. Adequately

supplement patients with calcium and vitamin D
Off-label use of denosumab may include but is not limited to:

1.
2.
D.
Osteoporosis (OP): postmenopausal women with OP at high risk of fracture.
Special considerations for denosumab:

1.
Men with OP
Women and men with low bone mass and at high risk of fracture

1.
VIII.
Behets Disease
Uveitis
Reactive Arthritis
JIA
Denosumab is given as a 60mg single subcutaneous injection once every 6

months.
Etanercept (Enbrel)
A.
Etanercept is medically necessary and has an FDA-approved indication for the

treatment of:
1.
Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing major

clinical response, inhibiting the progression of structural damage, and improving
physical function in patients with moderately to severely active RA. Enbrel can
be initiated in combination with methotrexate or used alone.
2.
Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately

to severely active polyarticular JIA in patients ages 2 and older.
9|Page
B.
C.
3.
Psoriatic Arthritis (PsA): reducing signs and symptoms, inhibiting the

progression of structural damage of active arthritis, and improving physical
function. Enbrel can be used in combination with methotrexate in patients who
do not respond adequately to methotrexate alone.
4.
Ankylosing Spondylitis (AS): reducing signs and symptoms in patients with

active AS.
5.
Plaque Psoriasis: treating adult patients with chronic moderate to severe plaque
psoriasis who are candidates for systemic therapy or phototherapy.
Special considerations with etanercept:

1.
2.
3.

4.

5.

6.
Off-label use of etanercept may include but is not limited to:

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
D.
Sarcoidosis
Myositis
Behet Disease
Uveitis
Reactive Arthritis

1.
2.
Etanercept is administered by subcutaneous injection.

In RA, AS, and PSA the recommended dose is 50 mg per week.
50 mg once weekly or 25 mg twice weekly.
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3.
4.
IX.
In JIA the recommended dose for pediatric patients ages 2 to 17 years is

0.8mg/kg per week (up to a maximum of 50 mg per week).
In Plaque Psoriasis, the recommended dosage is 50 mg twice a week for 3
months, and the 50 mg once week maintenance.
Golimumab (Simponi )
A.
B.
C.
Golimumab is medically necessary and has an FDA-approved indication for the

treatment of:
1.
Rheumatoid Arthritis (RA): moderately to severely active RA in adults, in

combination with methotrexate.
2.
Psoriatic Arthritis (PsA): active PsA in adults alone in or combination with

methotrexate.
3.
Ankylosing Spondylitis (AS): active AS in adults.
Special considerations with golimumab:

1.
2.
3.

4.

5.

6.
Off-label use of golimumab may include but is not limited to the following conditions:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Sarcoidosis
Myositis
Behets Disease
Uveitis
Reactive Arthritis
11 | P a g e
D.

1.
2.
X.
Golimumab is administered by subcutaneous injection.

In RA, PsA, and AS the dose is 50 mg every month.
Infliximab (Remicade)
A.
B.
Infliximab is medically necessary and has an FDA-approved indication for the treatment
of:
1.
Rheumatoid Arthritis (RA): in combination with methotrexate to reduce signs

and symptoms, inhibit progression of structural damage, and improve physical
function in moderately to severely active RA in combination.
2.
Psoriatic Arthritis (PsA): reducing signs and symptoms of active arthritis,

inhibiting the progression of structural damage, and improving physical function.
3.
Ankylosing Spondylitis (AS): reducing signs and symptoms in active AS.
4.
Adult Crohns Disease: reducing signs and symptoms and inducing and
maintaining clinical remission in adult patients with moderately to severely
active Crohns disease who have had an inadequate response to conventional
therapy. Reducing the number of enterocutaneous and rectovaginal fistulas and
maintaining fistula closure in adult patients with fistulizing Crohns disease.
5.
Pediatric Crohns Disease: reducing signs and symptoms and inducing and
maintaining clinical remission in pediatric patients with moderately to severely
active Crohns disease who have had an inadequate response to conventional
therapy.
6.
Ulcerative Colitis: reducing signs and symptoms, inducing and maintaining

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.
7.
Plaque Psoriasis: treatment of adult patients with chronic severe plaque psoriasis
who are candidates for systemic therapy and when other systemic therapies are
medically less appropriate.
Special considerations with infliximab:

1.
2.
3.

12 | P a g e
C.
4.

5.

6.
Off-label use of infliximab may include but is not limited to:

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
D.

1.
2.
3.
4.
5.
6.
7.
XI.
Sarcoidosis
Myositis
Behet Disease
Uveitis
Reactive Arthritis
In RA the recommended dose of infliximab is 3 mg/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.
In RA, for patients who have an incomplete response, consideration may be
given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks.
In AS the recommended dose is 5 mg/kg given as an intravenous infusion
followed with additional similar doses at 2 and 6 weeks after the first infusion,
then every 6 weeks thereafter.
In PSA the recommended dose is 5 mg/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.
In Crohns disease, the recommended dosage: Induction: 5 mg/kg week 0, 2 and
6. Maintenance: 5 mg/kg every 8 weeks. May be increased up to 10 mg/kg.
In Ulcerative Colitis, the recommended dosage: Induction: 5 mg/kg week 0, 2
and 6. Maintenance: 5 mg/kg every 8 weeks.
In Plaque Psoriasis, the recommended dosage: Induction: 5 mg/kg week 0, 2 and
6. Maintenance: 5 mg/kg every 8 weeks.
Pegloticase (KrystexxaTM)
A.
Pegloticase is medically-necessary and has an FDA-approved indication for the

treatment of:
1.
B.
Chronic Gout: adults patients refractory to conventional therapy
Special considerations for pegloticase:
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C.
1.
Patients at higher risk for G6PD deficiency should be screened due to risk of
hemolysis and methemoglobinemia.
2.
Exercise caution when using in patients with congestive heart failure.

1.
2.
3.
XII.
Rilonacept (Arcalyst)
A.
Rilonacept is medically necessary and has an FDA- approved indication for the
treatment of Cryoprin-Associated Periodic Syndromes (CAPS), in adults and children over
the age of 12 years including:
1.
Familial Cold Auto-Inflammatory Syndrome
2.
B.
C.
Muckle-Wells Syndrome
Special considerations with rilonacept:

1.
Live vaccines should not be given concurrently with rilonacept.
2.
IL-1 blocking agents (i.e. anakinra, canakinumab) increased risk of serious

infection.
3.
TNF- inhibitors increased risk of serious infection.

1.
2.
XIII.
Pegloticase is given as an intravenous infusion over no less than 120 minutes

Pegloticase should not be administered as an intravenous push or bolus.
Adult patient dosing is 8mg intravenously every 2 weeks.
Patients 12 to 17 years: A loading dose of 4.4 mg/kg, up to 320 mg, injected

subcutaneously. Administer as two separate injections on the same day if the
dose exceeds a maximum single injection volume of 2 ml. Maintenance dose is
2.2 mg/kg, up to 160 mg, injected subcutaneously once a week.
Patients 18 years and older: A loading dose of 320 mg (4 ml) administered as two
160 mg (2 ml) subcutaneous injections in separate sites on the same day.
Maintenance dose is 160 mg injected subcutaneously once a week.
Rituximab (Rituxan)
A.
Rituximab is medically necessary and has an FDA-approved indication for the treatment
of:
1.
Rheumatoid Arthritis (RA): in combination with methotrexate to reduce signs

and symptoms and to slow the progression of structural damage in adult patients
with moderately-to severely-active RA who have had an inadequate response to
one or more TNF antagonist therapies.
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B.
C.
2.
Granulomatosis with Polyangiitis (GPA; formerly Wegeners Granulomatosis):

adult patients in combination with glucocorticoids
3.
Microscopic Polyangiitis (MPA): adults patients in combination with

glucocorticoids
Special considerations for rituximab:

1.
2.
Monitor HBV carriers during and several months after therapy. Rituximab should
be discontinued if reactivation occurs.
3.
Rituximab should be discontinued if progressive multifocal leukoencephalopathy

occurs.
4.
Pneumocystis jiroveci pneumonia prophylaxis is recommended for patients with

GPA and MPA during treatment and for at least 6 months following the last
rituximab infusion.
5.

6.

7.
Rituxan therapy should be considered first line for any patient with prior treated
lymphoproliferative malignancy, skin melanoma, nonmelanoma skin cancer, or
solid malignancy within the last 5 years.
Off-label use of rituximab may include but is not limited to:

1.
2.
3.
4.
5.
6.
7.
8.
D.

Cutaneous Lupus, all subtypes
Vasculitides
Sjogrens Syndrome
Polymyositis
Dermatomyositis (juvenile and adult onset)

1.
2.
3.
Rituximab is administered as an intravenous infusion.

In RA, the recommended dose is two 1000 mg infusions separated by 2 weeks.
Subsequent courses should be administered every 24 weeks or based on clinical
evaluation, but no sooner than every 16 weeks
In GPA and MPA the recommended dose is 375mg/m2 once weekly for 4 weeks.
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XIV.
Tocilizumab (Actemra)
A.
B.
C.
D.
Tocilizumab is medically necessary and has an FDA-approved indication for the

treatment of :
1.
Rheumatoid Arthritis (RA): adult patients with moderately to severely active RA

who have had an inadequate response to one or more TNF-antagonist therapies.
2.
Systemic Juvenile Idiopathic Arthritis (SJIA): patients 2 years of age and older
with active SJIA.
Special considerations for tocilizumab:

1.
2.
Use with caution in patients who may be at increased risk of gastrointestinal

perforation.
3.
Laboratory monitoring is recommended due to potential consequences of

treatment-related changes in neutrophils, platelets, lipids, and liver function tests.
4.

5.

Off-label use of tocilizumab may include but is not limited to:

1.
Systemic Juvenile Idiopathic Arthritis all ages
2.
Polyarticular Juvenile Idiopathic Arthritis

1.
2.
3.
4.
5.
Tocilizumab is given as a 60-minute single intravenous drip infusion

Tocilizumab may be given as a monotherapy or in combination with
methotrexate.
In RA, the recommended starting dose is 4 mg/kg followed by an increase to 8
mg/kg based on clinical response.
In SJIA, the recommended dose for patients less than 30kg is 12mg/kg every 2
weeks
In SJIA, the recommended dose for patients 30kg or more is 8mg/kg every 2
weeks
Rationale
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FDA-Approved Indications
Abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), belimumab (Benlysta), canakinumab
(Ilaris), certolizumab pegol (Cimzia), denosumab (Prolia), etanercept (Enbrel), golimumab (Simponi),
infliximab (Remicade), pegloticase (Kyrstexxa), rituximab (Rituxan), and tocilizumab (Actemra) belong
to a class of drugs known as Biologic Response Modifiers (BRMs). Adalimumab, certolizumab pegol ,
etanercept , golimumab , and infliximab are in the class of BRMs that inhibit the cytokine Tumor
Necrosis Factor (TNF)-. Anakinra, rilonacept and canakinumab work as antagonists to the cytokine IL1. Abatacept is an inhibitor of T-cell co-stimulation. Rituximab is a B-cell depleting therapy, whereas
belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor. Tocilizumab is an interleukin-6
receptor inhibitor. Denosumab is a RANK ligand inhibitor. Pegloticase is a modified urate oxidase
enzyme specific toward uric acid. Each has been approved by the FDA for use in specific indications
based on the available peer-reviewed evidence (please see medically necessary policy statement for list of
indications).1-14 A mechanism should exist where patients demonstrating a favorable response to a specific
biologic medication are allowed to continue that same agent even if the patient transitions to a different
medical/prescription benefit plan.
Off-Label Use
Many autoimmune rheumatic diseases have severe multisystem manifestations, including internal organ
involvement and premature death. Unfortunately, for many of these conditions, standard (FDA approved)
therapies do not exist, or are only effective in a subset of patients. The rarity of some of these conditions
presents a barrier to performing large scale studies required for regulatory approval. However, valuable
information is obtained in the published clinical reports of biologic DMARD therapies for many less
common but disabling autoimmune conditions. When successful treatment options have been clearly
documented in peer-reviewed journals, patients should receive the opportunity to benefit from these
effective therapies. The following references are examples as new information will continue to be
published.
References are provided for the anti-TNF agents as a class for off-label use in Undifferentiated
Spondyloarthropathy, Sarcoidosis, Myositis, Behcets, Uveitis, and Reactive Arthritis.15-43 Additional
references for the off-label use of anakinra44-51, abatacept52-53, canakinumab54, denosumab55-56, rituximab5776
, and tocilizumab77-78 are listed below. A mechanism should exist where the rheumatologist or an NP/PA
guided by a rheumatologist can engage in a peer-to-peer review with a benefit provider representative to
appeal any negative decision on the use of biologic agents. The benefit provider representative should
have an accredited-Rheumatology or Immunology education background.
Biologic Molecule Description

Biologic Response Modifiers (BRMs), also called biologic agents, are a class of drugs created by living
cell cultures and are used to treat a number of diseases. These drugs target specific pathways of the
immune system. The United States Food and Drug Administration (FDA), the division of the U.S.
Department of Health and Human services charged with ensuring the safety and effectiveness of new
drugs before they can go on the market, has approved several BRMs. The following molecular
descriptions are taken from the agents U.S.-approved Prescribing Information.
Remicade (infliximab) is a chimeric (part mouse, part human) monoclonal antibody that blocks activity of
a key biologic response mediator called tumor necrosis factor (TNF) alpha. The action of Remicade is
to bind to and neutralize TNF- on the cell membrane and in the blood supply and to destroy TNF-
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producing cells, thus inhibiting inflammation. Remicade is supplied as a sterile, white lyophilized
powder for intravenous infusion. It is an infusible medication that has been approved for home IV
therapy, hospital outpatient administration or physician office administration.
Enbrel (etanercept) is a dimeric fusion protein that binds specifically to tumor necrosis factor (TNF) and
blocks its interaction with cell surface TNF receptors. Enbrel is supplied as white, preservative-free,
lyophilized powder for single-use parenteral administration after reconstitution with 1 ml of the supplied
sterile bacteriostatic water for injection, as a prefilled glass syringe and as a prefilled autoinjector glass
syringe. It is intended for use under the guidance and supervision of a physician. Patients may self-inject
only if their physician determines that it is appropriate and with medical follow-up, as necessary, after
proper training in reconstitution and injection technique.
Humira (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for the human tumor
necrosis factor and acts by blocking the interaction between TNF- and p55 and p75 receptors. It is
supplied in a single-use, 1 ml prefilled glass syringe and a prefilled autoinjector syringe as a sterile,
preservative-free solution for subcutaneous administration. Humira is intended for use under the guidance
of a physician. Patients may self-inject only if their physician determines that it is appropriate and with
medical follow-up, as necessary, after proper training in injection technique.
Simponi (golimumab) is a human IgG1 monoclonal antibody specific for human TNF- that exhibits
multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. Simponi is supplied
either as a single dose prefilled syringe or a single dose prefilled autoinjector. Simponi does not contain
preservatives.
Cimzia (certolizumab pegol) is a recombinant, humanized antibody to Fab fragment, with specificity for
human TNF- , conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab
fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to
PEG2MAL40K, to generate certolizumab pegol. Cimzia is supplied as either a sterile, white, lyophilized
powder for solution or as a sterile, solution in a single-use prefilled 1 ml glass syringe for subcutaneous
injection. Each single-use vial provides approximately 200 mg certolizumab pegol. Each prefilled syringe
delivers 200 mg of certolizumab pegol. No preservatives are present. A patient may self-inject Cimzia if a
physician determines that it is appropriate, with medical follow-up, as necessary, after proper training in
subcutaneous injection technique.
Kineret (anakinra) is a recombinant form of human interleukin-1 receptor antagonist, which functions to
block the pro-inflammatory interleukin-1 cytokine, which plays a role in inflammation and cell
destruction. Kineret is supplied in single-use preservative-free, 1 ml prefilled glass syringes with 27 gauge
needles. Patients or care providers should not be allowed to administer Kineret until he/she has
demonstrated a thorough understanding of procedures and an ability to inject the product.
Ilaris (canakinumab) is a recombinant, human anti-human-IL-1 monoclonal antibody that belongs to the
IgG1/ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or
448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons
when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the
protein backbone at asparagine 298 (Asn 298). Ilaris is supplied as a 180 mg white lyophilized powder for
solution for subcutaneous injection. Reconstitution with 1 ml of preservative-free Sterile Water for
Injection is required prior to subcutaneous administration of the drug, resulting in a total volume of 1.2 ml
reconstituted solution. The reconstituted Ilaris is a clear to slightly opalescent, colorless to a slight
brownish yellow tint, essentially free from particulates, 150 mg/ml solution.
Arcalyst (rilonacept) is a dimeric fusion protein consisting of the ligand-binding domains of the
extracellular portions of the human interleukin-1 receptor component (IL-R1) and IL-1 receptor accessory
18 | P a g e
protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Arcalyst blocks IL-1 beta signaling
by acting as a soluble decoy receptor that binds IL-1beta and prevents its interaction with cell surface
receptors. Arcalyst also binds IL-1alpha and IL-1 receptor antagonist (IL-1ra) with reduced affinity.
Arcalyst is supplied in sterile, single use 20 ml glass vials that contain 220 mg of Arcalyst as a white to
off-white preservative-free lyophilized powder. Reconstitution with 2.3 ml of preservative-free Sterile
Water for Injection is required prior to subcutaneous administration of the drug. The reconstituted
Arcalyst is a viscous, clear, colorless to pale yellow, essentially free from particulates, 80 mg/ml solution.
Orencia (abatacept) is a soluble fusion protein that consists of the extracellular domain of human
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3
domains) portion of human immunoglobulin G1 (IgG1). Orencia acts as a selective costimulation
modulator. It inhibits T cell activation by binding to CD80 and CD86, thereby blocking interaction with
CD28. Orencia is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral
administration. Following reconstitution with 10 ml of Sterile Water for Injection, USP, the solution of
Orencia is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of Orencia
provides 250 mg abatacept, 500 mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium
chloride for administration.
Rituxan (rituximab) is a genetically engineered chimeric murine/human monoclonal AgG, kappa antibody
directed against the CD20 antigen. CD20 is expressed on the majority of B-cells, but the antigen is not
found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. B cells are
believed to play a role in the pathogenesis of RA and associated chronic synovitis. Administration of
Rituxan results in a rapid and sustained depletion of circulating and tissue-based B cells. Rituxan is a
sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration. It is supplied
at a concentration of 10 mg/ml in either 100 mg (10 ml) or 500 mg (50 ml) single-use vials.
Actemra (tocilizumab) is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal
antibody of the immunoglobulin IgG1 subclass with a typical H2L2 polypeptide structure. Each light
chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are
linked intra- and inter-molecularly by disulfide bonds. Actemra has a molecular weight of approximately
148kDa. Actemra is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a
concentration of 20 mg/ml. Actemra is a colorless to pale yellow liquid, with a pH of about 6.5. Singleuse vials are available containing 80 mg/4 ml, 200 mg/10 ml, or 400 mg/20 ml of Actemra. Injectable
solutions of Actemra are formulated in an aqueous solution containing disodium phosphate dodecahydrate
and sodium dihydrogen phosphate dehydrate (as a 15 mmol/L phosphate buffer), polysorbate 80 (0.5
mg/ml), and sucrose (50 mg/ml).
Prolia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANK
ligand (RANKL). Denosumab has an approximate molecular weight of 147 kDa and is produced in
genetically engineered mammalian (Chinese hamster ovary) cells. Prolia is a sterile, preservative-free,
clear, colorless to pale yellow solution. Each 1 mL single-use prefilled syringe of Prolia contains 60 mg
denosumab (60mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for
Injection (USP), and sodium hydroxide to a pH of 5.2.
Krystexxa (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of
recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of
Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG] (10
kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase
subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of
pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa. Krystexxa is a sterile,
clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline.
19 | P a g e
Krystexxa concentrations are expressed as concentrations of uricase protein. Each mL of Krystexxa

contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen
Phosphate Dihydrate (Na2HPO42H2O), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium Dihydrogen
Phosphate Dihydrate (NaH2PO42H2O), and Water for Injection to deliver 8 mg of pegloticase (as
uricase protein).
Benlysta (belimumab) is a human IgG1 monoclonal antibody specific for soluble human B lymphocyte
stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight
of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammalian
cell expression system. Benlysta is supplied as a sterile, white to off-white, preservative-free, lyophilized
powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP, [see Dosage
and Administration (2.3)] each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid,
0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5.
Definitions
Induction: treatment designed as a first step toward treatment of a given condition.
Juvenile idiopathic arthritis (JIA): A chronic, inflammatory arthritis occurring in children less than 16
years of age which causes joint pain, swelling and stiffness and in some children, systemic symptoms.
The subtypes include: systemic, oligoarticular persistent, oligoarticular extended, polyarticularrheumatoid factor negative, polyarticular-rheumatoid factor positive, enthesitis-related arthritis and
psoriatic arthritis.
Monoclonal antibody: monoclonal antibodies are produced by a single clone of cells and are of
exceptional purity and specificity.
Refractory: resistant to ordinary treatment.
Rheumatoid Arthritis (RA): a chronic inflammatory disease characterized by symmetrical joint
involvement, which causes pain, swelling, stiffness, and loss of function in the joints.
Seronegative: producing a negative reaction to serological tests.
Spondyloarthropathy: the spondyloarthropathies (SpA) are a heterogeneous set of disorders which
include ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis and reactive arthritis characterized
by axial and peripheral joint involvement and frequent association with the HLA B27 antigen.
Tumor Necrosis Factor (TNF): a naturally occurring cytokine that is involved in normal inflammatory
and immune responses.
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References
Package Inserts
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Actemra [package insert]. South San Francisco, CA: Genentech; 2012.

Arcalyst [package insert]. Tarrytown, NJ: Regeneron; 2012.
Benlysta [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012.
Cimzia [package insert]. Smyrna, GA: UCB, Inc; 2012.
Enbrel [package insert]. Thousand Oaks, CA: Amgen; 2012.
Humira [package insert]. North Chicago, IL: Abbott Laboratories; 2012.
Ilaris [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2012.
Kineret [package insert]. Stockholm, Sweden: Biovitrum; 2012.
KrystexxaTM [package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc.; 2012
Orencia [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2012.
Prolia [package insert]. Thousand Oaks, CA: Amgen; 2012.
Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2012.
Rituxan [package insert]. South San Francisco, CA: Genentech; 2012.
Simponi [package insert]. Horsham, PA: Janssen Biotech, Inc; 2012.
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76. Seo P, Specks U, Keogh KA. Efficacy of rituximab in limited Wegener's granulomatosis with
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77. Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL. Rituximab is effective in the treatment
of refractory ophthalmic Wegener's granulomatosis. Arthritis Rheum. 2009 May;60(5):1540-7.
78. Isaksen K, Jonsson R, Omdal R. Anti-CD20 treatment in primary Sjogrens syndrome. Scan J
Immunol 2008;68:554-564.
79. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study.
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Sultan SM. Ng KP. Edwards JC. Isenberg DA. Clinical outcome following B cell depletion
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Approved by Board of Directors
08/2012
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Model Biologics Indications

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AMERICAN COLLEGE OF RHEUMATOLOGY

Model Biologics Indications

Committee on Rheumatologic Care

FOR DISTRIBUTION TO:

Members of the American College of Rheumatology

AMA CPT Copyright Statement

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

Adult Rheumatoid Arthritis: reducing signs and symptoms, inducing major

Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms in pediatric

Special considerations for abatacept:

Concomitant use with TNF antagonists increases the risk of infection.

Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,

During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and Human

Off-label use of abatacept may include but is not limited to:

Systemic Lupus Erythematosus

Dosage and administration (IV administration):

Abatacept is administered as an intravenous infusion. Following the initial

75-100 kg: dose is 750 mg

>100 kg: dose is 1,000 mg

Dosage and administration (SQ administration):

Abatacept may be administered by subcutaneous injection instead of infusion.

The recommended dose is 125mg by subcutaneous injection weekly.

Adalimumab is medically necessary and has an FDA-approved indication for the

Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing major

Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately

Psoriatic Arthritis (PsA): reducing signs and symptoms of active arthritis,

Ankylosing Spondylitis (AS): reducing signs and symptoms in patients with

Special considerations with adalimumab:

Concomitant use of anti-TNF- therapy with anakinra and abatacept increases

Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,

During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and Human

Dosage and administration:

Adalimumab is administered by subcutaneous injection.

Special considerations with anakinra:

Off-label use of anakinra may include but is not limited to:

Belimumab is medically-necessary and has an FDA-approved indication for the

Special Considerations for belimumab:

Live vaccines should not be given concurrently with belimumab

Dosage and administration:

Belimumab is an intravenous infusion delivered over 1 hour.

Canakinumab is medically necessary and has an FDA-approved indication for the

Familial Cold Autoinflammatory Syndrome

Special considerations with canakinumab:

In RA the recommended dose of anakinra is 100 mg/day administered by

Adult-Onset Stills Disease

Dosage and administration:

Concomitant use with TNF antagonists increases the risk of infection.

Live vaccines should not be given concurrently with canakinumab.

Off-label use of canakinumab may include but is not limited to:

1. Systemic Juvenile Idiopathic Arthritis

Dosage and administration:

Canakinumab is administered by subcutaneous injection every 8 weeks.

Certolizumab pegol (Cimzia )

Rheumatoid Arthritis (RA): moderately to severely active RA.

Crohns Disease: reducing signs and symptoms of Crohns disease and

Special considerations with certolizumab pegol:

Concomitant use of anti-TNF- therapy with anakinra and abatacept increases

Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,

During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and Human

Dosage and administration:

Certolizumab pegol is administered by subcutaneous injection.

Denosumab is medically necessary and has an FDA-approved indication for the

Hypocalcemia must be corrected prior to initiating denosumab. Adequately

Off-label use of denosumab may include but is not limited to: