Download Actemra CC

Utilization Review Policy
Subject:
tocilizumab injection for intravenous infusion (Actemra)
Date revised: 02/24/2010
Description
Tocilizumab is an interleukin-6 (IL-6) receptor inhibitor. IL-6 is a pro-inflammatory cytokine
that is involved in many physiologic processes. Tocilizumab is approved by the Food and Drug
Administration (FDA) for the following indication.
The treatment of rheumatoid arthritis (RA) in adults with moderate to severe active RA
who have had an inadequate response to one or more tumor necrosis factor (TNF)
antagonists. Tocilizumab can be given alone or in combination with disease modifying
antirheumatic drugs (DMARDs) such as methotrexate (MTX) or other nonbiologic
DMARDs.
Tocilizumab is available as a 20 mg/mL preservative-free solution in single-use vials: 80 mg/4
mL, 200 mg/10 mL and 400 mg/20 mL. Tocilizumab should be diluted before administration.
Using a 100 mL bottle or bag, a volume of 0.9% Sodium Chloride Injection equal to the volume
of tocilizumab is withdrawn. Then tocilizumab injection is added to the infusion bottle or bag.
The diluted solution is infused intravenously (IV) over 60 minutes. It should not be given IV
push.
Indications, Medically Necessary
1. RA in adults: Indicated for the treatment of moderate to severe active RA in patients
who meet all of the following criteria.

Tocilizumab is prescribed by a rheumatologist, and

Patient has had an inadequate response to at least 2 months of therapy with one of the
following non-biologic DMARDs: methotrexate (MTX), hydroxychloroquine, leflunomide
(Arava®), or sulfasalazine, and
Exceptions to having tried a non-biologic DMARD for 2 months can be made in the
following circumstances:
The patient could not tolerate the non-biologic DMARDs or if there are
contraindications to all four of these agents.

Patient has tried a TNF antagonist, adalimumab (Humira), certolizumab pegol (Cimzia),
etanercept (Enbrel), golimumab (Simponi) or infliximab (Remicade) for at least 2 months
and had an inadequate response or was intolerant to one of these TNF antagonists, and
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Tocilizumab (Actemra®)

The patient will be receiving tocilizumab in combination with MTX or another nonbiologic
DMARD (e.g., hydroxychloroquine, leflunomide, sulfasalazine), and
Note: patients are not required to use MTX concurrently with tocilizumab if there are
contraindications to MTX or the patient has a history of intolerance to MTX or to use
other nonbiologic DMARDs if there are contraindications or a history of intolerance.

Patients who are starting tocilizumab must have an absolute neutrophil count (ANC) ≥ 2000
cells/mm3, platelet count ≥ 100,000 cells/ mm3, and an alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal.
For patients who are continuing with tocilizumab there must be documentation that the
patient is or is not on another DMARD in conjunction with tocilizumab and the other drug
therapies that have been used to treat RA.
Dosing in RA: the starting dose is 4 mg/kg once every 4 weeks. Depending on clinical
response the dose can be increased to 8 mg/kg every 4 weeks. The maximum dose is 800 mg
every 4 weeks. Note: patients starting on tocilizumab must have baseline laboratory tests.
See Criteria above and Labs/Diagnostics required below.
Many dose modifications are recommended for the management of dose-related laboratory
changes such as increased liver enzymes, neutropenia, and thrombocytopenia. Dosing
modifications recommended in the prescribing information are as follows.
Liver Enzyme (ALT, AST) Abnormalities. Recommendations for Patients on Tocilizumab.
Lab Value
Recommendation
> 1 to 3 times ULN
Modify dose of concomitant DMARDs if appropriate.
For persistent increases in this range, reduce tocilizumab dose to
4 mg/kg or interrupt tocilizumab until ALT/AST have normalized.
> 3 to 5 times ULN
Interrupt tocilizumab dosing until < 3 times ULN and follow
(confirmed with repeat
recommendations above for > 1 to 3 times ULN.
testing)
For persistent increases > 3 times ULN, discontinue tocilizumab.
> 5 times ULN
Discontinue tocilizumab.
ULN = upper limit of normal. Some DMARDs such as methotrexate, leflunomide (Arava), or
sulfasalazine may increase liver enzymes.
Low Absolute Neutrophil Count (ANC). Recommendations for Patients on Tocilizumab.
Lab Value (cells/mm3)
Recommendation
ANC > 1000
Maintain dose.
ANC 500 to 1000
Interrupt tocilizumab dosing.
When ANC > 1000 cells/mm3 resume tocilizumab at 4 mg/kg and
increase to 8 mg/kg as clinically appropriate.
ANC < 500
Discontinue tocilizumab.
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Tocilizumab (Actemra®)
Low Platelet Count. Recommendations for Patients on Tocilizumab.
Lab Value (cells/mm3)
Recommendation
50,000 to 100,000
Interrupt tocilizumab dosing.
When platelet count is > 100,000 cells/mm3 resume tocilizumab at 4
mg/kg and increase to 8 mg/kg as clinically appropriate.
< 50,000
Discontinue tocilizumab.
Initial approval/extended approval: Initial approval is for 4 months (4 doses) of therapy
with 4 mg/kg initially and then every 4 weeks (weeks 0, 4, 8, and 12). Patients are evaluated
for response after the fourth dose.
Approve for an additional 12 months of therapy if the patient has responded (less joint pain,
morning stiffness, or fatigue; improved function or activities of daily living; decreased soft
tissue swelling in joints or tendon sheaths; improved laboratory values; reduced dosage of
corticosteroids) as determined by the prescribing rheumatologist. The patient may not have a
full response after 4 doses, but there should be some response.
If the response is inadequate after 1 or more doses of 4 mg/kg, the dose can be increased to 8
mg/kg every 4 weeks. Doses are also adjusted depending on laboratory tests for ANC,
platelets, and liver function tests. See tables above.
Duration of therapy in RA: indefinite if the patient is responding and tolerates the drug.
Labs/Diagnostics required: Patient should be screened for latent tuberculosis (TB)
infection prior to starting therapy and then every year while on tocilizumab. Screening may
include any of the following: history, tuberculin skin testing, interferon gamma release assay
(IGRA), chest x-ray. In general, patients with latent TB infection should begin preventive
therapy before starting tocilizumab.
Patients starting tocilizumab must have baseline labs including ANC, platelet counts, and
liver function tests (either ALT or AST) and these labs should be repeated every 4 to 8
weeks. Lipid parameters (total cholesterol, triglycerides, low density lipoprotein (LDL)
cholesterol, and/or high density lipoprotein (HDL) cholesterol) must be assessed at baseline
and then again about 4 to 8 weeks after starting tocilizumab.
Waste management: The initial dose in RA is 4 mg/kg and may be increased to 8 mg/kg.
For patients who are already on tocilizumab, the dose should be calculated and the number of
vials needed assessed. Usually the dose should be rounded to the next whole number of vials
to avoid wasting unused medication left in the vial. The maximum dose is 800 mg, so
persons with body weight > 100 kg should receive 800 mg maximum.
Exclusions: See below.
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Tocilizumab (Actemra®)
2. Systemic-onset juvenile idiopathic arthritis (JIA): Indicated for the treatment of
systemic-onset JIA in children or adolescents who meet all of the following criteria. [NOT
FDA-APPROVED INDICATION]

Tocilizumab is prescribed by a rheumatologist, and

Patient has tried at least one nonsteroidal anti-inflammatory drug (NSAID), and

Patient has tried at least one systemic corticosteroid (e.g., prednisone), and

Patient has had an inadequate response to a non-biologic DMARD such as methotrexate
(MTX) or sulfasalazine or a biologic DMARD such as etanercept (Enbrel), and
Exceptions to having tried a DMARD can be made in the following circumstances:
The patient could not tolerate a DMARD or if there are contraindications to all of
these agents.

Patients who are starting tocilizumab must have an absolute neutrophil count (ANC) ≥ 2000
cells/mm3, platelet count ≥ 100,000 cells/ mm3, and an alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal.
For patients who are continuing with tocilizumab there must be documentation of the other
drug therapies that have been used to treat systemic-onset JIA.
Dosing in systemic-onset JIA: the starting dose is 8 mg/kg once every 2 weeks. Limited
information is available on adjusting the dose or the interval for this indication. The
maximum dose is 8 mg/kg or 800 mg. Note: patients starting on tocilizumab must have
baseline laboratory tests. See Criteria above and Labs/Diagnostics required below.
Many dose modifications are recommended for the management of dose-related laboratory
changes such as increased liver enzymes, neutropenia, and thrombocytopenia. Dosing
modifications recommended in the prescribing information for RA in adults are as follows.
Liver Enzyme (ALT, AST) Abnormalities. Recommendations for Patients on Tocilizumab.
Lab Value
Recommendation
> 1 to 3 times ULN
Modify dose of concomitant DMARDs if appropriate.
For persistent increases in this range, reduce tocilizumab dose to
4 mg/kg or interrupt tocilizumab until ALT/AST have normalized.
> 3 to 5 times ULN
Interrupt tocilizumab dosing until < 3 times ULN and follow
(confirmed with repeat
recommendations above for > 1 to 3 times ULN.
testing)
For persistent increases > 3 times ULN, discontinue tocilizumab.
> 5 times ULN
Discontinue tocilizumab.
ULN = upper limit of normal. Some DMARDs such as methotrexate, leflunomide (Arava), or
sulfasalazine may increase liver enzymes.
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Tocilizumab (Actemra®)
Low Absolute Neutrophil Count (ANC). Recommendations for Patients on Tocilizumab.
Lab Value (cells/mm3)
Recommendation
ANC > 1000
Maintain dose.
ANC 500 to 1000
Interrupt tocilizumab dosing.
When ANC > 1000 cells/mm3 resume tocilizumab at 4 mg/kg and
increase to 8 mg/kg as clinically appropriate.
ANC < 500
Discontinue tocilizumab.
Low Platelet Count. Recommendations for Patients on Tocilizumab.
Lab Value (cells/mm3)
Recommendation
50,000 to 100,000
Interrupt tocilizumab dosing.
When platelet count is > 100,000 cells/mm3 resume tocilizumab at 4
mg/kg and increase to 8 mg/kg as clinically appropriate.
< 50,000
Discontinue tocilizumab.
Initial approval/extended approval: Initial approval is for 4 months (8 doses) of therapy
with 4 or 8 mg/kg initially and then every 2 weeks (weeks 0, 2, 4, 6, 8, 10, 12, and 14).
Patients are evaluated for response after the eighth dose.
Approve for an additional 12 months of therapy if the patient has responded (e.g., has
improvement in limitation of motion; less joint pain or tenderness; improved function or
activities of daily living; decreased duration of morning stiffness or fatigue; reduced dosage
of corticosteroids; decreased soft tissue swelling in joints or tendon sheaths; improved
laboratory values), as determined by the prescribing rheumatologist. Doses are also adjusted
depending on laboratory tests for ANC, platelets, and liver function tests. See tables above.
Duration of therapy in RA: indefinite if the patient is responding and tolerates the drug.
Labs/Diagnostics required: Patient should be screened for latent tuberculosis (TB)
infection prior to starting therapy and then every year while on tocilizumab. Screening may
include any of the following: history, tuberculin skin testing, interferon gamma release assay
(IGRA), chest x-ray. In general, patients with latent TB infection should begin preventive
therapy before starting tocilizumab.
Patients starting tocilizumab must have baseline labs including ANC, platelet counts, and
liver function tests (either ALT or AST) and these labs should be repeated every 4 to 8
weeks. Lipid parameters (total cholesterol, triglycerides, LDL cholesterol, and/or HDL
cholesterol) must be assessed at baseline and then again about 4 to 8 weeks after starting
tocilizumab.
Waste management: The initial dose in systemic onset JIA is usually 8 mg/kg every 2
weeks. For patients who are already on tocilizumab, the dose should be calculated and the
number of vials needed assessed. Usually the dose should be rounded to the next whole
number of vials to avoid wasting unused medication left in the vial.
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Tocilizumab (Actemra®)
Exclusions: See below.
Exclusions:
 Concomitant use with anakinra (Kineret), any TNF antagonist (such as etanercept
[Enbrel], adalimumab [Humira], golimumab [Simponi], infliximab [Remicade],
certolizumab pegol [Cimzia]), abatacept (Orencia), or rituximab (Rituxan).
 Tocilizumab is contraindicated in patients with significant active infections.
 Children and adolescents ≤ 18 years of age, except those with systemic-onset JIA.
 Juvenile idiopathic arthritis (JIA), any subtype beside systemic.
 Crohn’s disease.
 Castleman’s disease.
REFERENCES

Actemra® injection for intravenous infusion [package insert]. South San Francisco, CA: Genentech; January, 2010.
Rheumatoid arthritis

Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with
moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88-96.

Data on file. South San Francisco, CA: Genentech; January 15, 2010.

Fleischmann R, Burgos-Varga R, Ambs E, et al. LITHE: Tocilizumab inhibits radiographic progression and improves
physical function in rheumatoid arthritis (RA) patients (pts) at 2 yrs with increasing clinical efficacy over time [abstract
637]. Presented at: the American College of Rheumatology (ACR) 73 rd Annual Meeting; Philadelphia, PA; October 16-21,
2009.

Smolen JS, Beaulieu A, Rubbert-Roth A, et al; OPTION Investigators. Effect of interleukin-6 receptor inhibition with
tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.
Lancet. 2008;371:987-997.

Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in
rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination
with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968-2980.

Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients
with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre
randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516-1523.

Smolen JS, Gomez-Reino JJ, Davies C, et al. Long-term efficacy of tocilizumab in rheumatoid arthritis for up to 3.5 years.
[abstract 413]. Presented at: the American College of Rheumatology (ACR) 73rd Annual Meeting; Philadelphia, PA;
October 16-21, 2009.

Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor
antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761-1769.

Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled
trial of tocilizumab. Ann Rheum Dis. 2007;66:1162-1167.

Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis
patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular
endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12-19.

Maini RN, Taylor PC, Szechinski J, et al; CHARISMA Study Group. Double-blind randomized controlled clinical trial of
the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete
response to methotrexate. Arthritis Rheum. 2006;54:2817-2829.

Nishimoto N, Miyasaka N, Yamamoto K, et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor
monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and
efficacy in a 5-year extension study. Ann Rheum Dis. 2009;68:1580-1584.

Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs.
2009;69:609-632.
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Tocilizumab (Actemra®)
Juvenile idiopathic arthritis [NOT FDA-APPROVED INDICATION]

Woo P, Wilkinson N, Prieur AM, et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children
with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of
arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther. 2005;7:R1281-1288.

Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic
arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998-1006.

Hoffmann-La Roche. A study of tocilizumab in patients with active systemic juvenile idiopathic arthritis. In:
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2010 January 17] Available
from: http://www.clinicaltrials.gov/ct2/show/NCT00642460?term=tocilizumab+AND+systemic+juvenile&rank=1 NLM
Identifier: NCT00642460.

Yokota S, Hara T, Kikuchi M, et al. Drug-free remission of patients with systemic juvenile idiopathic arthritis receiving
tocilizumab for treatment [abstract 2054]. Arthritis Rheum. 2009;60Suppl:s768-769.

Hoffmann-La Roche. A study of tocilizumab in patients with active polyarticular-course juvenile idiopathic arthritis. In:
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2010 January 17] Available
from: http://www.clinicaltrials.gov/ct2/show/NCT00988221?term=tocilizumab+AND+polyarticular-course&rank=1 NLM
Identifier: NCT00988221.
Crohn’s disease [NOT FDA-APPROVED INDICATION]

Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in
active Crohn’s disease. Gastroenterology. 2004;126:989-996.
Castleman’s disease [NOT FDA-APPROVED INDICATION]

Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric
Castleman's disease. Intern Med. 2007;46:771-774.

Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor
antibody therapy. Blood. 2000;95:56-61.

Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric
Castleman disease. Blood. 2005;106:2627-2632.

Sullivan RJ, Pantanowitz L, Casper C, et al. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcomaassociated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin
Infect Dis. 2008;47:1209-1215.

Dispenzieri A. Castleman disease. Cancer Treat Res. 2008;142:293-330.

Stebbing J, Pantanowitz L, Dayyani F, et al. HIV-associated multicentric Castleman's disease. Am J Hematol.
2008;83:498-503.
ABBREVIATIONS
ALT = alanine aminotransferase
ANC = absolute neutrophil count
AST = aspartate aminotransferase
DMARD = disease modifying antirheumatic drug
FDA = Food and Drug Administration
HDL = high density lipoprotein
IGRA = interferon gamma release assay
IL-6 = interleukin-6
IV = intravenous
JIA = juvenile idiopathic arthritis
LDL = low density lipoprotein
mL = milliliter
MTX = methotrexate
RA = rheumatoid arthritis
TB = tuberculosis
TNF = tumor necrosis factor
ULN = upper limit of normal.
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Tocilizumab (Actemra®)
Disease Modifying Antirheumatic Drugs (DMARDs).
Generic Name
Trade Name
Traditional (Synthetic) DMARDs
azathioprine (oral)
generics, Imuran
cyclosporine (oral)
generics, Neoral, Sandimmune
d-penicillamine (oral)
Cuprimine, Depen
gold compounds
gold sodium thiomalate (injection)
Myochrysine®
auranofin (oral)
Ridaura
hydroxychloroquine (oral)
generics, Plaquenil
leflunomide (oral)
generics, Arava
methotrexate [MTX] (oral, injection)
generics, Rheumatrex
minocycline (oral)
generics, Minocin®
sulfasalazine (oral)
generics, Azulfidine En-tabs, Azulfidine
Biologic DMARDs
abatacept (injection)
Orencia
adalimumab (injection)
Humira
anakinra (injection)
Kineret
certolizumab pegol (injection)
Cimzia®
etanercept (injection)
Enbrel
golimumab (injection)
Simponi®
infliximab (injection)
Remicade
rituximab (injection)
Rituxan®
tocilizumab (injection)
Actemra®
Nonsteroidal anti-inflammatory drugs (NSAIDs) list.
Generic Name
diclofenac epolamine topical patch
diclofenac potassium
diclofenac sodium
diclofenac sodium topical gel
diclofenac sodium and misoprostol tablets
etodolac
fenoprofen
flurbiprofen
ibuprofen*
ibuprofen tablets and caffeine supplement capsules
indomethacin
ketoprofen
ketoprofen sustained-release
ketorolac, tablets, injectable
lansoprazole delayed-release capsules and naproxen
tablets
meclofenamate
mefenamic acid capsules
meloxicam tablets
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Brand Name Examples
Flector® Patch
Cataflam® , generics; Zipsor™
Voltaren®, Voltaren XR®, generics
Voltaren® Gel
Arthrotec
Lodine®, Lodine XL®, generics
Nalfon®, generics
Ansaid®, generics)
Motrin®, Advil®, generics
IC 400™ Kit, IC 800™ Kit
Indocin®, Indocin SR®, generics
Orudis®, generics
Oruvail®, generics
Toradol®, generics
Prevacid® NapraPAC™ 500
generics
Ponstel, generics
Mobic, generics
Tocilizumab (Actemra®)
Relafen®, generics
Naprosyn®, generics
Naprosyn EC®, generics
Naprelan®, generics
Anaprox®, Anaprox DS®, generics
Daypro®, generics
Feldene®, generics
Clinoril®, generics
generics
nabumetone
naproxen
naproxen delayed-release
naproxen controlled-release
naproxen sodium*
oxaprozin
piroxicam
sulindac
tolmetin
*Available without a prescription.
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