Medical Policy


Subject:Tocilizumab (Actemra®)
Policy #:  DRUG.00043Current Effective Date:  11/23/2015
Status:RevisedLast Review Date:  11/05/2015

Description/Scope

This document addresses the use of tocilizumab (Actemra, Genentech, Inc., Roche USA, South San Francisco, CA) in adults with moderately to severely active rheumatoid arthritis (RA), children 2 years of age and older with active polyarticular juvenile arthritis (PJIA) or active systemic juvenile idiopathic arthritis (SJIA), multicentric Castleman disease, and for other conditions.

Note: Please see the following documents for information on other drugs which may be used in the treatment of moderately to severely active RA, active PJIA or active SJIA:

Position Statement

Medically Necessary:

Tocilizumab is considered medically necessary for the treatment of an individual with moderately to severely active RA when all of the following criteria are met:

  1. Individual is 18 years of age or older; AND
  2. Agent is used for any of the following reasons:
    1. To reduce signs or symptoms; or
    2. To induce or maintain clinical response; or
    3. To inhibit the progression of structural damage; or
    4. To improve physical function; AND
  3. Individual has had an inadequate response to a trial of 1 or more disease modifying anti-rheumatic drugs (DMARDs) (for example, methotrexate [MTX]) or a tumor necrosis factor [TNF] antagonist drug); AND
  4. May be used alone or in combination with MTX or with other nonbiologic DMARDs.

Tocilizumab is considered medically necessary for the treatment of an individual with active PJIA when all of the following criteria are met:

  1. Individual is 2 years of age or older; AND
  2. Agent is used for any of the following reasons:
    1. To reduce signs or symptoms; or
    2. To induce or maintain clinical response; AND
  3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to 1 or more nonbiologic DMARDs (such as MTX).

Tocilizumab is considered medically necessary for the treatment of an individual with active SJIA when all of the following criteria are met:

  1. Individual is 2 years of age or older; AND
  2. Agent is used for any of the following reasons:
    1. To reduce signs or symptoms; or
    2. To induce or maintain clinical response; AND
  3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to 1 or more corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs).

Tocilizumab is considered medically necessary as subsequent therapy for the treatment of an individual with relapsed/refractory or progressive multicentric Castleman disease (MCD) when all of the following criteria are met:

  1. Used as a single agent; and
  2. Human immunodeficiency virus (HIV)-negative; and
  3. Human herpes-8 (HHV-8)-negative; and
  4. No concurrent clinically significant infection (for example, Hepatitis B or C); and
  5. No concurrent lymphoma.

Not Medically Necessary:

Tocilizumab is considered not medically necessary for an individual with any of the following:

  1. In combination with other biologic DMARDs such as anti-CD20 monoclonal antibodies, IL-1R antagonists, Janus kinase inhibitors (for example, tofacitinib citrate), selective co-stimulation modulators, or TNF antagonists; or
  2. At initiation of therapy, absolute neutrophil count (ANC) less than 2000/mm3, platelet count less than 100,000/mm3, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal (ULN); or
  3. Tuberculosis, invasive fungal infection, or other  active serious infections or a history of recurrent infections; or
  4. Individual has not had a tuberculin skin test (TST) or Centers for Disease Control and Prevention (CDC)-recommended equivalent to evaluate for latent tuberculosis prior to initiating tocilizumab.

Investigational and Not Medically Necessary:

Tocilizumab is considered investigational and not medically necessary when the criteria are not met and for all other indications, including but not limited to the treatment of:

Rationale

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody that binds and inhibits both soluble and membrane bound IL-6 found in inflamed joints. 

Tocilizumab for Rheumatoid Arthritis (RA)

Tocilizumab (Actemra) is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderately to severely active RA in individuals who have had an inadequate response to 1 or more DMARDs. Tocilizumab may be used as monotherapy or concomitantly with MTX or other nonbiologic DMARDs. The efficacy and safety of tocilizumab has been validated by multiple randomized, double-blind, multicenter studies in adults with moderately to severely active RA diagnosed according to American College of Rheumatology (ACR) criteria (Emery, 2008; Genovese, 2008; Huizinga, 2015); Jones, 2010; Kremer, 2011; Maini, 2006; Nishimoto, 2007, 2009a, and 2009b; Smolen, 2008; Yazici, 2012). These trials have consistently reported that tocilizumab is associated with significant symptomatic improvements in individuals with RA who had previously experienced DMARD-failures, MTX-failures, or TNF-failures as measured by the percent of subjects achieving a 20%, 50%, or 70% improvement in ACR measures (joint stiffness, pain, swelling, lab measures, and/or disability). The LITHE trial (Kremer, 2011), also demonstrated that individuals receiving tocilizumab in combination with MTX demonstrated significantly less joint damage and significant improvement in physical function after 1 year.

The 2012 ACR updated treatment recommendations for RA includes indications for use and switching between nonbiologic and biologic DMARDs, focusing on "common patients, not exceptional cases" (Singh, 2012). The guideline algorithm recommends initiating treatment using nonbiologic DMARD combination-therapy (including 2 or more DMARDs/double and triple therapy) for the majority of individuals with early RA with moderately or highly active disease and poor prognostic features or, moving to a biologic agent with or without MTX if prior options fail to control the disease. When switching from nonbiologic DMARDs to biologic DMARDs, physicians should use either an anti-TNF biologic or a non-TNF biologic if an individual has moderate or high disease activity after 3 months of MTX treatment or DMARD combination therapy.

Tocilizumab for Polyarticular Juvenile Idiopathic Arthritis (PJIA)

In 2013, tocilizumab was approved by the FDA for the treatment of active PJIA in children 2 years of age and older. Tocilizumab may be used as monotherapy or concomitantly with MTX. The FDA approval is based on data from the phase III (CHERISH) study (Brunner, 2014) that demonstrated clinically meaningful improvement in the signs and symptoms of PJIA with tocilizumab therapy. Participants in the 3-part study were 2 to 17 years of age with active PJIA of at least 6 months duration who had an inadequate clinical response or were intolerant to MTX. Treatment with a stable dose of MTX was permitted (but not required) and concurrent use of DMARDs (other than MTX) or other biologics (TNF antagonists or T-cell costimulation modulator) were not permitted in the study. At baseline, approximately half of the participants were taking oral corticosteroids and almost 80% were taking MTX.

Part I of the study consisted of a lead-in period of tocilizumab every 4 weeks for 16 weeks (n=188). At the conclusion of the open-label Part I, 91% of participants taking tocilizumab plus MTX and 83% taking tocilizumab as monotherapy achieved an ACR 30 response at week 16 compared to baseline. In Part II, the 24-week randomized double-blind placebo-controlled withdrawal phase of the trial, tocilizumab-treated participants experienced significantly fewer disease flares compared to placebo-treated participants, 26% (21 of 82) compared to 48% (39 of 81) of participants, respectively. The safety data collected to date is reported as consistent with that observed in previous studies of tocilizumab-treated individuals with SJIA (De Benedetti, 2012) and RA. Infections were the most common adverse events over 40 weeks. Laboratory abnormalities known to occur with tocilizumab were also observed in this study, including decreases in white blood cell counts and platelet counts, and elevation in ALT and AST liver enzyme levels.

Tocilizumab for Systemic Juvenile Idiopathic Arthritis (SJIA)

In 2011, tocilizumab was approved by the FDA for the treatment of active SJIA in children ages 2 years and older. Tocilizumab may be used as monotherapy or concomitantly with MTX.

The efficacy of tocilizumab for the treatment of active SJIA was assessed in a 12-week randomized, double-blind, placebo-controlled, parallel group, industry-funded two-arm (TENDER) study of 112 children, ages 2 to 17 years old, who had an inadequate clinical response to NSAIDs or corticosteroids due to toxicity or lack of efficacy (Di Benedetti, 2012). Participants treated with or without MTX were randomized to 1 of 2 treatment groups: 75 participants received tocilizumab infusions every 2 weeks and 37 were randomized to receive placebo infusions every 2 weeks. After 12 weeks or at the time of escape due to disease worsening, participants were treated with tocilizumab in the open-label extension phase.

The primary endpoint was the proportion of participants with at least 30% improvement in JIA ACR core set (JIA ACR30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Of participants with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated participants, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated participants. Responses were consistent in the open label extension (data available through 44 weeks).

The most common adverse events (at least 5%) seen in tocilizumab-treated participants in the 12-week controlled phase of the trial were upper respiratory tract infection, headache, nasopharyngitis and diarrhea. The rate of serious infections in the tocilizumab group was "11.5 per 100 patient years." In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was "11.4 per 100 patient years." The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. The FDA noted in the follow-up period to the trial, there were 3 cases of macrophage activation syndrome (MAS), a potentially fatal complication of childhood systemic inflammatory disorders. Therefore, tocilizumab carries a black boxed warning alerting users to the risk of serious infections (Actemra Product Information [PI] label, 2014).

Di Benedetti and colleagues (2015) investigated the effect of tocilizumab on growth and growth-related laboratory parameters in a phase III clinical trial of 112 children and adolescents ages 2-17 years with SJIA-associated stunted growth. After 12 weeks of tocilizumab therapy, male and female participants experienced above-normal mean height velocities of 73% and 83%, respectively (6.6 cm/year; p<0.0001 vs. World Health Organization norms). The mean standard deviation score significantly increased during year 1 (0.29) and year 2 (0.31) (both, p<0.0001). Normalization of insulin-like growth factor 1 (ICF-1) and bone formation were also significantly increased from baseline (p<0.0001).

Off-FDA Label Use of Tocilizumab for Castleman Disease

Castleman disease is an uncommon lymphoproliferative disorder, which has been associated with human herpes virus 8 (HHV-8) and Kaposi's sarcoma (KS), and may evolve towards HHV-8-associated non-Hodgkin lymphoma. The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline (CPG) in Oncology (NCCN Guidelines®, 2015) for non-Hodgkin's lymphomas (NHL) recommends off-label use of tocilizumab for Castleman disease. For multicentric Castleman disease (MCD), tocilizumab is recommended for use as subsequent therapy as a single agent for disease that has progressed following treatment of relapsed/refractory or progressive disease. This recommendation is based on a 2A category of evidence and uniform consensus.

Evidence in the peer-reviewed published medical literature regarding the efficacy and safety of tocilizumab to treat MCD consists of multiple single and small case studies (Matsuyama, 2007), a retrospective case series (n=21) (Kawabata, 2013), and a multicenter, prospective clinical trial reporting results of the first 60 weeks of tocilizumab treatment in 28 individuals with MCD (Nishimoto, 2005). In the Nishimoto trial (2005), participants ages 20 years or older (median age, 38 years) with a clinical or pathologically confirmed diagnosis of MCD (median disease duration, 4 years) were treated with 8 mg/kg tocilizumab every 2 weeks for 16 weeks (8 infusions). Two participants were seropositive for Kaposi's sarcoma-associated herpes virus (KSHV)/HHV-8; none were seropositive for HIV. Participants were allowed to use antitumor agents (n=4, including cyclophosphamide and melphalan plus prednisone), immunosuppressants (n=0), and corticosteroids (n=15) if dosing was stable for 4 weeks before the first dose of tocilizumab. After 16 weeks of treatment, an open-label extension phase allowed individual adjustments in the dose and treatment interval according to inflammatory symptoms and laboratory parameters. The primary endpoint was improvement in disease activity assessed by biochemical markers such as C-reactive protein (CRP), hemoglobin (Hb), serum albumin (Alb), and general fatigue (using a visual analog scale [VAS]). Within 16 weeks of treatment, tocilizumab consistently alleviated lymphadenopathy and the inflammatory parameters (p<0.001; paired t test vs. baseline). Significant increases were also reported in albumin, hemoglobin, high-density lipoprotein cholesterol values, total cholesterol levels, and body mass index. Fatigue measured by VAS showed significant improvement at week 16 (p=0.008; paired t test vs. baseline). No participant required transfusion during tocilizumab administration. Tocilizumab dose was decreased or the treatment interval was extended without exacerbation in 8 (28.6%) participants, while 11 of 15 participants (73.3%) on oral corticosteroids before study entry tolerated a reduced corticosteroid dose. Use of tocilizumab was generally well tolerated, with the most frequently occurring adverse events, including "common cold" (n=16), pruritis (n=6), and malaise (n=6), reported as transient and mild to moderate in severity.

The NCCN CPG for NHL also includes a category 2A recommendation for use of tocilizumab as "second line therapy as a single agent for relapsed or refractory unicentric Castleman disease for patients who are human immunodeficiency virus-negative and human herpes virus-8-negative." To date, there is a paucity of evidence in the peer-reviewed published medical literature evaluating the efficacy and safety of tocilizumab for the treatment of unicentric Castleman disease. A search of the ClinicalTrials.gov database has failed to identify any studies (recruiting or ongoing) that evaluate that use of tocilizumab for the treatment of unicentric Castleman disease. Additional study is required to determine the clinical efficacy of tocilizumab for unicentric Castleman disease, a condition with a milder clinical course and substantially better survival outcome than MCD.

Off-FDA Label and other Proposed Uses for Tocilizumab

At this time, the FDA has not approved the use of tocilizumab for the treatment of moderately to severely active RA in individuals with no prior treatment failure. There continues to be insufficient evidence in the published peer-reviewed medical literature to support the use of tocilizumab as first line therapy for this indication.

Ongoing phase I and II clinical trials and several cohort studies and case series published in the peer-reviewed literature have evaluated the use of tocilizumab in the treatment of adult onset Still's disease (AOSD) (Ortiz-Sanjuán, 2014; Puéchal,2011; Suematsu, 2011), ankylosing spondylitis (AS) (Shima, 2011; Sieper, 2013),Crohn's disease (Ito, 2004), graft versus host disease (GVHD) (Drobyski, 2011; Kennedy, 2014), large vessel vasculitis (LVV) (giant cell and Takayasu's arteritis) (Beyer, 2011; Loricera, 2014; Salvarani, 2012; Seitz, 2011), non-infectious uveitis (Papo, 2014); polymyositis (Narazaki, 2011), relapsing polychondritis, systemic lupus erythematosus (SLE) (Illei, 2010), tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Vaitla, 2011), and unicentric Castleman disease. At this time, the FDA has not approved the use of tocilizumab for the treatment of any of these conditions.  

Background/Overview

RA is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. The disease affects approximately 2.1 million Americans usually affecting people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. RA is three times more common in women than in men.

JIA is the most common form of arthritis in children, affecting roughly 100 in 100,000 children, of which PJIA accounts for about 30%. PJIA is a type of JIA characterized by inflammation in 5 or more joints within the first 6 months of onset of the disease. Small joints in the body such as hands and feet are most commonly affected. Girls are more frequently affected by PJIA than boys, and in teenagers, it often resembles RA. SJIA is a rare, potentially life-threatening disorder in children that causes severe inflammation throughout the body. The cause of the disease is unknown. SJIA affects about 10% of all children with JIA. SJIA is distinguished from other forms of JIA by features including spiking fevers, rash, swelling and inflammation of lymph nodes, liver, and spleen, and high white blood cell and platelet counts. Arthritis may persist even after the fevers and other symptoms have disappeared. Up to 30% of children will still have active disease after 10 years. Secondary medical complications include amyloidosis, growth failure, osteoporosis, deformities, and loss of function; non-medical complications may include serious developmental and social consequences.

Castleman disease, also known as angiofollicular lymph node hyperplasia, is a rare condition characterized by enlarged lymph nodes (lymphadenopathy). Involvement of a single node is classified as unicentric Castleman disease, a condition with a milder clinical course and substantially better survival outcome than MCD. MCD, by contrast, is characterized by generalized lymphadenopathy and hepatomegaly, fevers, night sweats and, frequently immunosuppression and HHV-8 infection. Both unicentric Castleman disease and MCD are associated with multiple malignancies. Recent U.S. estimates from a review by Fajgenbaum and colleagues (2014) report approximately 1000-1300 Americans have this rare disease; most cases in the U.S. are attributable to HIV or HHV-8. Diagnosis is usually achieved by resection of an affected lymph node and histologic evaluation. Timeliness of diagnosis is hampered by the tendency of clinicians to rule-out other potential causes before exploring the possibility of MCD. Although the etiology of MCD is not well understood, levels of IL-6 and other inflammatory cytokines are consistently elevated with this diagnosis. IL-6 is associated with a wide range of malignancies and autoimmune diseases and uncontrolled proliferation of this inflammatory marker plays a pivotal role in the cascade of symptoms that characterize MCD.

The following are important limitations of use of tocilizumab from thePI Label (Actemra PI, 2014):

Black Boxed Warning: Risk of Serious Infections

The following are Warnings and Precautions from the PI Label (Actemra PI, 2014):

Definitions

Anti-CD20 monoclonal antibody: A class of biologic DMARDs that targets a specific protein, known as CD20 found on the surface of normal and malignant B-lymphocytes. A drug in this class includes rituximab (Rituxan, Genentech, Inc. South San Francisco, CA), a genetically engineered monoclonal antibody.

Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing IL-1ß, Il-12 and/or IL-23, or by directly suppressing lymphocytes. Drugs in this class include the interleukin-1 receptor antagonists (IL-1Ra), interleukin-1 beta (IL-1ß) antagonists, interleukin-6 (IL-6) receptor antagonists, interleukin (IL)-12 and IL-23 antagonists, selective co-stimulation modulators, and the tumor necrosis factor (TNF) antagonists.

Castleman disease: A rare, non-cancerous disorder that affects the lymph nodes and other immune-cell structures throughout the body; Castleman disease has 2 variants: unicentric and multicentric Castleman disease (MCD); and, is also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia.

Disease activity score 28 (DAS28): A measure of disease activity used to monitor the treatment of RA. The score uses a formula that includes the number of tender joints and swollen joints (28 joints maximum).

Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).

Interleukin-1 beta (IL-1ß) antagonist: A class of biologic DMARDs that work by binding human IL-1ß and neutralize its activity by blocking its interaction with IL-1 receptors. A drug in this class includes canakinumab (Ilaris®, Novartis Pharma Stein AG, East Hanover, NJ).

Interleukin-1 receptor antagonist (IL-1Ra): A class of biologic DMARDs that inhibits inflammation and pain by blocking pro-inflammatory interleukin-1 cytokine which plays a role in cell destruction. A drug in this class includes anakinra (Kineret®, Amgen, Thousand Oaks, CA), a recombinant form of human IL-1Ra.

Interleukin-6 (IL-6) receptor antagonist: A class of biologic DMARDs shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation; produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as RA. A drug in this class includes tocilizumab (Actemra).

Nonbiologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown. Drugs in this class include azathioprine, hydroxychloroquine, leflunomide, MTX, minocycline, organic gold compounds, penicillamine, and sulfasalazine.

Selective co-stimulation modulator: A class of biologic DMARDs that inhibits T cell (T lymphocyte) activation; activated T lymphocytes are implicated in the development of RA and are found in the synovium of individuals with RA. A drug in this class includes abatacept (Orencia, Bristol-Myers Squibb Company, Princeton, NJ).

Tumor necrosis factor (TNF) antagonist: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response. Drugs in this class with an FDA-approved indication for the treatment of adults with moderately to severely active RA include adalimumab (Humira®, Abbott Laboratories, North Chicago, IL), certolizumab pegol (Cimzia®, UCB, Inc., Smyrna, GA), etanercept (Enbrel®, Immunex Corporation, Thousand Oaks, CA), golimumab (Simponi® and Simponi Aria®, Janssen  Biotech Inc., Horsham, PA), and infliximab (Remicade®, Janssen  Biotech Inc., Horsham, PA).

Coding

The following codes for treatments and procedures applicable to this document 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 member's 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 
J3262Injection, tocilizumab, 1 mg [Actemra]
  
ICD-10 Diagnosis 
D36.0Benign neoplasm of lymph nodes [specified as MCD]
M05.00-M05.9Rheumatoid arthritis with rheumatoid factor
M06.00-M06.09Rheumatoid arthritis without rheumatoid factor
M06.4Inflammatory polyarthropathy
M06.80-M06.89Other specified rheumatoid arthritis
M06.9Rheumatoid arthritis, unspecified
M08.20-M08.29 Juvenile rheumatoid arthritis with systemic onset
M08.3Juvenile rheumatoid polyarthritis (seronegative)
R59.0-R59.9Enlarged lymph nodes [specified as MCD]

When services are Not Medically Necessary:
When the code describes tocilizumab for the situations indicated in the Position Statement as not medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses including, but not limited to, those listed below; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

ICD-10 Diagnosis 
 All other diagnoses including, but not limited to, the following:
K50.00-K50.919Crohn's disease
M06.1Adult-onset Still's disease
M08.1Juvenile ankylosing spondylitis
M31.4-M31.6Aortic arch syndrome (Takayasu), giant cell arteritis with polymyalgia rheumatic, other giant cell arteritis
M32.0-M32.9Systemic lupus erythematosus
M45.0-M45.9Ankylosing spondylitis
  
References

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  26. Papo M, Bielefeld P, Vallet H, et al. Tocilizumab in severe and refractory non-infectious uveitis. Clin Exp Rheumatol. 2014; 32(4 Suppl 84):S75-S79.
  27. Puéchal X, DeBandt M, Berthelot JM, et al. Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken). 2011; 63(1):155-159.
  28. Salvarani C, Magnani L, Catanoso M, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford). 2012; 51(1):151-156.
  29. Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly. 2011; 141:w13156.
  30. Shima Y, Tomita T, Ishii T, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod Rheumatol. 2011; 21(4):436-439.
  31. Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014; 73(1):95-100.
  32. Smolen JS, Avila JC, Aletaha D. Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction. Ann Rheum Dis. 2012; 71(5):687-693.
  33. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. 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(9617):987-997.
  34. Suematsu R, Ohta A, Matsuura E, et al. Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan. Mod Rheumatol. 2012; 22(5):712-719.
  35. Vaitla PM, Radford PM, Tighe PJ, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011; 63(4):1151-1155.
  36. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012; 71(2):198-205.
  37. 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(9617):998-1006.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Actemra[Product Information], Genentech, Inc., Roche USA, South San Francisco, CA; November 2014. Available at: http://www.gene.com/download/pdf/actemra_prescribing.pdf. Accessed on September 24, 2015.
  2. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on September 24, 2015.
  3. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 24, 2015.
  4. NCCN Clinical Practice Guidelines in Oncology®. © 2015 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 24, 2015.
    • Non-Hodgkin's Lymphomas (V2.2015). March 3, 2015.
  5. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013; 65(10):2499-2512.
  6. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012; 64(5):625-639.
  7. Tocilizumab. In: DrugPoints System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated November 20, 2014. Available at: http://www.micromedexsolutions.com. Accessed on September 24, 2015.
  8. U.S. Food and Drug Administration (FDA). Actemra (Tocilizumab) Injection. Safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER). October 2013 Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm352022.htm. Accessed on September 24, 2015.
Websites for Additional Information
  1. U.S. National Library of Medicine. MedlinePlus. Juvenile rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html. Accessed on September 24, 2015.
  2. U.S. National Library of Medicine. MedlinePlus. Rheumatoid arthritis. Available at: http://www.nlm.nih.gov/medlineplus/rheumatoidarthritis.html. Accessed on September 24, 2015.
Index

QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
T-SPOT.TB Test (T-Spot)

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. 

Document History

Status

Date

Action

Revised11/05/2015Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised11/04/2015Hematology/Oncology Subcommittee review. Revised medically necessary statement, adding off-label use of tocilizumab for the treatment of multicentric Castleman disease when criteria are met. Revised Position Statement, specifying tocilizumab as investigational and not medically necessary for unicentric Castleman disease. Updated Description, Rationale, Background, Definitions, Coding, References, and Websites for Additional information sections. Removed ICD-9 codes from Coding section.
Revised08/06/2015MPTAC review. Clarified medically necessary statements for use of tocilizumab in RA, PJIA, and SJIA for consistency with clinical trial data and structured criteria in similar biologic DMARD documents. Other clarifications to the not medically necessary statement (criterion 4), and the investigational and not medically necessary statement. Updated Rationale, Background, References, and Websites for Additional Information sections.
Revised08/14/2014MPTAC review. Clarified medically necessary statement for tocilizumab for RA without a change to position. Added use of "Janus kinase inhibitors (for example, tofacitinib citrate)" as not medically necessary for use in combination with tocilizumab. Clarified not medically necessary statement to evaluate for latent TB, adding "prior to initiating therapy with tocilizumab." Other format changes and updates to Description, Rationale, Background, Definitions, References, and Websites for Additional Information sections.
Revised08/08/2013MPTAC review. Added medically necessary criteria for FDA approval of tocilizumab for active PJIA and removed PJIA from the investigational and not medically necessary statement. Revised medically necessary criteria for SJIA, removing "may be used alone or in combination with MTX" criterion. Updated Description, Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections.
Revised02/14/2013MPTAC review. Revised medically necessary criterion for use of tocilizumab in adult RA. Clarification to investigational and not medically necessary statement. Updated Rationale, Background, Definitions, References, Websites for Additional Information, and Index sections.
Revised05/10/2012MPTAC review. Revised not medically necessary criterion for specific laboratory testing prior to initiation of tocilizumab. Clarified not medically necessary criteria for evaluating for serious infections and tuberculosis. Added non-FDA approved conditions to the investigational and not medically necessary statement. Updated the Rationale, Definitions, Coding, and References.
Revised05/19/2011MPTAC review. Medically necessary statement added for active systemic juvenile idiopathic arthritis (SJIA). Medically necessary and not medically necessary statements reformatted. Investigational and not medically necessary statement updated with additional conditions. Updated Description, Rationale, Background, Definitions, Coding, References, Websites for Additional Information, and Index sections.
 01/01/2011Updated Coding section with 01/01/2011 HCPCS changes; removed C9264 deleted 12/31/2010.
 07/01/2010Updated Coding section with 07/01/2010 HCPCS changes.
New05/13/2010MPTAC review. Initial document development.