|Policy #:||DRUG.00043||Current Effective Date:||10/06/2015|
|Status:||Revised||Last Review Date:||08/06/2015|
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), 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:
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:
Tocilizumab is considered medically necessary for the treatment of an individual with active PJIA when all of the following criteria are met:
Tocilizumab is considered medically necessary for the treatment of an individual with active SJIA when all of the following criteria are met:
Not Medically Necessary:
Tocilizumab is considered not medically necessary for an individual with any of the following:
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:
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 one 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 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), Castleman's disease (Nishimoto, 2005), Crohn's disease (CD) (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), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Vaitla, 2011). At this time, the FDA has not approved the use of tocilizumab for the treatment of any of these conditions.
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.
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):
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.
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 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-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-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).
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:
|J3262||Injection, tocilizumab, 1 mg [Actemra]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
|M05.00-M05.9||Rheumatoid arthritis with rheumatoid factor|
|M06.00-M06.09||Rheumatoid arthritis without rheumatoid factor|
|M06.80-M06.89||Other specified rheumatoid arthritis|
|M06.9||Rheumatoid arthritis, unspecified|
|M08.20-M08.29||Juvenile rheumatoid arthritis with systemic onset|
|M08.3||Juvenile rheumatoid polyarthritis (seronegative)|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|714.0-714.1||Rheumatoid arthritis, Felty's syndrome|
|714.2||Other rheumatoid arthritis with visceral or systemic involvement [excluding adult-onset Still's disease]|
|714.30-714.31||Polyarticular juvenile rheumatoid arthritis|
|714.4-714.9||Chronic postrheumatic arthropathy, other and unspecified inflammatory polyarthropathies|
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||[For dates of service on or after 10/01/2015]|
|All other diagnoses including, but not limited to, the following:|
|M06.1||Adult-onset Still's disease|
|M08.1||Juvenile ankylosing spondylitis|
|M31.4-M31.6||Aortic arch syndrome (Takayasu), giant cell arteritis with polymyalgia rheumatic, other giant cell arteritis|
|M32.0-M32.9||Systemic lupus erythematosus|
|R59.0-R59.9||Enlarged lymph nodes|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|All other diagnoses including, but not limited to, the following:|
|446.5||Giant cell arteritis|
|555.0-555.9||Regional enteritis (Crohn's disease)|
|710.0||Systemic lupus erythematosus|
|785.6||Enlargement of lymph nodes [Castleman's disease]|
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
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.
|Revised||08/06/2015||Medical Policy & Technology Assessment Committee (MPTAC) 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.|
|Revised||08/14/2014||MPTAC 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.|
|Revised||08/08/2013||MPTAC 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.|
|Revised||02/14/2013||MPTAC 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.|
|Revised||05/10/2012||MPTAC 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.|
|Revised||05/19/2011||MPTAC 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.|
|01/01/2011||Updated Coding section with 01/01/2011 HCPCS changes; removed C9264 deleted 12/31/2010.|
|07/01/2010||Updated Coding section with 07/01/2010 HCPCS changes.|
|New||05/13/2010||MPTAC review. Initial document development.|