Clinical UM Guideline

 

Subject: Tocilizumab (Actemra®)
Guideline #: CG-DRUG-81 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

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 or giant cell arteritis, children 2 years of age and older with active polyarticular juvenile arthritis or active systemic juvenile idiopathic arthritis, multicentric Castleman disease, chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome, and for other conditions.

Note: Please see the following related documents for additional information:

Note: For additional information on review of clinically equivalent cost effective criteria for the product addressed in CG-DRUG-81, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Clinical Indications

Medically Necessary:

  1. Giant Cell Arteritis
    Tocilizumab is considered medically necessary for the treatment of an individual with giant cell arteritis when the following criteria are met:
    1. Individual is 18 years of age or older; and
    2. Agent is used in combination with a tapering course of corticosteroids (such as, prednisone); or
    3. Agent is used as a single agent following discontinuation of corticosteroids.
  2. Rheumatoid Arthritis
    Tocilizumab is considered medically necessary for the treatment of an individual with moderately to severely active rheumatoid arthritis 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 one or more disease modifying anti-rheumatic drugs (for example, methotrexate) or a tumor necrosis factor antagonist drug; and
    4. May be used alone or in combination with methotrexate or with other nonbiologic disease modifying anti-rheumatic drugs.
  3. Polyarticular Juvenile Arthritis
    Tocilizumab is considered medically necessary for the treatment of an individual with active polyarticular juvenile arthritis 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 one or more nonbiologic disease modifying anti-rheumatic (such as methotrexate).
  4. Systemic Juvenile Arthritis
    Tocilizumab is considered medically necessary for the treatment of an individual with active systemic juvenile idiopathic arthritis 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 one or more corticosteroids or nonsteroidal anti-inflammatory drugs.
  5. Multicentric Castleman Disease
    Tocilizumab is considered medically necessary as subsequent therapy for the treatment of an individual with relapsed/refractory or progressive multicentric Castleman disease when all of the following criteria are met:
    1. Used as a single agent; and
    2. Human immunodeficiency virus negative; and
    3. Human herpes-8 negative; and
    4. No concurrent clinically significant infection (for example, Hepatitis B or C); and
    5. No concurrent lymphoma.
  6. Cytokine Release Syndrome
    Tocilizumab is considered medically necessary for the treatment of an individual 2 years of age or older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.

Not Medically Necessary:

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

  1. In combination with other biologic disease modifying anti-rheumatic drugs such as anti-CD20 monoclonal antibodies, IL-1R antagonists, Janus kinase inhibitors (for example, tofacitinib citrate), selective co-stimulation modulators, or tumor necrosis factor antagonists; or
  2. At initiation of therapy, absolute neutrophil count less than 2000/mm3, platelet count less than 100,000/mm3, or alanine aminotransferase or aspartate aminotransferase greater than 1.5 times the upper limit of normal; 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 or Centers for Disease Control and Prevention-recommended equivalent to evaluate for latent tuberculosis prior to initiating tocilizumab (in the setting of non-emergent use only).

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

  1. Adult onset Still’s disease; or
  2. Ankylosing spondylitis; or
  3. Crohn’s disease; or
  4. Takayasu’s arteritis; or
  5. Systemic lupus erythematosus; or
  6. Tumor necrosis factor receptor-associated periodic syndrome; or
  7. Unicentric Castleman disease.
Coding

The following codes for treatments and procedures applicable to this guideline 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.

HCPCS

 

J3262

Injection, tocilizumab, 1 mg [Actemra]

 

 

ICD-10 Diagnosis

 

C90.00-C95.92

Leukemias

D47.Z2

Castleman disease

M05.00-M05.9

Rheumatoid arthritis with rheumatoid factor

M06.00-M06.09

Rheumatoid arthritis without rheumatoid factor

M06.4

Inflammatory polyarthropathy

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)

M31.5

Giant cell arteritis with polymyalgia rheumatica

M31.6

Other giant cell arteritis

R65.10-R65.11

Systemic inflammatory response syndrome (SIRS) of non-infectious origin [cytokine release syndrome]

T45.1X5A-T45.1X5S

Adverse effect of antineoplastic and immunosuppressive drugs

Discussion/General Information

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody in a class of drugs called biologic disease modifying anti-rheumatic drugs (DMARDs). Tocilizumab binds and inhibits both soluble and membrane bound IL-6 found in inflamed joints.

Tocilizumab for Giant Cell Arteritis

Tocilizumab has received U.S. Food and Drug Administration (FDA) approval for the treatment of giant cell arteritis in adults. The efficacy and safety of subcutaneously administered tocilizumab was assessed in a multicenter, randomized, double-blind, placebo-controlled, phase III parallel-group study of 250 individuals ages 50 and older with a confirmed diagnosis of new-onset, active, or refractory disease (that is, diagnosis of giant cell arteritis greater than 6 weeks before baseline and previous treatment with ≥ 40 milligrams per day prednisone [or equivalent] for at least 2 consecutive weeks at any time) (Stone, 2017). The study consisted of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2). The primary efficacy endpoint was the proportion of participants in sustained remission at week 52 (tocilizumab plus 26 weeks prednisone taper vs. placebo plus 26 weeks prednisone taper). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to week 52, and normalization of C-reactive protein (CRP) (to < 1 milligram per deciliter [mg/dL]). Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of giant cell arteritis and/or erythrocyte sedimentation rate (ESR) ≥ 30 millimeters per hour (mm/hr) attributable to giant cell arteritis. A single CRP elevation (≥ 1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (≥ 1 mg/dL) at the next study visit. Participants not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis (NCT01791153). A greater proportion of participants in the tocilizumab groups administered at 162 mg weekly (responders, n=56 [56%]) and 162 mg every other week (responders, n=26 [53%]) plus 26 weeks prednisone taper achieved sustained remission (that is, meeting all of the following components: absence of giant cell arteritis signs and symptoms, normalization of ESR, normalization of CRP, and adherence to the prednisone tapering regimen) from week 12 through week 52 compared with the placebo plus 26 weeks prednisone taper group (responders, n=7 [14.0%]). Both tocilizumab treatment arms also demonstrated sustained remission compared with the placebo plus 52 weeks prednisone taper group (responders, n=9 [17.6%]). The cumulative prednisone dose was lower in tocilizumab-treated participants relative to placebo.

The overall safety profile observed in the tocilizumab treatment groups was consistent with the known safety profile of the drug; however, there was an overall higher incidence of infections in the study participants compared with other individuals with rheumatoid arthritis. The rate of adverse events was 200.2/9.7 events per 100 patient years for infection/serious infection in the tocilizumab weekly group and 160.2/4.4 events per 100 patient years in the tocilizumab every other week group compared to 156.0/42 events per 100 patient years in the placebo plus 26 week prednisone taper group and 210.2/12.5 events per 100 patient years in the placebo plus 52 week taper groups. 

Tocilizumab for Rheumatoid Arthritis

Tocilizumab has received FDA approval for the treatment of moderately to severely active rheumatoid arthritis in individuals who have had an inadequate response to one or more DMARDs. Tocilizumab may be used as monotherapy or concomitantly with methotrexate (MTX) or other nonbiologic DMARDs. The efficacy and safety of tocilizumab was validated in multiple randomized, double-blind, multicenter studies in adults with moderately to severely active rheumatoid arthritis 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 rheumatoid arthritis who had previously experienced DMARD failures, MTX failures, or tumor necrosis factor antagonist (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.

Tocilizumab for Treatment-Naive Rheumatoid Arthritis

Bijlsma and colleagues (2016) reported outcomes from a 2-year, multicenter, randomized, double-blind, double-dummy clinical trial (U-Act-Early) conducted at 21 rheumatology outpatient departments in the Netherlands that compared the efficacy and safety of tocilizumab with or without MTX versus initiation of MTX monotherapy in individuals with treatment-naive rheumatoid arthritis. Study participants (n=317) were diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2.6. Participants were randomly assigned (1:1:1) to tocilizumab plus MTX (n=106, the tocilizumab plus MTX arm), or tocilizumab plus placebo-MTX (n=103, the tocilizumab arm), or MTX plus placebo-tocilizumab (n=108, the MTX arm). Tocilizumab was administered at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. MTX was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. Participants not achieving remission on their initial regimen switched from placebo to active treatments; participants in the tocilizumab plus MTX arm switched to standard of care therapy (typically MTX combined with a TNF antagonist). When sustained remission was achieved, MTX (and placebo-MTX) was tapered and stopped, and then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of participants achieving sustained remission (defined as DAS28 < 2.6 with a swollen joint count ≤ 4, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups. Analysis was based on an intention-to-treat (ITT), with a similar proportion of participants in the three groups (range, 72%-78%). The most frequent reasons for study dropouts were adverse events or intercurrent illness (27 participants, 34%) and insufficient response (26 participants, 33%). A total of 91 of 106 (86%) participants in the tocilizumab plus MTX arm achieved sustained remission on the initial regimen compared with 86 of 103 (84%) participants in the tocilizumab arm, and 48 of 108 (44%) participants in the MTX arm (95% confidence interval [CI] 1.59-2.51 for tocilizumab plus MTX vs. MTX; 95% CI 1.48-2.32 for tocilizumab vs. MTX; p<0.0001 for both comparisons). For the entire study, 91 of 106 (86%) participants in the tocilizumab plus MTX arm, 91 of 103 (88%) in the tocilizumab arm, and 83 of 108 (77%) in the MTX arm achieved sustained remission (95% CI 1.00-1.29 for all groups: tocilizumab plus MTX vs. MTX [p=0.06]; tocilizumab vs. MTX [p=0.0356]; and, tocilizumab plus MTX vs. tocilizumab [p=0.59]). Post hoc endpoints were the proportion of participants achieving sustained drug-free remission and the first drug-free remission, with both outcomes reported as significantly higher in the tocilizumab-treated arms compared with the MTX arm; however, no between-group differences were reported in the duration of sustained drug-free remission, time to onset of sustained drug-free remission, and for flare and remission after restart of medication. The most common adverse event in all three treatment groups was nasopharyngitis, occurring in 38 of 106 (36%) participants in the tocilizumab plus MTX arm, 40 of 103 (39%) in the tocilizumab arm, and 37 of 108 (34%) in the MTX arm. The occurrence of serious adverse events did not differ between the treatment groups and no deaths occurred during the study. Limitations of this study are inclusion of a predominately Dutch, Caucasian population and short duration of symptoms that may not be generalized to other early rheumatoid arthritis populations. At this time, the FDA has not approved the use of tocilizumab for the treatment of moderately to severely active rheumatoid arthritis in individuals with no prior treatment failure.

Other Considerations

In 2015, the ACR updated treatment recommendations for rheumatoid arthritis (Singh, 2015) including guidance on DMARDS, biologic agents (including tocilizumab), tofacitinib, and glucocorticoids in established and early rheumatoid arthritis. Recommendations were issued on using a “treat-to-target approach,” discontinuing and tapering medications, and the use of DMARDS and biologic agents for individuals with high-risk comorbidities such as serious infections, hepatitis, congestive heart failure, and malignancy. The ACR stated that their “treatment recommendations apply to common clinical situations, since the panel considered issues common to most patients, not exceptions.” Concerning the potential use of tocilizumab (a non-TNF biologic) for early disease (defined as < 6 months, disease activity moderate or high despite monotherapy with a DMARD), the ACR recommends use of combination DMARDs or use of a TNF inhibitor (antagonist) or a non-TNF inhibitor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: low). For established disease (defined as > 6 months), if the disease activity remains moderate or high despite monotherapy with a DMARD, the recommendation is to use combination traditional DMARDs or add a TNF inhibitor or a non-TNF inhibitor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: moderate to very low).  For individuals with high-risk comorbid conditions with established rheumatoid arthritis with moderate or high disease activity and a history of a previously treated lymphoproliferative disorder, the ACR conditionally recommends using combination DMARD therapy, abatacept or tocilizumab rather than a TNF inhibitor.

Tocilizumab for Polyarticular Juvenile Idiopathic Arthritis

Tocilizumab has received FDA approval for the treatment of active polyarticular juvenile idiopathic arthritis 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; Brunner 2015) that demonstrated clinically meaningful improvement in the signs and symptoms of polyarticular juvenile idiopathic arthritis with tocilizumab therapy. Participants in the 3-part study were 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis 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 one-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 ACR30 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 systemic juvenile idiopathic arthritis (De Benedetti, 2012) and rheumatoid arthritis. 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

Tocilizumab has received FDA approval for the treatment of active systemic juvenile idiopathic arthritis 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 systemic juvenile idiopathic arthritis 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 nonsteroidal anti-inflammatory drugs (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 PI label, 2017).

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 systemic juvenile idiopathic arthritis-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).

Tocilizumab for Cytokine Release Syndrome

Tocilizumab (intravenous) has received FDA approval for the treatment of an individual 2 years of age or older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS). In a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematological malignancies, 45 adults and pediatric-aged participants of median age 12 years (range, 3-23 years) (n=25 children [2 to 12 years]; n=17 adolescents [12 to 18 years]) received tocilizumab 8 mg/kg (12 mg/kg for participants less than 30 kg) with or without additional high-dose corticosteroids for the first episode of severe or life-threatening CAR T-cell-induced CRS. A median of one dose of tocilizumab (range, one to four doses) was administered. Participants were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, no more than two doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment. Treatment resulted in a clinical response to the first CRS episode in 69% of participants (95% CI, 53% to 82%). A confirmed resolution of CRS within 14 days (that is, lack of fever and off vasopressors for at least 24 hours) occurred in 15 participants (range, 9 to 75 years) in a second study. No adverse reactions related to tocilizumab were reported (Actemra PI label, 2017).

Off-FDA Label Use of Tocilizumab for Castleman Disease

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 multicentric Castleman disease.

The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline (CPG) in Oncology (NCCN Guidelines®, 2017) for B-cell lymphomas (V3.2017) recommends off-label use of tocilizumab for Castleman disease. For multicentric Castleman disease, 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 evaluating the efficacy and safety of tocilizumab to treat multicentric Castleman disease 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 multicentric Castleman disease (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 multicentric Castleman disease (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, hemoglobin, serum albumin, 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 B-cell lymphomas (V3.2017) 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, the FDA has not approved tocilizumab for use in the treatment of unicentric Castleman disease.

Other Off-FDA Label Use of Tocilizumab

Several phase I and II studies and case series have evaluated the use of tocilizumab in the treatment of AA amyloidosis and chronic inflammatory disorders (Lane, 2016), adult onset Still’s disease (Ortiz-Sanjuan, 2014; Puechal,2011; Suematsu, 2011), ankylosing spondylitis (Shima, 2011; Sieper, 2013),Crohn’s disease (Ito, 2004), graft versus host disease (Drobyski, 2011; Kennedy, 2014), Takayasu’s arteritis (Beyer, 2011; Loricera, 2014; Salvarani, 2012; Seitz, 2011), non-infectious uveitis (Papo, 2014); polymyositis (Narazaki, 2011), recurrent epithelial ovarian cancer (in combination with carboplatin/doxorubicin) (Dijkgraaf, 2015), relapsing polychondritis, schizophrenia (Miller, 2016), systemic lupus erythematosus (Illei, 2010), systemic sclerosis (Khanna, 2016), tumor necrosis factor receptor-associated periodic syndrome (Vaitla, 2011). To date, the FDA has not approved the use of tocilizumab for the treatment of any of these conditions.

FDA Boxed Warnings and Product Information (PI) for Tocilizumab

Black Box Warning: Risk of Serious Infections

The following are important limitations of use of tocilizumab (Actemra PI, 2017):

Additional precautions and warnings, drug interactions, contraindications of use, and screening recommendations are available on the current PI label for tocilizumab (Actemra PI, 2017).

Definitions

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-Ra, IL-1ß, IL-6, IL-12, IL-17A, 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 rheumatoid arthritis. 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).

Nonbiologic 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.

References

Peer Reviewed Publications:

  1. Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis. 2011; 70(10):1874-1875.
  2. Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016; 388(10042):343-355.
  3. Brunner H, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: 2-year data from CHERISH. Arthritis Rheumatol. 2014; 66 (Suppl 11):S5-S6.
  4. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015; 74(6):1110-1117.
  5. De Benedetti F, Brunner HI, Ruperto N, et al. Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: results from a phase III trial. Arthritis Rheumatol. 2015; 67(3):840-848.
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  7. Dijkgraaf EM, Santegoets SJ, Reyners AK, et al. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-α2b in patients with recurrent epithelial ovarian cancer. Ann Oncol. 2015; 26(10):2141-2149.
  8. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant. 2011; 17(12):1862-1868.
  9. 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(11):1516-1523.
  10. Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004; 50(5):1412–1419.
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  13. Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010; 62(2):542-552.
  14. 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(4):989-996; discussion 947.
  15. 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(1):88-96.
  16. Kawabata H, Kadowaki N, Nishikori M, et al. Clinical features and treatment of multicentric Castleman's disease: a retrospective study of 21 Japanese patients at a single institute. J Clin Exp Hematop. 2013; 53(1):69-77.
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  18. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016; 387(10038):2630-2640.
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  20. Lane T, Gillmore JD, Wechalekar AD, et al. Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature. Clin Exp Rheumatol. 2015; 33(6 Suppl 94):S46-S53.
  21. Loricera J, Blanco R, Castaneda S, et al. Tocilizumab in refractory aortitis: study on 16 patients and literature review. Clin Exp Rheumatol. 2014; 32(3 Suppl 82):S79-S89.
  22. Loricera J, Blanco R, Hernández JL, et al. Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015; 44(6):717-723.
  23. Maini RN, Taylor PC, Szechinski J, et al. 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(9):2817-2829.
  24. Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease. Intern Med. 2007; 46(11):771-774.
  25. Miller BJ, Dias JK, Lemos HP, Buckley PF. An open-label, pilot trial of adjunctive tocilizumab in schizophrenia. J Clin Psychiatry. 2016; 77(2):275-276.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Actemra [Product Information], Genentech, Inc., Roche USA, South San Francisco, CA; August 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125276s114lbl.pdf. Accessed on September 8, 2017.
  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 8, 2017.
  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 8, 2017.
  4. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 8, 2017.
    • B-cell Lymphomas (V3.2017). March 27, 2017.
  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, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016; 68(1):1-26.
  7. Tocilizumab. In: DrugPoints System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated September 8, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 8, 2017.
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. 

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

11/01/2017

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00043 Tocilizumab (Actemra®) to new clinical utilization management guideline document with the same title. Clarified NMN statement for latent tuberculosis testing, adding “(in the setting of non-emergent use only).”