Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Tocilizumab (Actemra®) for Intravenous Infusion

Policy #:08.00.85g

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

Tocilizumab (Actemra®) for intravenous infusion is considered medically necessary and, therefore, covered for the following indications when, for each individual indication, all of the associated criteria are met:

Moderately to severely active rheumatoid arthritis
  • In individuals 18 years of age or older
  • Active or latent tuberculosis (TB) has been ruled out
  • When used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs)
  • There is documentation of inadequate response, intolerance, or contraindication to a 3-month trial of one or more DMARDs
  • For individuals who have not previously received a biologic DMARD to treat adult rheumatoid arthritis, tocilizumab (Actemra®) for intravenous infusion is only eligible for coverage when the individual has a documented failure, contraindication, or intolerance to infliximab (Remicade®) or golimumab (Simponi Aria®), or there is a clinical reason that a trial of infliximab (Remicade®) or golimumab (Simponi Aria®) would be otherwise inappropriate for the individual.

Active systemic juvenile idiopathic arthritis (Still's disease)
  • In individuals 2 years of age or older
  • Active or latent tuberculosis (TB) has been ruled out
  • When used alone or in combination with methotrexate
  • There is documentation of inadequate response, intolerance, or contraindication to nonsteroidal anti-inflammatory drugs (NSAIDS) and/or corticosteroids.

Active polyarticular juvenile idiopathic arthritis (PJIA)
  • In individuals 2 years of age or older
  • Active or latent tuberculosis (TB) has been ruled out
  • When used alone or in combination with methotrexate

Cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR) T cell therapy (e.g., tisagenlecleucel [Kymriah], axicabtagene ciloleucel [Yescarta])
  • In individuals 2 years of age or older
  • Severe or life-threatening cytokine release syndrome (CRS), per The National Cancer Institute Common Terminology criteria for adverse events (CTCAE v4.0) Grading System. Symptoms may include: hemodynamic instability despite intravenous fluids and vasopressor support; rapid clinical deterioration; worsening of respiratory distress, including pulmonary infiltrates, increasing oxygen requirements including high oxygen flow and/or need for mechanical ventilation.
  • Active or latent tuberculosis (TB) has been ruled out

EXPERIMENTAL/INVESTIGATIONAL

All other uses for tocilizumab (Actemra®) for intravenous infusion are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, tocilizumab (Actemra®) for intravenous infusion is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

CONSIDERATION FOR ADMINISTRATION

Tocilizumab (Actemra®) for intravenous infusion has not been studied, and its use should be avoided in combination with biological disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies, and selective co-stimulation modulators, due to the increased possibility of immunosuppression and increased risk of infection.

THE NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE v4.0) GRADING SYSTEM


*In, Lee, DW, Gardner R. Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on January 8, 2010, for treatment of adults with moderately to severely active rheumatoid arthritis, after at least one TNF antagonist has been tried and failed. On October 11, 2012, based on the safety and efficacy outcomes from further Phase III and post-marketing studies, the FDA expanded the approval for the treatment of adult individuals with moderately to severely active RA who have had an inadequate response to one or more DMARDs.

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on April 15, 2011, for treatment of individuals ages 2 and older with active systemic juvenile idiopathic arthritis, also known as Still's disease.

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on April 29, 2013, for the treatment of individuals ages 2 and older with active polyarticular juvenile idiopathic arthritis (PJIA).

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on August 30, 2017, for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.

Description

Tocilizumab (Actemra®) for intravenous infusion, a humanized monoclonal antibody, inhibits the interleukin-6 receptor that binds specifically to both the soluble and membrane-bound interleukin-6 receptors, thereby blocking the inflammatory response.

ACTIVE RHEUMATOID ARTHRITIS

Tocilizumab (Actemra®) for intravenous infusion was approved by the US Food and Drug Administration (FDA) on January 8, 2010, for the treatment of adult individuals with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. In phase II and phase III clinical trials, tocilizumab (Actemra®), when used in combination with methotrexate or alone, has been shown to be effective in reducing the signs and symptoms of RA in individuals who had an inadequate response to TNF antagonists.

On October 11, 2012, based on the safety and efficacy outcomes from further Phase III and post-marketing studies, the FDA expanded the approval for the treatment of adult individuals with moderately to severely active RA who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). These studies showed a statistically significant greater percentage of individuals achieving ACR20 at Week 24 with the use of tocilizumab (Actemra®) for intravenous infusion plus a DMARD when compared to the placebo plus a DMARD.

RA is a chronic inflammatory autoimmune disorder that involves inflammation of the synovial joints and can result in erosion of cartilage and bone. The American College of Rheumatology's guidelines for the treatment of RA recommend that newly diagnosed individuals with RA begin treatment with DMARDs. DMARDs act to slow down disease progression, and some act with mild chemotherapeutic action, causing immunosuppression.

Furthermore, DMARDs can be subdivided into the traditional small-molecular-mass, chemically synthesized non-biologic DMARDs (such as, but not limited to, methotrexate, sulfasalazine, azathioprine, leflunomide, hydroxychloroquine sulfate, and cyclosporine) and the newer biologic DMARDs. Examples of biologic DMARDs include, but are not limited to, etanercept (Enbrel®), adalimumab (Humira®), anakinra (Kineret®), abatacept (Orencia®), rituximab (Rituxan®), and infliximab (Remicade®).

Tocilizumab (Actemra®) for intravenous infusion is administered by intravenous infusion in adults once every 4 weeks over 60 minutes.

SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on April 15, 2011, for the treatment of individuals ages 2 years and older with active systemic juvenile idiopathic arthritis (SJIA), also known as Still's disease. SJIA is a rare, potentially life-threatening disease in children that causes severe inflammation throughout the body. The occurrence of fever spikes; rash; swelling and inflammation of the lymph nodes, liver, and spleen; and high white blood cell and platelet counts differentiate SJIA from other juvenile idiopathic forms of arthritis. The prevalence of juvenile idiopathic arthritis is estimated to be 1 to 2 per 1,000 children, and SJIA affects about 10 percent of all juvenile idiopathic arthritis patients.

Tocilizumab (Actemra®) for intravenous infusion was used in an international, multi-center controlled trial of 112 individuals with SJIA, ages 2 to 17 years of age, who had inadequate clinical response to nonsteriodal anti-inflammatory drugs or corticosteroids due to toxicity or lack of efficacy. Eighty-five percent of those who received tocilizumab (Actemra®) for intravenous infusion responded to treatment, compared to 24 percent of individuals who received the placebo. Response was defined as at least a 30 percent improvement in the American College of Rheumatology's juvenile idiopathic arthritis efficacy variables, as well as the absence of fever in the preceding 7 days. However, among those who received tocilizumab (Actemra®), there were three cases of macrophage-activation syndrome, a potentially fatal complication of childhood systemic inflammatory disorders.

Tocilizumab (Actemra®) for intravenous infusion is administered by intravenous infusion in individuals 2 years of age and older once every 2 weeks over 60 minutes, and may be administered alone or in combination with methotrexate.

POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on April 29, 2013 for the treatment of individuals ages 2 years and older with active polyarticular juvenile idiopathic arthritis (PJIA). PJIA is a subset of juvenile idiopathic arthritis (JIA) and comprises 20 to 30 percent of all patients with JIA. The diagnosis of PJIA is made when five or more joints are affected in the first 6 months after disease onset. Management of PJIA may include medications such as corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), and may further require DMARDs, including immunomodulators or biologic agents.

Tocilizumab (Actemra®) for intravenous infusion was investigated in a three-part trial of 188 individuals with active PJIA, ages 2 to 17 years of age, who had inadequate clinical response to methotrexate or were intolerant to methotrexate. Part I was a 16-week, open-label trial of tocilizumab (Actemra®), followed by Part II, which was a 24-week randomized double-blind placebo-controlled withdrawal period. Finally, Part III was a 64-week open-label extension.

In Part I, response to treatment was defined as at least a 30 percent improvement in the American College of Rheumatology's (ACR) juvenile idiopathic arthritis efficacy variables. After 16 weeks of therapy, 91% and 83% of patients, respectively, achieved an ACR 30 response compared to baseline, while receiving concomitant methotrexate or on tocilizumab (Actemra®) for intravenous infusion monotherapy. ACR 50/70 responses were 84% and 64%, respectively, for patients receiving concomitant methotrexate, and 80% and 55%, respectively, for patients on tocilizumab (Actemra®) for intravenous infusion monotherapy.

Those who achieved an ACR 30 response (n=163) entered Part II of the study, where patients were randomized to tocilizumab (Actemra®) for intravenous infusion or placebo (1:1 ratio). The results of this study reported that those receiving tocilizumab (Actemra®) for intravenous infusion experienced significantly fewer disease flares compared to placebo-treated patients (26% versus 48%). Also, more patients treated with tocilizumab (Actemra®) for intravenous infusion showed ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.

Tocilizumab (Actemra®) for intravenous infusion is administered by intravenous infusion in individuals 2 years of age and older once every 4 weeks over 60 minutes, and may be administered alone or in combination with methotrexate.

CYTOKINE RELEASE SYNDROME (CRS)

Cytokine release syndrome (CRS) occurs when immune-based chemotherapy or introduction of immune cells, such as chimeric antigen receptor (CAR) T cells, cause an abnormally large activation of the cells involved in the immune system (e.g., lymphoctyes or myeloid cells) which then release inflammatory cytokines. Symptoms of CRS may develop within minutes, hours, or days after the infusion. Symptoms range from mild to severe or life-threatening and may include fever, hypotension, mental status changes, tachycardia; worsening of respiratory distress, including pulmonary infiltrates, increasing oxygen requirements, or need for mechanical ventilation; organ toxicity; and seizures. The severity of CRS is defined in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0) grading system, where a score of one is non-life threatening (e.g., fever, nausea) and a score of five is death.

Tocilizumab (Actemra®) for intravenous infusion was approved by the FDA on August 30, 2017 for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening CRS in adults and pediatric patients 2 years of age and older.

The efficacy of tocilizumab (Actemra®) for severe or life-threatening CRS was reviewed in a retrospective analysis of pooled outcome data from clinical trials of CAR T cell therapies for hematological malignancies. Forty-five patients received tocilizumab (Actemra®) 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids. The analysis only reviewed the first episode of CRS in each patient. The median time from start of CRS to first dose of tocilizumab was 4 days (range, 0–18 days). Resolution of CRS was defined as lack of fever and off vasopressors for at least 24 hours. Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, no more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment. The results of this review concluded that 31 patients (69%) achieved a clinical response to the first CRS episode.

Tocilizumab (Actemra®) for intravenous infusion is administered by intravenous infusion in individuals 2 years of age and older over 60 minutes. A maximum dose of 800 mg per infusion is recommended. A maximum of four doses administered at least eight hours apart may be prescribed, if necessary. Tocilizumab (Actemra®) for intravenous infusion may be administered alone or in combination with corticosteroids.

SAFETY

Tocilizumab (Actemra®) for intravenous infusion should be interrupted if an individual develops a serious infection or an opportunistic infection or sepsis, until the infection is controlled. Other safety concerns that require monitoring during tocilizumab (Actemra®) for intravenous infusion therapy are elevated liver enzymes, elevated low-density lipoproteins or bad cholesterol, hypertension, and gastrointestinal perforations.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


American Hospital Formulary Service (AHFS). Drug Information 2017. Tocilizumab (Actemra®). [Lexicomp Online Web site]. Last modified: 12/11/2015. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed September 19, 2017.

Beukelman T, Patkar N, Saag K. 2011 American College of Rheumatology Recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63(4):465-482.

Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course Juvenile Idiopathic Arthritis: data from a Phase 3 trial. Presented at the American College of Rheumatology Annual Scientific Meeting in Washington, D.C.; November 9-14, 2012. ACR Oral presentation; ACR Abstract #1597.

DeBenedetti, Fabrizio, Brunner, et al. Tocilizumab in patients with systemic juvenile idiopathic arthritis: efficacy data from the placebo-controlled 12-week part of the phase 3 TENDER trial [abstract]. Arthritis Rheum. 2010;62(Suppl 10):1434.

Elsevier’s Clinical Pharmacology Compendium. Tocilizumab (Actemra®). 09/05/17. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed September 19, 2017.

Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968-80.

Kremer JL, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at 1 year: The LITHE study. Arthritis Rheum. 2010; Epub.

Larsen RA. Treatment of relapsed or refractory acute lymphoblastic leukemia in adults. [UpToDate Web site]. 09/08/17. Available at: https://www.uptodate.com/contents/treatment-of-relapsed-or-refractory-acute-lymphoblastic-leukemia-in-adults?source=search_result&search=cytokine%20release%20syndrome&selectedTitle=5~119 [via subscription only]. Accessed September 20, 2017.

Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95.

Lexi-Drugs Compendium. Tocilizumab (Actemra®). 09/18/17. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed September 19, 2017.

Kimura Y. Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis. UpToDate. 04/27/2016. Available at: https://www.uptodate.com/contents/systemic-juvenile-idiopathic-arthritis-clinical-manifestations-and-diagnosis?source=search_result&search=Systemic%20juvenile%20idiopathic%20arthritis&selectedTitle=2~150 [via subscription only] . Accessed September 19, 2017.

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):2499-512.

Schoels MM, van der Heijde D, Breedveld FC, et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis. 2013; 72(4): 583–589.

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):625-39.

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. Review.

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):987-9.

Tocilizumab (Actemra®). Genentech Inc. Prescribing Information. 08/2017. Available at: http://www.gene.com/gene/products/information/actemra/pdf/pi.pdf . Accessed September 19, 2017.

Truven Health Analytics. Micromedex® DrugDex® Compendium. DrugDex®. Tocilizumab (Actemra®). [Micromedex® Solutions Web site]. 09/08/17. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed September 19, 2017.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Kymriah (tisagenlecleucel) Product Labeling. [FDA Web site]. 10/18/2017. Available at: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm . Accessed October 23, 2017.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Tocilizumab (Actemra®) Product Labeling. [FDA Web site]. Last modified: 08/30/2017. Available at:
https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed September 19, 2017.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Yescarta (axicabtagene ciloleucel) Product Labeling. [FDA Web site]. 08/30/2017. Available at: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581222.htm. Accessed October 23, 2017.

Weiss PF. Polyarticular juvenile idiopathic arthritis: Treatment. UpToDate. 12/09/2015. Available at: https://www.uptodate.com/contents/polyarticular-juvenile-idiopathic-arthritis-treatment [via subscription only]. Accessed September 19, 2017.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

See Attachment A for ICD-10 Codes and Narratives


HCPCS Level II Code Number(s)

J3262 Injection, Tocilizumab, 1mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References

Attachment A: Tocilizumab (Actemra®) for Intravenous Infusion
Description: ICD-10 CODES AND NARRATIVES




Policy History

08.00.85g
12/19/2018This policy has been reissued in accordance with the Company's annual review process.
11/15/2017This policy has been updated to communicate the Company's coverage criteria for tocilizumab (Actemra®) for the treatment of cytokine release syndrome (CRS).


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 11/15/2017
Version Issued Date: 11/15/2017
Version Reissued Date: 12/19/2018

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