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 four 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 or methotrexate 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 two years of age and older once every two 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 two 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), or 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 two years of age and older once every four 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 v5.0) 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 two 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 four 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 two 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 two 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.
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.
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.
THE FOLLOWING MODIFIER IS USED WHEN REPORTING
Tocilizumab (Actemra®) for Intravenous Infusion
JA Intravenous administration
Policy: MA08.010j:Programmed Death Receptor-1 (PD-1) Antagonists (e.g., Keytruda®, Opdivo®) and Programmed Death-Ligand 1 (PD-L1) Antagonists (e.g., Tecentriq®, Bavencio®, Imfinzi™)
Policy: MA08.012c:Off-label Coverage for Prescription Drugs and/or Biologics
Policy: MA08.019g:Infliximab and Related Biosimilars
Policy: MA08.022j:Rituximab (Rituxan®) Infusion and Related Biosimilars, and Rituximab/Hyaluronidase Human for Subcutaneous Injection (Rituxan Hycela®)
Policy: MA08.028d:Abatacept (Orencia®) for Injection for Intravenous Use
Policy: MA08.059f:Ipilimumab (Yervoy®)
Policy: MA08.070c:Golimumab (Simponi® Aria™) Intravenous (IV) Injection
Policy: MA08.093e:Chimeric Antigen Receptor (CAR) Therapy