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Rituximab is a genetically engineered, chimeric monoclonal antibody that binds the CD20 antigen found on the surface of normal and malignant B-lymphocytes and promotes depletion of these cells. More than 90% of B-cell non-Hodgkin lymphomas (NHL) are CD20-positive. B-cells also play a role in the pathogenesis of rheumatoid arthritis and other autoimmune diseases.

Several formulations of rituximab have been approved by the U.S. Food and Drug Administration (FDA). Three intravenous formulations are commercially available, Rituxan^®and rituximab biosimilars, Truxima^® , Ruxience™, and Riabni™.  A biosimilar is a drug that is biogengineered to be similar, but is not identical to the original formulation.  Rituximab and hyaluronidase (Rituxan Hycela™), another rituximab product, is a combination of rituximab and human hyaluronidase, a naturally occurring endoglycosidase enzyme. Hyaluronidase acts by increasing tissue permeability and aids in the dispersion and delivery of rituximab into systemic circulation. Rituxan Hycela™ is administered by subcutaneous injection.

The FDA has approved intravenous rituximab (Rituxan®) for treatment of patients with the following conditions:

• Chronic Lymphocytic Leukemia (CLL)
  • Previously untreated and previously treated CD20-positive CLL, in combination with fludarabine and cyclophosphamide
• Granulomatosis with Polyangiitis (GPA or Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
  • Adult and pediatric patients 2 years and older with GPA and MPA, in combination with glucocorticoids
• Non-Hodgkin's Lymphoma (NHL)
  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
• Pemphigus Vulgaris (PV)
  • Adult patients with moderate to severe pemphigus vulgaris
• Rheumatoid Arthritis (RA)
  • Adult patients with moderately- to severely- active RA who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies, in combination with methotrexate

The FDA has approved three rituximab biosimilars, Truxima^® , Ruxience™, and Riabni™, which are administered intravenously.

Truxima® is FDA approved for treatment of adult patients with the following conditions:

• Chronic Lymphocytic Leukemia (CLL) 
  • Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide 
• Non-Hodgkin’s Lymphoma (NHL)
  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens

• Rheumatoid arthritis in adult patients with moderately to severely active RA who have inadequate response to one or more TNF antagonist therapies, in combination with methotrexate 
• Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids.

Ruxience™ and Riabni™ are FDA approved for treatment of adult patients with the following conditions:

• Chronic Lymphocytic Leukemia (CLL)
  • Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC).
• Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in combination with glucocorticoids
• Non-Hodgkin’s Lymphoma (NHL)
  • Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent.
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens.

The FDA has approved subcutaneous rituximab (Rituxan Hycela™) for treatment of adult patients with the following conditions:

• Chronic Lymphocytic Leukemia (CLL)
  • Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).
• Diffuse Large B-cell Lymphoma (DLBCL)
  • Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens
• Follicular Lymphoma (FL)
  • Relapsed or refractory, follicular lymphoma as a single agent
  • Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy

Severe adverse reactions have occurred in patients receiving rituximab, including: infusion reactions; mucocutaneous reactions; hepatitis B virus reactivation; progressive multifocal leukoencephalopathy; tumor lysis syndrome; infections; cardiac arrhythmias; renal toxicity; and bowel obstruction and perforation. Due to these safety concerns, the FDA requires the prescribing information for rituximab to include a black box warning.

I.   Initial and Renewal Review for Oncologic Indications

Intravenous rituximab (Rituxan®, Truxima® , Ruxience™, Riabni™) may be considered MEDICALLY NECESSARY AND APPROPRIATE for oncologic indications when ALL of the following criteria are met:

• Diagnosis of ONE of the following:
  • Acute lymphoblastic/lymphocytic leukemia (ALL); OR
  • Central nervous system (CNS) lymphoma, including but not limited to:
    • Primary CNS lymphoma; or
    • Leptomeningeal metastases from lymphomas; OR
  • Hodgkin lymphoma, including but not limited to:
    • Nodular lymphocyte-predominant Hodgkin lymphoma; OR
  • Non-Hodgkin's lymphoma (NHL), including but not limited to:
    • AIDS-related B-cell lymphoma; or
    • B-cell lymphoma; or
    • Burkitt lymphoma; or
    • Castleman's disease (angiofollicular lymph node hyperplasia); or
    • Chronic lymphocytic leukemia (CLL); or
    • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); or
    • Diffuse large B-cell lymphoma (DLBCL); or
    • Follicular lymphoma; or
    • Gastric mucosa-associated lymphoid tissue (MALT) lymphoma; or
    • Hairy cell leukemia; or
    • Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma; or
    • Histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma; or
    • Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma; or
    • Lymphoblastic lymphoma; or
    • Mantle cell lymphoma; or
    • Nodal marginal zone lymphoma; or
    • Non-gastric MALT lymphoma; or
    • Pediatric aggressive mature B-cell lymphoma; or
      
    • Post-transplant lymphoproliferative disorder (PTLD); or
    • Primary cutaneous B-cell lymphoma; or
    • Primary mediastinal large B-cell lymphoma; or
      
    • Splenic marginal zone lymphoma. OR
  • Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma); AND
• No FDA labeled contraindications to therapy (see table 1 below); AND
• Requested dose is within the FDA labeled dose for the labeled indications or is supported in literature for additional indications.

Subcutaneous rituximab (Rituxan Hycela^®) may be considered MEDICALLY NECESSARY AND APPROPRIATE for oncologic indications when ALL of the following criteria are met:

• Diagnosis of ONE of the following:
  • AIDS-related B-cell lymphoma; or
  • Burkitt lymphoma; or
  • Castleman's disease (angiofollicular lymph node hyperplasia); or
  • Chronic lymphocytic leukemia (CLL); or
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); or
  • Diffuse large B-cell lymphoma (DLBCL); or
  • Follicular lymphoma (FL); or
  • Gastric mucosa-associated lymphoid tissue (MALT) lymphoma; or
  • Hairy cell leukemia; or
  • Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma; or
  • Mantle cell lymphoma; or
  • Nodal marginal zone lymphoma; or
  • Non-gastric MALT lymphoma; or
  • Post-transplant lymphoproliferative disorder (PTLD); or
  • Primary cutaneous B-cell lymphoma; or
  • Splenic marginal zone lymphoma;
• AND
• No FDA labeled contraindications to therapy (see table 1 below); AND
• For initial review, the patient has received one full dose of intravenous rituximab; AND
• Requested dose is within the FDA labeled dose for the labeled indications or is supported in literature for additional indications.

II.  Initial Review for Non-Oncologic Indications

Intravenous rituximab (Rituxan®, Truxima®, Ruxience™, Riabni ™) may be considered MEDICALLY NECESSARY AND APPROPRIATE for non-oncologic indications when ALL of the following criteria are met:

• Diagnosis of ONE of the following:
  • Autoimmune hemolytic anemia (AIHA); OR
  • Autoimmune mucocutaneous blistering disease (pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, or epidermolysis bullosa acquisita) AND ONE of the following:
    • Will receive glucocorticoid therapy in combination with rituximab; OR
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one glucocorticoid; OR
  • Chronic graft versus host disease AND BOTH of the following:
    • Failed an immunosuppressant OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one immunosuppressant; AND
    • Failed glucocorticoid therapy OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one glucocorticoid; OR
  • Chronic idiopathic/immune thrombocytopenic purpura (ITP) AND ONE of the following:
    • Had an inadequate response to splenectomy, glucocorticoid therapy, or immune globulin therapy; or
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to immune globulin therapy AND at least one glucocorticoid; OR
  • Dermatomyositis AND BOTH of the following:
    • Failed an immunosuppressant OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one immunosuppressant; AND
    • Failed glucocorticoid therapy OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one glucocorticoid; OR
  • Granulomatosis with polyangiitis (GPA or Wegener’s granulomatosis) and microscopic polyangiitis (MPA) AND ONE of the following:
    • Will receive glucocorticoid therapy in combination with rituximab; or
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one glucocorticoid; OR
  • Idiopathic membranous nephropathy AND ONE of the following: 
    • Failed an alkylating agent (e.g. cyclophosphamide) or a calcineurin inhibitor (e.g. cyclosporine); or 
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one alkylating agent (e.g. cyclophosphamide) AND at least one calcineurin inhibitor (e.g. cyclosporine); OR
  • Moderately to severely active rheumatoid arthritis in a patient 18 years of age or older AND failed at least one tumor necrosis factor (TNF) antagonist OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one TNF antagonist; OR
  • Neuromyelitis optica spectrum disorder; OR
  • Polymyositis AND BOTH of the following:
    • Failed an immunosuppressant OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one immunosuppressant; AND
    • Failed glucocorticoid therapy OR has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one glucocorticoid; OR
  • Prior to renal transplantation, at high risk of antibody-mediated rejection, including highly sensitized patients and those receiving an ABO incompatible organ; OR
  • Thrombotic thrombocytopenic purpura (TTP) AND ONE of the following:
    • Will receive plasma exchange and glucocorticoid therapy in combination with rituximab; or
    • Documented intolerance, FDA labeled contraindication, or hypersensitivity to plasma exchange AND at least one glucocorticoid;

• AND
• No FDA labeled contraindications to therapy (see table 1 below); AND
• Not currently being treated with another biologic immunomodulator; AND
• For patients not currently receiving rituximab, has been screened for hepatitis B infection and has begun therapy if appropriate; AND
• Requested dose is within the FDA labeled dose for the labeled indications or is supported in literature for additional indications (see table 2 below); AND
• For commercial health plan members only, rituximab is administered in accordance with site of service criteria (see policy XI-06); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).

III.  Renewal Review for Non-Oncologic Indications

Intravenous rituximab (Rituxan®, Truxima®, Ruxience™, Riabni ™) may be considered MEDICALLY NECESSARY AND APPROPRIATE for non- oncologic indications when ALL of the following criteria are met:

• Previously approved for the requested therapy through the initial review process; AND
• Has shown positive clinical response to rituximab therapy (e.g., stabilization and/or slowing of disease progression, or decrease in symptom severity and/or frequency); AND
• No FDA labeled contraindications to therapy with rituximab (see table 1 below); AND
• Not currently being treated with another biologic immunomodulator; AND
• Requested dose is within the FDA labeled dose for the labeled indications or is supported in literature for additional indications (see table 2 below); AND
• For commercial health plan members only, rituximab is administered in accordance with site of service criteria (see policy XI-06).

IV.  Experimental/Investigative Uses

The use of intravenous (Rituxan®, Truxima®, Ruxience™, Riabni™) or subcutaneous rituximab (Rituxan Hycela^®) is considered EXPERIMENTAL/INVESTIGATIVE for all other indications due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Table 1.  FDA Labeled Contraindications

Table 2.  Dosing for Non-Oncologic Indications

NOTE:  See documentation submission requirements below if the requested dose is higher or more frequent than the dosing criteria provided in this table.

Documentation Submission:

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization. In addition, the following documentation must also be submitted:

Initial Review for Non-Oncologic Indications

1. Clinical notes describing the diagnosis and clinical features of the diagnosis.
2. For patients not currently receiving rituximab, laboratory results for hepatitis B screening. If the test was positive, describe follow-up therapy.
3. Clinical notes describing current and past medications for the diagnosis, including response to the medications.
4. The dose being requested, including the patient's weight if the diagnosis requires weight-based dosing. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.
5. For commercial health plan members only, the site of service for rituximab administration is specified, including CMS place of service code (see policy XI-06). If rituximab is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.
6. For commercial health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).
   

Renewal Review for Non-Oncologic Indications

1. Documentation of prior approval for rituximab through the initial review process.
2. Documentation supporting positive clinical response (e.g., slowing of disease progression or decrease in symptom severity and/or frequency).
3. Clinical notes describing current and past medications for the diagnosis, including response to the medications.
4. The dose being requested, including the patient's weight if the diagnosis requires weight-based dosing. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.
5. For commercial health plan members only, the site of service for rituximab administration is specified, including CMS place of service code (see policy XI-06). If rituximab is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.