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RiTUXimab

Pronunciation

Pronunciation

(ri TUK si mab)

Index Terms

  • Anti-CD20 Monoclonal Antibody
  • C2B8 Monoclonal Antibody
  • IDEC-C2B8
  • Rituximab, inj

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Rituxan: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Rituxan

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody
  • Antirheumatic Miscellaneous
  • Immunosuppressant Agent
  • Monoclonal Antibody

Pharmacology

Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. B-cells are believed to play a role in the development and progression of rheumatoid arthritis. Signs and symptoms of RA are reduced by targeting B-cells and the progression of structural damage is delayed.

Distribution

RA: 3.1 L; GPA/MPA: 4.5 L

Onset of Action

Immune thrombocytopenia: Initial response: 7 to 56 days; Peak response: 14 to 180 days (Neunert 2011)

NHL: B-cell depletion: Within 3 weeks.

Rheumatoid arthritis (RA): B-cell depletion: Within 2 weeks.

Time to Peak

SubQ: Median: 3 days (range: 2 to 4 days)

Duration of Action

NHL: Detectable in serum 3 to 6 months after completion of treatment; B-cell depletion is sustained for up to 6 to 9 months and B-cell recovery begins ~6 months following completion of treatment; median B-cell levels return to normal by 12 months following completion of treatment

RA: B-cell depletion persists for at least 6 months.

Half-Life Elimination

CLL: Median terminal half-life: 32 days (range: 14 to 62 days)

NHL: Median terminal half-life: 22 days (range: 6 to 52 days)

RA: Mean terminal half-life: 18 days (range: 5 to 78 days)

GPA/MPA: 23 days (range: 9 to 49 days)

Use: Labeled Indications

Chronic lymphocytic leukemia: Treatment of previously untreated or previously treated CD20-positive chronic lymphocytic leukemia (CLL) (in combination with fludarabine and cyclophosphamide).

Granulomatosis with polyangiitis: Treatment of granulomatosis with polyangiitis (GPA; Wegener granulomatosis) (in combination with glucocorticoids).

Microscopic polyangiitis: Treatment of microscopic polyangiitis (MPA) (in combination with glucocorticoids).

Non-Hodgkin lymphomas: Treatment of CD20-positive non-Hodgkin lymphomas (NHL):

Relapsed or refractory, low-grade or follicular B-cell NHL (as a single agent)

Follicular B-cell NHL, previously untreated (in combination with first-line chemotherapy, and as single-agent maintenance therapy if response to first-line rituximab with chemotherapy)

Nonprogressing (including stable disease), low-grade B-cell NHL (as a single agent after first-line CVP treatment)

Diffuse large B-cell NHL, previously untreated (in combination with CHOP chemotherapy [or other anthracycline-based regimen])

Rheumatoid arthritis: Treatment of moderately to severely active rheumatoid arthritis (in combination with methotrexate) in adult patients with inadequate response to one or more TNF antagonist therapies.

Limitations of use: Rituximab is not recommended for use in patients with severe, active infections.

Off Label Uses

Antibody-mediated rejection in cardiac transplantation (treatment)

Based on the American Heart Association's Scientific Statement for Antibody-Mediated Rejection in Cardiac Transplantation and the International Society of Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients, rituximab, usually in combination with other immune therapies, may be a reasonable option for the secondary treatment of patients with AMR of the cardiac allograft. ISHLT guidelines state rituximab may be added to the current regimen to reduce the risk of recurrent rejection. There are currently no large randomized trials evaluating treatments for AMR in cardiac transplantation; recommendations are based on consensus.

Autoimmune hemolytic anemia (refractory) (adults)

Data from a meta-analysis of 21 observational studies with a total of 409 patients supports the use of rituximab in the management of refractory autoimmune hemolytic anemia (AIHA) [Reynaud 2015]. Data from a retrospective study in patients with refractory AIHA also supports the use of rituximab for refractory AIHA [Roumier 2014]. Data from another small retrospective study which included patients with refractory AIHA also supports the use of rituximab in its management [Gobert 2011]. Additionally, clinical experience also suggests the utility of rituximab in the treatment of refractory autoimmune hemolytic anemia in patients who are not candidates for splenectomy or refractory to splenectomy [Lechner 2010]. Additional data may be necessary to further define the role of rituximab in this condition.

Autoimmune hemolytic anemia (refractory) (children/adolescents)

Data from 2 small prospective studies support the use of rituximab in the treatment of refractory autoimmune hemolytic anemia [Rao 2008], [Zecca 2003]. Additional data may be necessary to further define the role of rituximab in this condition.

Burkitt lymphoma

Data from a large multicenter study supports the use of rituximab (in combination with chemotherapy) in the treatment of Burkitt lymphoma [Hoelzer 2014]. Results from CALGB 10 022, a phase II study in patients with Burkitt leukemia/lymphoma also support the use of rituximab in combination with chemotherapy for the treatment of this disease [Rizzieri 2014]. A small study evaluated the addition of rituximab to HyperCVAD chemotherapy for the treatment of Burkitt lymphoma; the results support the use of rituximab added to the chemotherapy regimen [Thomas 2006].

CNS lymphoma

Data from 2 retrospective studies support the use of rituximab (in combination with high-dose methotrexate) for the treatment of newly diagnosed primary CNS lymphoma [Gregory 2013], [Holdhoff 2014]. Data from a prospective multicenter trial supports the addition of rituximab to methotrexate-based chemotherapy and whole brain radiotherapy for the management of newly diagnosed primary CNS lymphoma in immunocompetent patients [Shah 2007]. Data from a limited number of patients in a small study suggest that rituximab (in combination with temozolomide) may be beneficial for the treatment of refractory primary CNS lymphoma [Wong 2004]. Additional data may be necessary to further define the role of rituximab in this condition.

Graft-versus-host disease (chronic, steroid-refractory)

Data from a small study suggest that rituximab may be beneficial in the treatment of chronic graft-versus-host disease (GVHD) that is refractory to systemic corticosteroid treatment [Cutler 2006]. Additional data may be necessary to further define the role of rituximab in this condition.

Based on the American Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease, the use of rituximab is considered a second-line treatment option for chronic, steroid-refractory GVHD; patients with cutaneous or musculoskeletal chronic GVHD manifestations have a higher likelihood of response [Wolff 2011].

Hodgkin lymphoma (nodular lymphocyte-predominant), advanced

Data from phase II studies support the use of rituximab in the treatment of nodular lymphocyte-predominant Hodgkin lymphoma [Advani 2014], [Ekstrand 2003], [Schulz 2008]. Clinical experience suggests that rituximab may be used for advanced disease (either as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or for relapsed disease in combination with ifosfamide, carboplatin and etoposide [ICE]), but not for newly diagnosed early stage disease [Advani 2013].

Idiopathic membranous nephropathy (resistant)

Data from a randomized controlled phase III study supports the use of rituximab for the treatment of severe membranous nephropathy which has not responded to nonimmunosuppressive antiproteinuric therapy [Dahan 2016]. Data from other small studies (including follow up data) support the use of rituximab in the management of severe, persistent or refractory idiopathic or primary membranous nephropathy [Fervenza 2008], [Fervenza 2010], [Ruggenenti 2012], [Ruggenenti 2015]. Additional data may be necessary to further define the role of rituximab in this condition.

Immune thrombocytopenia (refractory) (adults)

Rituximab in the management of refractory or relapsed immune thrombocytopenia (ITP) has been primarily evaluated in noncontrolled settings, demonstrating benefit in the majority of patients either as complete or partial response. In consensus guidelines, rituximab is recommended as second-line therapy.

Immune thrombocytopenia (refractory) (children/adolescents)

The majority of data for the use of rituximab in refractory ITP are from noncontrolled settings and predictors for response have varied in long-term follow-up studies. In consensus guidelines, rituximab is recommended as a treatment option for children and adolescents with persistent or chronic ITP who have not responded to previous therapy.

Lupus nephritis (refractory) (adults)

Data from a pilot study and a retrospective study in patients with lupus nephritis refractory to initial standard therapy suggested that rituximab may be beneficial for the treatment of refractory lupus nephritis [Melander 2009], [Vigna-Perez 2006]. In a pooled analysis of patients who received rituximab for the treatment of lupus nephropathy, second-line therapy with rituximab was effective, particularly in patients with severe or refractory disease or with an exacerbation after immunosuppressive treatment [Diaz-Largares 2012].

Based on guidelines from the American College of Rheumatology and the Joint European League Against Rheumatism and European Renal Association- European Dialysis and Transplant Association, rituximab may be a treatment option for the management of refractory lupus nephritis after failure with other treatments, including 6 months of one induction therapy or cyclophosphamide and mycophenolate [Bertsias 2012], [Hahn 2012].

Mucosa-associated lymphoid tissue lymphoma (gastric) (advanced)

Data from a small study supports the use of rituximab in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which was either H. pylori negative or persistent following standard H. pylori treatment [Martinelli 2005]. Based on an analysis of the SEER-Medicare database, survival was not improved if rituximab was added to systemic therapy for gastric MALT compared to rituximab alone in elderly patients receiving initial therapy for their disease. Rituximab monotherapy produces durable remissions and may be an option for elderly patients [Olszewski 2013].

Nephrotic syndrome, severe, refractory (pediatrics)

Data from 4 small studies supports the use of rituximab in the treatment of children with severe, refractory nephrotic syndrome [Dello Strologo 2009], [Fujinaga 2010], [Guigonis 2008], [Prytula 2010]. Additional data may be necessary to further define the role of rituximab in this condition.

Pemphigus vulgaris (refractory)

Data from a small prospective study supports the use of rituximab (in combination with IV immune globulin) in patients with pemphigus vulgaris that was refractory to multiple lines of therapy, including systemic corticosteroids and with minimal response to IV immune globulin alone [Ahmed 2006]. Clinical experience and data from retrospective studies also suggest the utility of rituximab in the management of refractory pemphigus vulgaris [Cholera 2016], [El Tal 2006], [Kasperkiewicz 2011]. Additional data may be necessary to further define the role of rituximab in this condition.

Post-transplant lymphoproliferative disorder

Data from 2 international multicenter phase II studies support the use of rituximab (either followed by CHOP chemotherapy or as monotherapy) for the treatment of posttransplant lymphoproliferative disorder [Choquet 2006], [Trappe 2012].

Splenic marginal zone lymphoma

Data from 3 retrospective studies suggests the utility of rituximab (either as a single agent or in combination with chemotherapy) in the management of splenic marginal zone lymphoma [Else 2012], [Kalpadakis 2013], [Tsimberdou 2006]. Additional data may be necessary to further define the role of rituximab in this condition.

Thrombotic thrombocytopenic purpura (acquired)

There are no randomized trials evaluating the use of rituximab with plasma exchange in the management of acquired thrombotic thrombocytopenic purpura (TTP). Data are limited to several case reports, case series, and a phase 2 trial demonstrating significant reductions in ADAMTS13 autoantibodies and increases in ADAMTS13 activity, with low relapse rates (approximately 10%).

Waldenström macroglobulinemia

Data from a phase II multicenter study supports the use of rituximab (in combination with cyclophosphamide and dexamethasone) for the treatment of Waldenström macroglobulinemia [Dimopoulos 2007]. Data from phase II studies also support the use of rituximab, either as a single agent, or in combination with bortezomib, bortezomib and dexamethasone, bendamustine, or carfilzomib and dexamethasone for the treatment of Waldenström macroglobulinemia [Dimopoulos 2002], [Dimopoulos 2013], [Ghobrial 2010], [Rummel 2005], [Treon 2009], [Treon 2014]. Additional data may be necessary to further define the role of rituximab in this condition.

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Known type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML); patients with severe, active infections

Dosing: Adult

Note: Pretreatment with acetaminophen and an antihistamine is recommended for all indications. For oncology uses, antihyperuricemic therapy and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3). In patients with chronic lymphocytic leukemia (CLL), Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment). In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), PCP prophylaxis is recommended during and for 6 months after rituximab treatment. For patients with rheumatoid arthritis (RA), premedication with methylprednisolone 100 mg IV (or equivalent) is recommended 30 minutes prior to each dose.

Rituxan SubQ [Canadian product]: Note: All patients must receive the initial rituximab dose by IV infusion using the Rituxan IV formulation; patients who do not receive a full IV dose should not receive subsequent dosing with Rituxan subQ formulation; continue with the IV formulation/infusions. Patients who tolerate and successfully receive a full initial dose of Rituxan IV formulation may receive subsequent dosing by subQ injection using Rituxan subcutaneous formulation.

Chronic lymphocytic leukemia: IV: 375 mg/m2 on the day prior to fludarabine/cyclophosphamide in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with fludarabine and cyclophosphamide)

Chronic lymphocytic leukemia (off-label combination): IV: 375 mg/m2 on the day prior to bendamustine in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine) (Eichorst 2016)

Granulomatosis with polyangiitis (GPA; Wegener granulomatosis): IV: 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone IV for 1 to 3 days followed by daily prednisone)

Microscopic polyangiitis (MPA): IV: 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone IV for 1 to 3 days followed by daily prednisone)

Non-Hodgkin lymphoma (NHL; relapsed/refractory, low-grade or follicular CD20-positive, B-cell): IV: 375 mg/m2 once weekly for 4 or 8 doses (as a single agent)

Re-treatment following disease progression: 375 mg/m2 once weekly for 4 doses

For maintenance therapy (as a single agent, in patients with response to induction therapy), the following recommendations have been made:

IV: 375 mg/m2 every 3 months until disease progression or maximum duration of 2 years (Rituxan IV Canadian product labeling 2016)

SubQ [Canadian product]: If the patient has tolerated previous rituximab IV infusion, therapy may be administered SubQ at a fixed dose of 1,400 mg every 3 months until disease progression or maximum duration of 2 years (Rituxan SC Canadian product labeling 2016).

NHL (diffuse large B-cell): IV: 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses (in combination with CHOP chemotherapy [or other anthracycline-based regimen])

Rituxan SubQ [Canadian product]: Note: For use only in patients who tolerated and received a full initial dose of rituximab IV formulation.

Cycle 1: Rituxan IV: 375 mg/m2 given on day 1 of initial chemotherapy cycle (in combination with CHOP chemotherapy)

Cycles 2 thru 8: Rituxan SubQ: 1,400 mg (fixed dose) given on day 1 of each chemotherapy cycle for up to 8 doses (includes initial IV dose) (in combination with CHOP chemotherapy)

NHL (follicular, CD20-positive, B-cell, previously untreated):

IV: 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses (in combination with first-line chemotherapy)

Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy; begin 8 weeks after completion of combination chemotherapy): SubQ: 1400 mg (fixed dose) once every 2 months until disease progression or maximum duration of 2 years.

Rituximab SubQ [Canadian product]: Note: For use only in patients who tolerated and received a full initial dose of rituximab IV formulation.

Cycle 1: Rituxan IV: 375 mg/m2 given on day 1 of initial chemotherapy cycle (in combination with first-line chemotherapy)

Cycles 2 thru 8: Rituxan SubQ: 1,400 mg (fixed dose) given on day 1 of each chemotherapy cycle for up to 8 doses (includes initial IV dose) (in combination with first-line chemotherapy)

Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy; begin 8 weeks after completion of combination chemotherapy): SubQ: 1,400 mg (fixed dose) once every 2 months until disease progression or maximum duration of 2 years.

NHL (nonprogressing, low-grade, CD20-positive, B-cell, after 6 to 8 cycles of first line CVP are completed): IV: 375 mg/m2 once weekly for 4 doses every 6 months for a maximum of 16 doses (as a single agent)

NHL: Combination therapy with ibritumomab: IV: 250 mg/m2 IV day 1; repeat in 7 to 9 days with ibritumomab (also see Ibritumomab monograph)

Rheumatoid arthritis: IV: 1,000 mg on days 1 and 15 (in combination with methotrexate); subsequent courses may be administered every 24 weeks (based on clinical evaluation), if necessary may be repeated no sooner than every 16 weeks

Antibody-mediated rejection in cardiac transplantation, treatment (off-label use): IV: 375 mg/m2 once weekly for 1 to 4 doses (AHA [Colvin 2015]; ISHLT [Costanzo 2010]) or 1,000 mg on days 7 and 21 or on days 7 and 22 (AHA [Colvin 2015])

Autoimmune hemolytic anemia, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses (may continue systemic corticosteroids); a second course may be administered for relapse (Gobert 2011; Reynaud 2015; Roumier 2014)

Burkitt lymphoma (off-label use): IV: 375 mg/m2 on day 1 and 11 of cycles 1 and 3 and days 2 and 8 of cycles 2 and 4 (Thomas 2006) or 375 mg/m2 at the start of each chemotherapy cycle, followed by 2 additional doses 3 and 6 weeks after the completion of chemotherapy (Hoelzer 2014) or 50 mg/m2 on day 8 and 375 mg/m2 on days 10 and 12 of cycle 2 followed by 375 mg/m2 on day 8 of cycles 3 to 7 (Rizzieri 2014).

CNS lymphoma (off-label use): IV:

Newly diagnosed: 375 mg/m2 on day 3 every 14 days (in combination with high-dose methotrexate) until disease progression or unacceptable toxicity, or for 2 doses beyond a complete response followed by monthly treatments for up to a total of 1 year (Holdhoff 2014) or 500 mg/m2 on day 1 of each cycle for 5 to 7 induction cycles (in combination with high-dose methotrexate, vincristine, and procarbazine, followed by whole-brain radiotherapy) (Shah 2007)

Refractory disease: 375 mg/m2 on day 1 every 28 days (in combination with temozolomide) for 4 cycles, then followed by temozolomide monotherapy (Wong 2004)

Graft-versus-host disease (GVHD), chronic, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses; a second course of 4 weekly doses may be administered 8 weeks after initial therapy for lack of or incomplete response (Cutler 2006) or 375 mg/m2 once weekly for 4 to 8 doses (Wolff 2011)

Hodgkin lymphoma, nodular lymphocyte-predominate, advanced (off-label use): IV: 375 mg/m2 once weekly for 4 weeks (Ekstrand 2003; Schulz 2008) or 375 mg/m2 once weekly for 4 weeks followed by maintenance dosing of 375 mg/m2 once weekly for 4 weeks every 6 months for 2 years (Advani 2014). May be administered as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP], or for relapsed disease, in combination with ifosfamide, carboplatin and etoposide [RICE]) (Advani 2013).

Idiopathic membranous nephropathy, resistant (off-label use): IV: 375 mg/m2 once weekly for 4 doses; repeat cycle at 6 months (Fervenza 2010) or 1,000 mg (flat dose) on days 1 and 15; may repeat cycle at 6 months (Fervenza 2008) or 375 mg/m2 once weekly for 2 doses (Dahan 2016) or 375 mg/m2 once weekly for 4 doses (Ruggenenti 2012; Ruggenenti 2015) or 375 mg/m2 as a single dose and repeated at least 1 week later only if circulating B-cells >5/mm3 were detected (Ruggenenti 2012; Ruggenenti 2015)

Immune thrombocytopenia, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Arnold 2007; Godeau 2008; Provan 2010) or some patients may have a response with a dose of 100 mg (flat dose) once weekly for 4 weeks (Zaja 2010).

Lupus nephritis, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Diaz-Largares 2012; Melander 2009) or 1,000 mg (flat dose) on days 0 and 15 (Diaz-Largares 2012) or 500 to 1,000 mg (flat dose) on days 1 and 15 (Vigna-Perez 2006)

Mucosa-associated lymphoid tissue lymphoma (gastric), advanced (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Martinelli 2005)

Pemphigus vulgaris, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses (some patients also continued immunosuppressant therapy); may repeat a second time (based on response) if needed (Cholera 2016; El Tal 2006; Kasperkiewicz 2008) or 375 mg/m2 once weekly of weeks 1, 2, and 3 of a 4-week cycle, repeat for 1 additional cycle, then 1 dose per month for 4 months (total of 10 doses in 6 months), in combination with IV immune globulin (Ahmed 2006) or 1,000 mg once every 2 weeks for 2 doses (some patients also continued immunosuppressant therapy) (Cholera 2016; Kasperkiewicz 2008)

Posttransplant lymphoproliferative disorder (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Choquet 2006) or 375 mg/m2 once weekly for 4 doses, followed 4 weeks later with 4 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (Trappe 2012)

Splenic marginal zone lymphoma (off-label use): IV: 375 mg/m2 once weekly for 6 weeks followed by 375 mg/m2 once every 2 months for 1 to 2 years (Kalpadakis 2013) or 375 mg/m2 once weekly for 4 weeks as monotherapy or 375 mg/m2 on day 1 of each chemotherapy cycle for up to 6 cycles; 1 to 2 additional cycles of rituximab monotherapy may be administered if needed (Else 2012). Additional data may be necessary to further define the role of rituximab in this condition.

Thrombotic thrombocytopenic purpura (acquired) (off-label use): IV: 375 mg/m2 once weekly for 4 doses (in combination with plasma exchange); up to 4 additional doses may be administered for ADAMTS13 levels remaining below normal or for persistently detectable anti-ADAMTS13 IgG antibodies (Scully 2007; Scully 2011). Rituximab should be timed to be administered immediately following plasma exchange; allow 24 hours after rituximab before the next plasma exchange (McDonald 2010; Sayani 2015).

Waldenström macroglobulinemia (off-label use): IV:

Single-agent rituximab: 375 mg/m2 once weekly for 4 weeks as a single agent; may repeat cycle one time after 12 weeks (Dimopoulos 2002).

In combination with cyclophosphamide and dexamethasone: 375 mg/m2 on day 1 every 21 days for 6 cycles (Dimopoulos 2007).

In combination with bortezomib: 375 mg/m2 on days 1, 8, 15, and 22 during cycles 1 and 4; treatment is continued for 6 cycles, with a total of 8 rituximab doses (Ghobrial 2010).

In combination with bortezomib and dexamethasone: 375 mg/m2 on days 1, 8, 15, and 22 during cycles 2 and 5; treatment is administered for 6 cycles, with a total of 8 rituximab doses (Dimopoulos 2013) or 375 mg/m2 on day 11 every 21 days for 4 cycles (induction); after a 12-week break, 4 additional maintenance cycles (spaced 12 weeks apart) were administered (Treon 2009).

In combination with bendamustine: 375 mg/m2 on day 1 every 28 days for 4 cycles; single rituximab doses were also administered 1 week prior to the first cycle and 4 weeks after the last cycles (for a total of 6 rituximab doses) (Rummel 2005).

In combination with carfilzomib and dexamethasone: 375 mg/m2 on days 2 and 9 every 21 days for 6 induction cycles, followed by 375 mg/m2 on day 2 every 8 weeks for 8 maintenance cycles (Treon 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Pretreatment with acetaminophen and an antihistamine is recommended.

Autoimmune hemolytic anemia, refractory (off-label use): IV: 375 mg/m2 once weekly for 2 to 4 doses (may continue systemic corticosteroids); a second course may be administered for relapse (Rao 2008; Zecca 2003).

Immune thrombocytopenia, refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Parodi 2009; Provan 2010; Wang 2005)

Nephrotic syndrome, severe, refractory (off-label use): IV: 375 mg/m2 once weekly for 2 to 4 doses or 375 mg/m2 (maximum dose: 500 mg) as a single dose (Dello Strologo 2009; Fujinaga 2010; Guigonis 2008; Prytula 2010). Additional data may be necessary to further define the role of rituximab in this condition.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

IV: Withdraw necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL with NS or D5W. Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other medications. Compatible in polyvinyl chloride (PVC) and polyethylene bags.

Subcutaneous [Canadian product]: Withdraw appropriate dose from vial into syringe (further dilution is not required).

Administration

Note: Some pediatric protocols utilize an alternate rituximab administration rate. Refer to specific protocol for administration rate guidelines.

For IV administration only. Do not administer IV push or bolus. If an infusion reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate. Discontinue infusion in the event of serious or life-threatening cardiac arrhythmias.

IV: Initial infusion: Start infusion at a rate of 50 mg/hour; if there is no infusion reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.

Subsequent infusions:

Standard infusion rate: If patient tolerated initial infusion, start at 100 mg/hour; if there is no infusion reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.

Accelerated infusion rate (90 minutes): For patients with previously untreated follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid as part of their combination chemotherapy regimen, have a circulating lymphocyte count <5,000/mm3, or have no significant cardiovascular disease. After tolerance has been established (no grade 3 or 4 infusion-related event) at the recommended infusion rate in cycle 1, a rapid infusion rate may be used beginning with cycle 2. The daily corticosteroid, acetaminophen, and diphenhydramine are administered prior to treatment, then the rituximab dose is administered over 90 minutes, with 20% of the dose administered over the first 30 minutes and the remaining 80% is given over 60 minutes (Sehn 2007). If the 90-minute infusion in cycle 2 is tolerated, the same rate may be used for the remainder of the treatment regimen (through cycles 6 or 8).

Rituxan SC [Canadian product]: For subcutaneous administration only under supervision of an experienced healthcare provider; not for self-administration. Do not administer IV. Inject over 5 minutes into abdominal wall only. Do not administer in other body sites (has not been studied) and avoid skin that is bruised, tender, hard, and/or red or where there are moles or scars. Administer other subcutaneous medications at different sites; avoid area where rituximab is injected. If the injection is interrupted, it may be resumed or administered in a different location.

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Protect vials from direct sunlight. Solutions for infusion in NS or D5W are stable at 2°C to 8°C (36°F to 46°F) for 24 hours and at room temperature for an additional 24 hours (although because there is no preservative, the manufacturer recommends storing refrigerated).

Rituxan SC [Canadian product]: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original packaging to protect from light. Following transfer from vial to syringe, the manufacturer states that the solution is stable for 48 hours at 2°C to 8°C (36°F to 46°F) and subsequently 8 hours at 30°C (86°F) in diffused daylight.

Drug Interactions

Abatacept: RiTUXimab may enhance the adverse/toxic effect of Abatacept. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: RiTUXimab may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions.

>10%:

Cardiovascular: Peripheral edema (8% to 16%), hypertension (6% to 12%)

Central nervous system: Fatigue (13% to 39%), chills (3% to 33%), neuropathy (≤30%), headache (17% to 19%), insomnia (≤14%), pain (12%)

Dermatologic: Skin rash (10% to 17%), pruritus (5% to 17%), night sweats (15%)

Endocrine & metabolic: Weight gain (11%)

Gastrointestinal: Nausea (8% to 23%), diarrhea (10% to 17%), abdominal pain (2% to 14%)

Hematologic & oncologic: Lymphocytopenia (48%; grades 3/4: 40%; median duration: 14 days), anemia (8% to 35%; grades 3/4: 3%), leukopenia (NHL: 14%, grades 3/4: 4%; CLL: grades 3/4: 23%; GPA/MPA: 10%), neutropenia (NHL: 14%, grades 3/4: 4% to 6%, median duration: 13 days; CLL: grades 3/4: 30% to 49%; late-onset: <1%, occurs >40 days after last dose), thrombocytopenia (12%; grades 3/4: 2% to 11%), cytopenia (may be prolonged), febrile neutropenia (CLL)

Hepatic: Increased serum ALT (≤13%)

Hypersensitivity: Angioedema (11%)

Immunologic: Antibody development (human antichimeric antibody [HACA] positive: 1% to 23%)

Infection: Infection (19% to 62%), bacterial infection (19%)

Neuromuscular & skeletal: Weakness (2% to 26%), muscle spasm (≤17%), arthralgia (6% to 13%)

Respiratory: Cough (13%), rhinitis (3% to 12%), epistaxis (≤11%)

Miscellaneous: Infusion related reaction (lymphoma: first dose: 77%, decreases with subsequent infusions and may include rigors; CLL: 59%, grades 3/4: 7% to 9%; RA: first infusion: 32%; GPA/MPA: 12%), fever (5% to 53%)

1% to 10%:

Cardiovascular: Hypotension (10%), flushing (5%)

Central nervous system: Dizziness (10%), anxiety (2% to 5%), migraine (RA: 2%), paresthesia (2%)

Dermatologic: Urticaria (2% to 8%)

Endocrine & metabolic: Hyperglycemia (9%), increased lactate dehydrogenase (7%)

Gastrointestinal: Vomiting (10%), dyspepsia (RA: 3%)

Infection: Viral infection (10%), fungal infection (1%)

Neuromuscular & skeletal: Back pain (10%), myalgia (10%)

Respiratory: Dyspnea (≤10%), throat irritation (2% to 9%), bronchospasm (8%), upper respiratory tract infection (RA: 7%), sinusitis (6%)

<1% (Limited to important or life-threatening): Acute mucocutaneous toxicity, acute renal failure, acute respiratory distress, anaphylactoid reaction, anaphylaxis, angina pectoris, aplastic anemia, arthritis (polyarticular), bone marrow depression, bronchiolitis obliterans, cardiac arrhythmia, cardiac failure, cardiogenic shock, encephalitis, fulminant hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, hepatitis, hypogammaglobulinemia (prolonged), hypoxia, increased serum immunoglobulins (hyperviscosity syndrome in Waldenstrom’s macroglobulinemia), interstitial pneumonitis, intestinal obstruction, intestinal perforation, Kaposi’s sarcoma (progression), laryngeal edema, lichenoid dermatitis, lupus-like syndrome, mucositis, myelitis, myocardial infarction, nephrotoxicity, optic neuritis, pancytopenia (prolonged), pemphigus (paraneoplastic; uncommon), pleurisy, pneumonia, pneumonitis, polymyositis, progressive multifocal leukoencephalopathy, pure red cell aplasia, reactivated tuberculosis, reactivation of HBV, reversible posterior leukoencephalopathy syndrome, serum sickness, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, toxic epidermal necrolysis, tumor lysis syndrome, uveitis, vasculitic rash, vasculitis (systemic), ventricular fibrillation, ventricular tachycardia, vesiculobullous dermatitis, viral infection (reactivation; includes JC virus infection, cytomegalovirus, herpes simplex virus, parvovirus B19, varicella-zoster virus, West Nile disease, and hepatitis C), wheezing

ALERT: U.S. Boxed Warning

Infusion reactions:

Rituximab administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of rituximab infusion have been reported. Approximately 80% of fatal infusion reactions occurred in association with the first infusion.

Monitor patients closely. Discontinue rituximab infusion for severe reactions and administer medical treatment for grade 3 or 4 infusion reactions.

Mucocutaneous reactions:

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab.

Hepatitis B virus reactivation:

Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation.

Progressive multifocal leukoencephalopathy:

Progressive multifocal leukoencephalopathy (PML) and death can occur in patients receiving rituximab.

Warnings/Precautions

Concerns related to adverse effects:

• Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1 to 77 days); evaluate abdominal pain or repeated vomiting.

• Cardiovascular effects: Discontinue infusion for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after the infusion in patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.

• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment. Monitor blood counts.

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with rituximab and in some cases may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection prior to treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation. Screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc); monitor patients for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment. If viral hepatitis develops, initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported up to 24 months after discontinuation. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during rituximab treatment. The safety of resuming rituximab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management.

- American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation. Screen for HBV infection with HBsAG and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or unresolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg positive/anti-HBc positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• Infections: Use is not recommended in patients with severe active infection. Serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and after completing rituximab. Infections have been observed in patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia >11 months after rituximab exposure. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral hepatitis and initiate antiviral therapy. Discontinue rituximab in patients who develop other serious infections and initiate appropriate anti-infective treatment.

• Infusion reactions: [US Boxed Warning]: Serious (including fatal) infusion-related reactions have been reported, usually with the first infusion; fatalities have been reported within 24 hours of infusion; monitor closely during infusion; discontinue for severe reactions and provide medical intervention for grades 3 or 4 infusion reactions. Reactions usually occur within 30 to 120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylactoid events. Closely monitor patients with a history of prior cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (>25,000/mm3). Prior to infusion, premedicate patients with acetaminophen and an antihistamine (and methylprednisolone for patients with RA). Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, corticosteroids) should be available for immediate use; treatment is symptomatic. If infusion reaction occurs, temporarily or permanently discontinue infusion (depending on the severity of the reaction and required interventions). After symptoms resolve, infusion may be resumed with at least a 50% infusion rate reduction. Due to the potential for hypotension, consider withholding antihypertensives 12 hours prior to treatment.

• Mucocutaneous reactions: [US Boxed Warning]: Severe and sometimes fatal mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis and vesiculobullous dermatitis) have been reported; onset has been variable but has occurred as early as the first day of exposure. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of reexposure following mucocutaneous reactions has not been evaluated. Subcutaneous rituximab [Canadian product] has been associated with localized cutaneous reactions (eg, pain, erythema, swelling, induration, rash, pruritus, hemorrhage); may occur >24 hours after administration. Reactions have been mostly mild to moderate and have resolved without intervention.

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) due to JC virus infection has been reported with rituximab; may be fatal. Cases were reported in patients with hematologic malignancies receiving rituximab either with combination chemotherapy, or with hematopoietic stem cell transplant. Cases were also reported in patients receiving rituximab for autoimmune diseases who had received concurrent or prior immunosuppressant therapy. Onset may be delayed, although most cases were diagnosed within 12 months of the last rituximab dose. A retrospective analysis of patients (n=57) diagnosed with PML following rituximab therapy, found a median of 16 months (following rituximab initiation), 5.5 months (following last rituximab dose), and 6 rituximab doses preceded PML diagnosis. Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Carson 2009). Promptly evaluate any patient presenting with neurological changes; consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.

• Renal toxicity: May cause fatal renal toxicity in patients with hematologic malignancies. Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome. Monitor for signs of renal failure; discontinue rituximab with increasing serum creatinine or oliguria.

• Tumor lysis syndrome: Tumor lysis syndrome leading to acute renal failure requiring dialysis (some fatal) may occur within 12 to 24 hours following the first dose when used as a single agent in the treatment of NHL. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy, hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care as indicated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Live vaccines should not be given concurrently with rituximab; there is no data available concerning secondary transmission of live vaccines with or following rituximab treatment. Rheumatoid arthritis patients should be brought up to date with nonlive immunizations (following current guidelines) at least 4 weeks before initiating therapy; response to some immunizations may be lower in some patients receiving rituximab.

Special populations:

• Elderly: Use with caution in the elderly. There is a higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis) and the incidence of grade 3 or 4 adverse reactions are higher in elderly patients.

• Granulomatosis with polyangiitis (GPA; Wegener granulomatosis)/microscopic polyangiitis (MPA): The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with GPA or MPA after rituximab-induced B-cell depletion. There are only limited data on subsequent courses of rituximab for GPA or MPA; safety and efficacy of re-treatment have not been established.

• Rheumatoid arthritis: There are limited data on the safety of other biologics or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients with rheumatoid arthritis with B-cell depletion following rituximab treatment. Monitor patients closely for infection if biologic agents or DMARDS are used concomitantly. The use of rituximab is not recommended in RA patients who have not had prior inadequate response to one or more TNF antagonists.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Monitoring Parameters

CBC with differential and platelets (obtain prior to treatment and at weekly to monthly intervals and more frequently in patients with lymphoid malignancies, or at 2- to 4-month intervals in rheumatoid arthritis patients, GPA and MPA), electrolytes (in patients at risk for TLS), renal function (in patients at risk for TLS), fluid/hydration status balance; blood pressure, vital signs.

Screen all patients for HBV infection prior to therapy initiation (eg, HBsAG and anti-HBc measurements). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment. Hepatitis B virus (HBV) screening recommendations (ASCO provisional clinical opinion update [Hwang 2015]): Screen for HBV infection with hepatitis B surface antigen (HBsAG) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or unresolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Monitor for infusion reactions; signs of active hepatitis B infection (during and for up to 12 months after therapy completion); cardiac monitoring during and after infusion (in rheumatoid arthritis patients and in patients with pre-existing cardiac disease or if arrhythmias develop during or after subsequent infusions); monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting); signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); if PML is suspected, obtain brain MRI scan and lumbar puncture; signs/symptoms of TLS and/or mucocutaneous skin reactions.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have demonstrated adverse effects including decreased (reversible) B-cells and immunosuppression. Rituximab crosses the placenta and can be detected in the newborn. In one infant born at 41 weeks' gestation, in utero exposure occurred from week 16 to 37; rituximab concentrations were higher in the neonate at birth (32,095 ng/mL) than the mother (9,750 ng/mL) and still measurable at 18 weeks of age (700 ng/mL infant; 500 ng/mL mother) (Friedrichs 2006).

B-cell lymphocytopenia lasting <6 months may occur in exposed infants. Retrospective case reports of inadvertent pregnancy during rituximab treatment collected by the manufacturer (often combined with concomitant teratogenic therapies) describe premature births and infant hematologic abnormalities and infections; no specific pattern of birth defects has been observed (limited data) (Chakravarty 2010).

Effective contraception should be used in women of reproductive potential during and for 12 months following treatment with rituximab.

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). Based on limited data, if pregnancy occurs during rituximab treatment, the pregnancy may continue provided rituximab treatment is withheld. In general, although the risk of B-cell depletion in the newborn is increased, if postponing rituximab treatment would significantly compromise maternal outcome in patients diagnosed with B-cell lymphoma during pregnancy, rituximab use is not discouraged during the pregnancy (Peccatori 2013). An international consensus panel has published guidelines for hematologic malignancies during pregnancy. In patients with aggressive lymphomas, rituximab (as a component of the R-CHOP chemotherapy regimen) may be administered in the second and third trimesters, however, the cytotoxic portion of the regimen should not be administered within 3 weeks prior to anticipated delivery (Lishner 2016).

Other agents are preferred for treating lupus nephritis in pregnant women (Hahn 2012). When treating rheumatoid arthritis, it is recommended to discontinue use and switch to a safer medication prior to conception unless no other pregnancy compatible medication is able to control maternal disease (Götestam Skorpen 2016).

Data collection to monitor pregnancy and infant outcomes following exposure to rituximab is ongoing. A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, diarrhea, rhinorrhea, muscle spasms, back pain, insomnia, or night sweats. Have patient report immediately to prescriber signs of infection, signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; diarrhea), angina, tachycardia, arrhythmia, severe dizziness, passing out, loss of strength and energy, severe headache, severe nausea, vomiting, bruising, bleeding, shortness of breath, excessive weight gain, swelling of arms or legs, severe muscle pain, severe joint pain, burning or numbness feeling, or signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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