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Rituximab – Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 5
METHODOLOGY ...................................................................................................................... 5
DEFINITIONS ............................................................................................................................ 5
RECOMMENDATIONS .............................................................................................................. 6
UW HEALTH IMPLEMENTATION ............................................................................................14
REFERENCES .........................................................................................................................14
APPENDIX A – ACCF/AHA GRADING ....................................................................................20
APPENDIX B – RITUXIMAB INDICATIONS, DOSING, AND LEVEL OF EVIDENCE ..............21
CPG Contact for Content:
Name: Carl Nelson, PharmD – Department of Pharmacy
Phone Number: (608) 890-9858
Email Address: cnelson@uwhealth.org
Name: Cindy Gaston, PharmD, BCPS – Department of Pharmacy
Phone Number: (608) 265-8161
Email Address: cgaston@uwhealth.org
CPG Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS – Drug Policy Program Manager, Department of Pharmacy
Phone Number: (608) 263-1328
Email Address: ptrapskin@uwhealth.org:
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Guideline Authors:
C. Nelson, PharmD; C. Gaston, PharmD, BCPS
Coordinating Team Members:
C. Nelson, PharmD
Review Individuals/Bodies:
C. Bartels, MD; J. Juozevicius, MD; A. Waclawik; MD, E. Williams, MD
Committee Approvals/Dates:
Clinic Administered Medication Policy Committee
Pharmacy and Therapeutics Committee- December 2015
Release Date:
Original release: November 2013
Most recent update: December 2015
Next Review Date: December 2018
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Executive Summary
Guideline Overview
This guideline includes recommendations for appropriate screening, vaccination, administration and
monitoring of rituximab when utilized for the treatment of autoimmune disorders. Evidence-based dosing
and place in therapy is included for specific autoimmune disorders.)
Target Population
Adult inpatient and ambulatory patients
Key Practice Recommendations
General Recommendations
1. Screening for infectious risk factors is required prior to initiation of rituximab.(Class I, Level C)
2. If a patient develops a reactivation of hepatitis B during treatment with rituximab, discontinue therapy
and initiate hepatitis B treatment. (Class I, Level C)
3. Do not administer rituximab to patients with severe infections or hypogammaglobulinemia with very
low CD4 or CD8 levels. (Class III, Level C)
4. Delay therapy in patients with severe, acute, active infections. (Class I, Level C)
5. Evaluate the risk/benefit ratio of rituximab therapy in patients with chronic infections. If rituximab is
given, monitor more frequently for exacerbation of infection. Class I, Level C)
6. Do not administer rituximab in patients with severe heart failure (NYHC IV). (Class III, Level C
7. Vaccination (Class I, Level C)
7.1 Administer indicated, inactivated vaccines prior to rituximab (ideally four weeks prior to initiation).
Class I, Level C)
7.2 Do not administer live vaccines within 4 weeks of initiating rituximab or during rituximab therapy.
(Class I, Level C)
7.3 Do not administer Bacillus Calmette-Guerin (BCG) vaccine to patients with autoimmune
inflammatory disease. (Class III, Level C)
8. Concomitant administration with other biologic agents is not recommended. Discontinue TNF
inhibitors prior to rituximab therapy. (Class I, Level C)
9. Round doses of rituximab by ≤ 10% to the nearest 100 mg. (Class I, Level C)
10. Premedicate patients prior to every infusion to prevent infusion reactions.
11. Administration rates
11.1 The National Cancer Institute for grading adverse reactions can be utilized to grade the severity
of infusion reactions with rituximab. (Class I, Level C)
11.2 If severe hypersensitivity or infusion reactions occur, then slow or stop the infusion. (Class I,
Level C)
11.3 First infusion rates (FIR) – Table 1. (Class I, Level C)
11.4 Rapid infusion rate (RIR). Table 1. (Class IIa, Level C)
Table 1. Rituximab Infusion Rates
Rituximab Infusion
Rate Initial Rate of Infusion Titration of Infusion
Maximum Rate
of Infusion
First Infusion Rate
(FIR) 50 mg/h for 30 minutes
Increase rate by
50 mg/h every 30 minutes 400 mg/h
Rapid Infusion Rate
(RIR) 240 mL/h for 30 minutes Increase rate to 480 mL/h 480 mL/h
12. Monitoring (Class I, Level C)
12.1 Monitor patients closely for infusion reactions
12.2 Monitor CBC without differential and platelet counts routinely
12.3 Monitor for symptoms of bacterial, fungal, and viral infections
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Disease Specific Recommendations
13. Autoimmune Hemolytic Anemia (AIHA)
14. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
15. Cryoglobulinemic vasculitis
16. Dermatomyositis/Polymyositis (DM/PM)
17. Eosinophilic granulomatosis with polyangiitis (EPGA) – Churg-Straus
18. Goodpasture’s syndrome
19. Granulomatosis with polyangiitis (GPA) – Wegner’s Granulomatosis
20. Immune (Idiopathic) thrombocytopenia purpura (ITP)
21. Microscopic Polyangiitis (MPA)
22. Multiple Sclerosis (MS)
23. Myasthenia Gravis (MG)
24. Neuromyelitis Optica (NMO)
25. Polyarteritis Nodosa
26. Rheumatoid Arthritis (RA)
27. Sjögren’s syndrome
28. Systemic lupus erythematosus (SLE)
Companion Documents
1. Rituximab Dose Rounding and Rapid Infusion Rate Delegation Protocol – Adult - Inpatient/Outpatient
2. Intravenous Administration of Formulary Medications – Adult– Inpatient/Ambulatory Clinical Practice
Guideline
3. Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting - Adult -
Inpatient/Ambulatory Clinical Practice Guideline
4. Extravasation of Chemotherapeutic Agents – Adult/Pediatric – Inpatient/Ambulatory
Pertinent UWHC Policies & Procedures
1. Policy 8.30 Management of Clinic Administered Medications with Internal Pharmacy Prior
Authorization
2. Policy 8.33 High Alert Medication Administration
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Scope
Disease/Condition(s):
The use of rituximab for the treatment of non-lymphoma hematology, neurology, and rheumatology
conditions in adult patients is evaluated. Use of rituximab for treatment of lymphoma and transplant
patients is excluded.
Clinical Specialty & Intended Users:
Prescribing physicians in hematology, neurology, rheumatology; mid-level providers; pharmacists, nurses
CPG objective:
Standardization of cost-effective therapies for the treatment of auto-immune disorders.
Major Outcomes Considered:
Improvement in patient outcomes while minimizing adverse effects and cost of therapy.
Methodology
A modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system
developed by the American Heart Association and the American College of Cardiology Foundation has
been used to assess the Quality and Strength of the evidence in this Clinical Practice Guideline.
(Appendix A).1
Cost of therapy is a consideration of treatment recommendations.
Table 1. Cost comparison of therapies for autoimmune disorders
Drug Dose Estimated Annual Cost Medication
Rituximab
1000 mg x 2 doses every 6 months $37,392.00
375 mg/m2 x 4 doses every 6 months $56,088.00
Adalimumab 40 mg every 2 weeks $51,826.00
Etanercept 50 mg weekly $57,300.00
IV Immune Globulin 0.4 – 1 mg/kg monthly (70 kg) $22,305.72 - 55,764.24
Infliximab 700 mg every 8 weeks $58,094.00
Cyclophosphamide
1425 mg IV every month $11,723.00
100 mg PO daily $11,300.00
Definitions
1. TNF inhibitors – Tumor necrosis factor (TNF) inhibitors
Medications include adalimumab (Humira®), certolizumab (Cimzia®), etanercept (Enbrel®),
golimumab (Simponi®), and infliximab (Remicade®)
2. DMARD – Disease modifying anti-rheumatic drugs (DMARD) include hydroxychloroquine,
leflunomide, cyclosporine, sulfasalazine, methotrexate, azathioprine, cyclophosphamide, and
mycophenolate
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Introduction
Rituximab is a chimeric murine human recombinant monoclonal antibody targeting the CD20 surface
antigen of normal and abnormal B-lymphocytes. Rituximab is bound specifically to the antigen CD20,
which is located on pre-B and mature B-lymphocytes. The antigen is expressed on the majority of B-cell
non-Hodgkin’s lymphomas (NHL); however, it is not found on hematopoietic stem cells, pro-B-cells,
normal plasma cells or other normal tissue.2-4 The CD20 surface antigen is responsible for regulation of
early steps in the activation process for cell cycle initiation and differentiation. B-cells contribute in the
pathogenesis of rheumatoid arthritis by acting at multiple sites in the autoimmune/inflammatory process
such as production of rheumatoid factor and other autoantibodies, antigen presentation, T-cell activation,
and pro-inflammatory cytokine production. Many other immune disorders have a component of B-cell
activation and thus rituximab has become the focus of therapy for these disorders as well.5
Recommendations
General Recommendations
1. Screening for infectious risk factors is required prior to initiation of rituximab.6-9 (Class I, Level C)
1.1. Hepatitis B – Screen patients for hepatitis B surface antigen (HBsAg), antibodies against hepatitis
B surface antigen (anti-HBs), and antibodies against hepatitis B core antigen (anti-HBc), to
identify patients with acute, chronic or resolved hepatitis B infection.6,8,10,11 (Class I, Level C)
1.1.1. Administer hepatitis B vaccine to patients with negative HBsAg and anti-HBc.6
1.1.2. If hepatitis B virus (HBV), HBsAg and HBV DNA are negative, but anti-HBc is positive, it is
safe to administer rituximab.6
1.1.3. Treat chronic hepatitis B prior to initiating rituximab.12
1.2. Hepatitis C – Screen patients for chronic hepatitic C prior to initiating rituximab and assess need
for treatment of active infection.6,8,11 (Class I, Level C)
1.3. Consider monitoring IgG concentrations prior to initiating therapy.8,13 (Class IIB, Level C) Patients
with IgG < 6 g/L may be at a higher risk of infection.
2. If a patient develops a reactivation of hepatitis B during treatment with rituximab, discontinue therapy
and initiate hepatitis B treatment.9 (Class I, Level C)
3. Do not administer rituximab to patients with severe infections or hypogammaglobulinemia with very
low CD4 or CD8 levels.8 (Class III, Level C)
4. Delay therapy in patients with severe, acute, active infections.6,8 (Class I, Level C)
5. Evaluate the risk/benefit ratio of rituximab therapy in patients with chronic infections. If rituximab is
given, monitor more frequently for exacerbation of infection.6,8 (Class I, Level C)
6. Do not administer rituximab in patients with severe heart failure (NYHC IV).6 (Class III, Level C)
7. Vaccination (Class I, Level C)
7.1. Administer indicated, inactivated vaccines prior to rituximab (ideally four weeks prior to
initiation).2,6,8,12 Class I, Level C)
7.1.1. Tetanus
7.1.2. Pneumococcal
7.1.3. Influenza (inactivated)
7.1.4. Hepatitis B
7.2. Do not administer live vaccines within 4 weeks of initiating rituximab or during rituximab therapy:
varicella zoster, intranasal influenza, measles/mumps/rubella, typhoid fever (oral), yellow fever 2,6
(Class I, Level C)
7.3. Do not administer Bacillus Calmette-Guerin (BCG) vaccine to patients with autoimmune
inflammatory disease.7 (Class III, Level C)
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8. Concomitant administration with other biologic agents is not recommended. 6,8,14 Discontinue TNF
inhibitors prior to rituximab therapy (i.e., do not overlap therapies). (Class I, Level C).
9. Round doses of rituximab by ≤ 10% to the nearest 100 mg. (Class I, Level C)
10. Premedicate patients prior to every infusion to prevent infusion reactions.2,6,8 (Class I, Level C)
10.1. Premedicate all patients with acetaminophen and an antihistamine.
10.2. Administer glucocorticoids as premedication if the patient has experienced severe infusion
reactions in the past or it is included in the treatment regimen.
11. Administration rates
Due to the chimeric structure of rituximab, infusion reactions are common and potentially life
threatening.2 Severe reactions are more likely to occur within 30 to 120 minutes of infusion initiation
and with the first infusion.
11.1. The National Cancer Institute for grading adverse reactions can be utilized to grade the severity
of infusion reactions with rituximab (Table 2).15 (Class I, Level C)
Table 2. National Cancer Institute for Infusion Reactions
Grade Definition
1 Mild reaction; no interruption of infusion or treatment required
2 Mild symptoms responsive to interruption of therapy or treatment
3
Prolonged reactions, not rapidly responsive to therapy, or
recurrence of symptoms
4 Life threatening reactions requiring vasopressors or ventilation
5 Death
11.2. If severe hypersensitivity or infusion reactions occur, then slow or stop the infusion.2 (Class I,
Level C)
11.2.1. Restart the infusion at one-half of the previous rate.
11.2.2. Treat with emergency medications as required (e.g., corticosteroids, bronchodilators,
fluids, epinephrine, oxygen)
11.3. First infusion rates (FIR)2 (Class I, Level C)
11.3.1. Utilize FIR for all first doses, if the previous infusion was administered more than 6
months ago or if previous rituximab infusion was poorly tolerated.
11.3.2. Initiate infusion at 50 mg/hour. If no infusion reactions occur, increase rate by 50
mg/hour at 30-minute intervals to a maximum rate of 400 mg/hour. (Table 3.)
11.3.3. Monitor vital signs prior to infusion prior to infusion, every 15 minutes times four, then
every hour until completed.
11.4. Rapid infusion rate (RIR).2,16-18 (Class IIa, Level C)
11.4.1. Patients eligible for RIR must meet the following criteria:
11.4.1.1. Previous infusion less than 6 months ago
11.4.1.2. Previous infusion was well tolerated without slowing or stopping the infusion or
treatment of infusion reactions. (Table 3)
11.4.1.3. Most recent circulating lymphocyte count is less than 5000 cells/mm3
11.4.1.4. Patient does not have heart failure with New York Heart Classification (NYHC)
III or IV
11.4.1.5. Patient is not enrolled in a study that does not allow rapid infusion.
11.4.2. Initiate infusion at 240 mL/h for 30 minutes, if tolerated increase to 480 mL/h for the
remainder of the infusion.
11.4.3. Monitor vital signs prior to infusion and every 15 minutes for the first 60 minutes, then
every 30 minutes until the infusion is complete.
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Table 3. Infusion Rates for Rituximab
Rituximab Infusion
Rate Initial Rate of Infusion Titration of Infusion
Maximum Rate
of Infusion
First Infusion Rate
(FIR) 50 mg/h for 30 minutes 50 mg/h every 30 minutes 400 mg/h
Rapid Infusion Rate
(RIR) 240 mL/h for 30 minutes to 480 mL/h 480 mL/h
12. Monitoring (Class I, Level C)
12.1. Monitor patients closely for infusion reactions, which include fever, chills, rigors, pruritus,
urticaria/rash, angioedema, sneezing, throat irritation, cough and/or bronchospasm, and
arthralgias.2
12.1.1. Monitor blood pressure, heart rate, temperature, and respirations during infusion
12.1.2. Use medical management (e.g., corticosteroids, bronchodilators, fluids, epinephrine) to
treat severe infusion reactions.
12.2. Monitor CBC without differential and platelet counts routinely.2
12.3. Monitor for symptoms of bacterial, fungal, and viral infections.
Disease Specific Recommendations
13. Autoimmune Hemolytic Anemia (AIHA)
13.1. Warm AIHA (wAIHA)
Rituximab is recommended for patients with wAIHA who experience relapse after treatment with
corticosteroids.19-24 (Class IIa, Level B)
13.1.1. Corticosteroids (e.g., prednisone 1 mg/kg/day for 3 weeks) are first line therapy for
patients with wAIHA.19 (Class I, Level B)
13.1.2. One small randomized trial demonstrated that corticosteroids plus rituximab were more
effective than corticosteroids alone for inducing remission as the initial treatment of
wAIHA.25 (Class IIa, Level B)
13.1.3. Splenectomy is an alternate second line therapy for patients with wAIHA who do not
respond to corticosteroids. (Class I, Level B)
13.2. Cold AIHA (CAD) - Rituximab is recommended for patients with CAD who cannot avoid low
temperature triggers. (Class IIa, Level B)
13.3. Steroids and splenectomy are usually not effective treatments for CAD.
13.4. Target of therapy: stabilization of therapeutic markers for anemia (hemoglobin, reticulocyte
count, serum lactate dehydrogenase, indirect bilirubin, etc.).
13.5. The ordering of rituximab for AIHA is restricted to the Hematology service or approval by a
Hematology attending physician.
13.6. Dosing: the usual dose of rituximab for AIHA is 375 mg/m2 IV weekly for 4 doses. (Class IIa,
Level B)
13.7. Evaluate patient response to rituximab 16 - 24 weeks after initiation. (Class I, Level B)
13.7.1. Patients with a moderate response should be retreated when response dissipates,
when drug effect (measured by detectable CD19+ B-lymphocytes) begins to wane, or
every 24 weeks.
14. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Rituximab is a treatment option for patients who do not respond to intravenous immunoglobulin
(IVIG), or to help reduce the frequency of IVIG treatments.26-33 (Class IIb, Level B)
14.1. Corticosteroids (daily prednisone, pulsed dexamethasone, etc.), IVIG, and plasmapheresis have
been shown to have similar efficacy in CIDP and are first line treatments.34 (Class IIa, Level A)
14.2. Target of therapy: improvement in muscle strength or nerve conduction as measured by such
tests as the Neurological Disability Score (NDS), Medical Research Council (MRC) strength
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score, quantitative sensory score (QSS), the adjusted Inflammatory Neuropathy Cause and
Treatment (INCAT) scale, or others.
14.3. Predictive factors for a therapeutic response to rituximab in CIDP may include neuropathy
associated with antibodies to myelin-associated glycoprotein (anti-MAG).27,29
14.4. The ordering of rituximab for CIDP is restricted to the Neurology service or approval of a
Neurology attending physician.
14.5. Dosing: the usual dose of rituximab for CIDP is 375 mg/m2 IV weekly for 4 doses.
14.5.1. An alternate dosing regimen for rituximab in patients with CIDP is 1000 mg IV every 14
days for 2 doses.35
14.6. Evaluate patient response to rituximab 16-24 weeks after initiation. (Class 1, Level B)
14.6.1. Patients with a moderate response should be retreated when response dissipates, or
every 24 weeks.
15. Cryoglobulinemic vasculitis
Rituximab is an option for patients with cryoglobulinemic vasculitis (CV) associated with hepatitis C
unresponsive to glucocorticoids and immunosuppressants or intolerant to anti-viral therapy.36-38
(Class IIa, Level B)
15.1. In patients with glomerulonephritis or severe leg ulcerations treat in combination with anti-viral
therapy.38
15.2. Dosing: 375 mg/m2 IV weekly for 4 doses.36,38 (Class IIb, Level C)
15.2.1. An alternate dosing regimen for rituximab in patients with CV is 1000 mg IV every 14
days for 2 doses.37
15.3. Administer rituximab with or without glucocorticoids.37 (Class IIb, Level C)
15.4. A second course of therapy may be required.37,38 (Class IIb, Level C)
15.5. Monitor efficacy with Birmingham Vasculitis Activity Score.36,37,39,40 (Class I, Level C)
16. Dermatomyositis/Polymyositis (DM/PM)
Rituximab is a treatment option in patients with refractory DM/PM.41-47 (Class IIb, Level B) Refractory
DM/PM: patients who have failed to respond to at least one immunosuppressant medication (with or
without concomitant corticosteroid therapy).
16.1. Corticosteroids (e.g., prednisone 1 mg/kg/day, methylprednisolone, etc.) are the first line
treatment for DM/PM. (Class I, Level B)
16.2. Immunosuppressants (azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, etc.)
are second line therapies for patients refractory to corticosteroids. (Class IIb, Level B)
16.3. Target of therapy: improvement in symptoms (muscle weakness, skin manifestations, etc.),
stabilization of therapeutic markers of muscle injury (creatine kinase, etc.), or complete
remission.
16.4. Predictive factors for a therapeutic response to rituximab in DM/PM may include the presence of
anti-Jo-1 or anti-Mi-2 autoantibodies.48
16.5. The ordering of rituximab for DM/PM is restricted to the Rheumatology and Neurology services
or approval by a Rheumatology/Neurology attending or fellow physicians.
16.6. Dosing: the usual dose of rituximab for DM/PM is 375 mg/m2 IV weekly for 4 doses. (Class IIb,
Level C)
16.6.1. An alternate dose of rituximab for DM/PM is 1000 mg IV every 14 days for 2 doses.
16.7. Evaluate patient response to rituximab 16-24 weeks after initiation. (Class 1, Level B)
16.7.1. Patients with a moderate response should be retreated when response dissipates, when
drug effect (measured by detectable CD19+ B-lymphocytes) begins to wane, or every
24 weeks.
17. Eosinophilic granulomatosis with polyangiitis (EPGA) – Churg-Straus
Rituximab may improve outcomes in patients with EPGA refractory to first line treatment with
glucocorticoids.49-53 (Class IIb, Level C)
17.1. Both dosing regimens of 1000 mg IV every 14 days for 2 doses and 375 mg/m2 IV weekly for 4
doses have been utilized in case reports.54
17.2. Monitor ESR, absolute eosinophil count, end organ function.
17.3. Cyclophosphamide is an alternative treatment for EPGA and may be more cost-effective.
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17.4. Bronchospasm and infectious complications may complicate therapy.54,55
18. Goodpasture’s syndrome
Insufficient evidence is available to recommend the use of rituximab for the treatment of
Goodpasture’s syndrome.38,56 (Class III, Level C)
19. Granulomatosis with polyangiitis (GPA) – Wegner’s Granulomatosis
Rituximab is indicated for the treatment of GPA in combination with glucocorticoids.2,57-62 (Class I,
Level A)
19.1. Dosing: 375 mg/m2 IV weekly for 4 doses or 500 mg on days 0 and 14 and every 6 months.63
(Class I, Level A)
19.2. With initial treatment administer glucocorticoids in combination with rituximab (e.g., prednisone
1 mg/kg/day or methylprednisolone 1000 mg IV for 3 days) (Class I, Level A)
19.3. Repeat doses may be required at 6 to 11 month intervals; however, sparse data limits
recommending routine repeat courses of therapy.2 (Class IIb, Level B)
19.4. Monitor clinical efficacy with the Birmingham Vasculitis Activity Score for WG (BVAS/WG) or the
Birmingham Vasculitis Activity Score (BVAS).39,64 (Class I, Level B)
19.5. Cyclophosphamide is an alternative treatment for GPA and may be more cost-effective.57,58,65
(Class I, Level B)
20. Immune (Idiopathic) thrombocytopenia purpura (ITP)
Rituximab is recommended for patients with ITP who have not responded to, or who relapsed after,
treatment with corticosteroids and splenectomy or who are not candidates for splenectomy.3,4,66-69
(Class IIa, Level B)
20.1. Corticosteroids (e.g., prednisone 1 mg/kg/day or dexamethasone 40 mg pulses) are first line
treatment for ITP. (Class 1, Level B)
20.2. Splenectomy produced the highest levels of complete remission in patients who relapse after
corticosteroid therapy. (Class IIa, Level B)
20.3. Use of rituximab as second line therapy may decrease the need for splenectomy.70
20.4. Target of therapy: improvement in symptoms (bleeding, etc.) and stabilization of therapeutic
markers for thrombocytopenia (e.g., platelet counts).
20.5. The ordering of rituximab for ITP is restricted to the Hematology service or approval of a
Hematology attending physician.
20.6. Dosing: the usual dose of rituximab for ITP is 375 mg/m2 IV weekly for 4 doses. (Class IIa,
Level B)
20.6.1. An alternate dosing regimen for rituximab in patients with ITP is 1000 mg IV every 14
days for 2 doses.71
20.7. Evaluate patient response to rituximab 16 - 24 weeks after initiation. (Class 1, Level B)
20.7.1. Patients with a moderate response should be retreated when response dissipates, when
drug effect (measured by detectable CD19+ B-lymphocytes) begins to wane, or every
24 weeks
21. Microscopic Polyangiitis (MPA)
Rituximab in combination with glucocorticoids for the treatment of MPA is non-inferior to
cyclophophamide.2,57-59,62 (Class I, Level A)
21.1. Dosing: 375 mg/m2 IV weekly for 4 doses (Class I, Level A)
21.2. FDA approved for the treatment of MPA in combination with glucocorticoids.
21.2.1. Initiate methylprednisolone 14 days or less prior to rituximab or concomitantly during
rituximab course of therapy
21.2.2. Taper prednisone based on symptoms.
21.3. For the treatment of severe vasculitis, administer methylprednisolone 1000 mg IV daily for 3
days followed by prednisone 1 mg/kg (maximum 80 mg).
21.4. Safety and efficacy of retreatment is not well established.
21.5. Cyclophosphamide is an alternative treatment for MPA and may be more cost effective.57,58,65
Consider cyclophosphamide for initial therapy in patients when teratogenicity is not a
consideration. (Class IIb, Level C)
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21.6. Rituximab is preferred in patients with relapsing disease.57 (Class IIb, Level C)
21.7. Monitor clinical efficacy with the Birmingham Vasculitis Activity Score (BVAS).39
22. Multiple Sclerosis (MS)
Rituximab is a treatment option for patients with relapsing-remitting multiple sclerosis (RRMS).72-75 An
adequate trial of a disease modifying therapy is recommended before consideration of rituximab
treatment. (Class IIa, Level B)
22.1. Rituximab treatment has not been shown to change time to confirmed disease progression in
patients with primary progressive multiple sclerosis.74,76,77 (Class III, Level B)
22.2. Disease modifying therapies (e.g. interferon beta 1a, glatiramer acetate, fingolimod, etc.) are
first line therapy for RRMS. (Class IIa, Level A)
22.3. Target of therapy: improvement in symptoms (generally measured by the Expanded Disability
Status Scale (EDSS), decrease in relapse rate, or clinical remission.
22.4. The ordering of rituximab for MS is restricted to the Neurology service or approval of a
Neurology attending physician.
22.5. Dosing: the usual administration regimen of rituximab for MS is 1000 mg IV every 14 days for 2
doses. (Class IIa, Level B)
22.5.1. An alternate dosing regimen for rituximab in patients with MS is 375 mg/m2 IV weekly for
4 doses.
22.6. Evaluate patient response to rituximab 16-24 weeks after initiation. (Class 1, Level B)
22.6.1. Patients with a moderate response should be retreated when response dissipates, when
drug effect (measured by detectable CD19+ B-lymphocytes) begins to wane, or every
24 weeks.
23. Myasthenia Gravis (MG)
Rituximab is recommended as a treatment option for patients with refractory MG.78-85 (Class IIa, Level
B) Refractory MG: patient whose disease has failed to respond to thymectomy and at least 1 or 2
immunosuppressive drugs (with or without concomitant oral corticosteroids).78
23.1. Acetylcholinesterase inhibitors (e.g., pyridostigmine) are first line therapy for newly diagnosed
MG and can serve as monotherapy for mild disease.86,87 (Class IIa, Level B)
23.1.1. Patients with positive MuSK antibodies (up to 7.5% of patients) may not respond
adequately to acetylcholinesterase inhibitors.
23.2. Thymectomy is indicated in MG patients with thymoma.86,87 (Class 1, Level B)
23.2.1. Thymectomy is recommended in patients with generalized MG who are AChR antibody
positive and under the age of 60. (Class IIa, Level B)
23.2.2. Patients with MuSK positive antibodies may not adequately respond to thymectomy.
23.3. Immunosuppressants (corticosteroids, azathioprine, cyclosporine, mycophenolate, and
tacrolimus) are recommended for short, and long, term symptom treatment of MG in patients
who do not adequately respond to acetylcholinesterase inhibitors. (Class IIa, Level B).
23.4. Target of therapy: improvement in symptoms (generally measured by the Myasthenia Gravis
Foundation of America Clinical Classification scale in the literature), decrease in relapse rate, or
clinical remission.
23.5. Predictive factors for a therapeutic response to rituximab in MG may include positive MuSK
antibodies.86,88
23.6. The ordering of rituximab for MG is restricted to the Neurology service or approval of a
Neurology attending physician.
23.7. Dosing: the usual administration regimen of rituximab for MG is 375 mg/m2 IV weekly for 4
doses. (Class IIa, Level B)
23.8. Evaluate patient response to rituximab 16 - 24 weeks after initiation. (Class 1, Level B)
23.8.1. Patients with a moderate response should be re-treated when response dissipates or
when drug effect (measured by detectable CD19+ B-lymphocytes) begins to wane.
24. Neuromyelitis Optica (NMO)
Rituximab is recommended for the maintenance treatment of NMO for patients who are steroid
dependent.89-92 (Class IIa, Level C)
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24.1. Acute relapses of NMO should be treated with corticosteroids (methylprednisolone 1 gram IV
daily for 3-5 days).93-95 (Class 1, Level C)
24.2. Immunosuppressants (azathioprine, mycophenolate mofetil) are alternate maintenance
treatments for steroid-dependent NMO and may be more cost-effective.93,96 (Class IIb, Level C)
24.2.1. Disease modifying therapies (interferon beta 1a, natalizumab, fingolimod, etc.) are not
treatment options and may exacerbate NMO symptoms. (Class III, Level C)
24.3. Target of therapy: improvement in symptoms (generally measured by EDSS), decrease in
relapse rate, or clinical remission.
24.4. The ordering of rituximab for NMO is restricted to the Neurology service or approval of a
Neurology attending physician.
24.5. Dosing: the usual dose of rituximab for NMO is 375 mg/m2 IV weekly for 4 doses. (Class IIa,
Level C)
24.5.1. An alternate dosing regimen of rituximab for NMO is 1000 mg IV every 14 days for 2
doses.
24.6. Evaluate patient response to rituximab 16-24 weeks after initiation. (Class 1, Level C)
24.6.1. Patients with a moderate response should be re-treated when drug effect (measured by
detectable CD19+ B-lymphocytes) begins to wane, or every 24 weeks.97
25. Polyarteritis Nodosa
Patients with polyarteritis nodosa associated with hepatitis B or hepatitis C and unresponsive to
prednisone and plasmapheresis may respond to rituximab.98-100 (Class IIb, Level C)
25.1. Dosage regimens of 375 mg/m2 weekly for 4 weeks or 1000 mg IV every 14 days for 2 doses
have been utilized.
25.2. Treat polyarteritis nodosa not associated with viral infections with glucocorticoids, not
rituximab.38 (Class III, Level C)
25.3. Monitor clinical manifestations, virologic parameters100
26. Rheumatoid Arthritis (RA)
Rituximab is indicated for patients with moderate or high disease activity with insufficient response to
at least 3 month trials of DMARD and TNF inhibitor therapy, or patients with an intolerance or
contraindication to DMARD/TNF inhibitor therapy, or a history of a malignancy diagnosis, or MS.
2,12,101
(Class I, Level A)
26.1. If moderate or high disease activity exists after treatment with one anti-TNF agent, consider a
trial of another TNF inhibitor before initiating rituximab.12,102,103 (Class IIb, Level C)
26.1.1. If a patient experiences a serious adverse event with a TNF inhibitor, then a non-TNF
inhibitor should be trialed.12 (Class I, Level C)
26.1.2. If a patient experiences a non-serious adverse event with a TNF inhibitor, then consider
another TNF- inhibitor prior to rituximab. (Class IIb, Level C)
26.2. Treat RA patients with methotrexate or methotrexate plus prednisone prior to rituximab, unless
contraindicated.2,6,12,14 (Class I, Level A)
26.2.1. Extent and duration of response improves when giving methotrexate concomitantly with
rituximab.14
26.2.2. If methotrexate is contraindicated, administer rituximab with leflunomide or without
additional DMARD agents.8 (Class IIb, Level B)
26.3. Predictive factors for a therapeutic response to rituximab for RA include positive rheumatoid
factor, anti citrullinated protein antibody (ACPA) or increased IgG concentration.104 (Class IIb,
Level B)
26.4. Abatacept or tocilizumab may be preferable in patients with negative rheumatoid factor.8 (Class
IIb, Level C)
26.5. The ordering of rituximab for RA is restricted to the Rheumatology service or approval of a
Rheumatology attending physician.
26.6. Dosing: the usual dose of rituximab for RA is 1000 mg IV every 14 days for 2 doses.
26.7. Evaluate clinical response to rituximab 16 – 24 weeks after initiation.6,8 (Class I, Level C)
26.7.1. Monitor validated disease activity scores, along with functional ability and radiographic
progression.6
ξ Simplified Disease Activity Index (SDAI)105
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13
ξ Clinical Disease Activity Index (CDAI)105
ξ Modified Disease Activity Scores (DAS)106,107
26.7.2. Target therapy to low dose activity or remission as monitored by SDAI ≤ 1195,108 109
26.8. The duration of response is commonly six months or more; patients with a moderate response
should be re-treated when response dissipates, but not more often than every 24 weeks, 6,110
(Class IIa, Level B)
26.9. Seropositive RA patients failing to respond to the first cycle of rituximab may or may not
respond to a second course of therapy. Consider alternative therapy prior to administering a
second course of rituximab in non-responders.6,111-115 (Class IIa, Level C)
27. Sjögren’s syndrome
Rituximab is indicated for severe, active, primary and secondary Sjögren’s’ syndrome with
extraglandular manifestations to decrease saliva production, pain, fatigue and extraglandular
manifestations.116-120 (Class I, Level B).
27.1. Dosing: 375 mg/m2 IV every week for 2 – 4 doses or 1000 mg IV every 14 days x 2 doses.
(Class I, Level B)
27.2. Duration of effect varies among patients, but most parameters return to normal within 6 to 9
months.
27.3. Corticosteroids are not required in conjunction with rituximab for the treatment of Sjögren
Syndrome.117 (Class IIa, Level B)
27.4. Retreatment with another cycle of therapy can be effective.118,121 (Class IIa, Level B)
27.5. Monitor disease progression and regression with European Sjögren’s Syndrome Disease
Activity Index (ESSDAI)122 (Class I, Level C)
28. Systemic lupus erythematosus (SLE)
Rituximab induces remission or partial remission for SLE patients with moderate to severe disease
refractory to other therapies and is indicated for patients failing at least two conventional
immunosuppressive therapies.123-133 (Class I, Level B).
28.1. Rituximab in effective for patients with arthritis, skin vasculitis, hemolytic anemia,
thrombocytopenia, nephritis, and neuropsychiatric symptoms related to SLE in patients
refractory to standard therapy with corticosteroids, azathioprine, immune globulin, or
cyclophosphamide.123,125,128,134
28.2. Effective doses in clinical trials include 375 mg/m2 IV every week for 4 doses or 1000 mg IV
every 14 days for 2 doses per cycle.123-125,135 (Class I, Level B)
28.3. Failure to achieve B cell depletion is associated with a poor response.124,125
28.4. Concomitant administration of immunosuppressive agents in conjunction with rituximab may be
required to maintain remission.124-126,136-138 (Class IIb, Level C)
28.5. Time to relapse after administration of rituximab is highly variable.124,125
28.6. Retreatment can be effective in reducing disease activity125,139,140
28.7. Monitor patients with SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment
Group (BILAG index)141,142
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14
UW Health Implementation
Potential Benefits and Harms:
The potential benefit of this guideline is to standardize care across UW Health for the treatment of auto-
immune disorders with rituximab and decrease medication cost. Potential harm includes risk of infusion
reaction and other adverse drug reactions from rituximab.
Qualifying Statements
Information included in this guideline is based on available literature and many low quality trials. If
additional, higher quality trials are published, recommendations may change.
Implementation Plan/Tools
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
2. Links to this guideline will be updated and/or added in appropriate Health Link or equivalent tools,
including: rituximab medication order record
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.
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Appendix A – ACCF/AHA GRADING
ACCF/AHA Clinical Practice Guideline Methodology Summit Report1
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21
Appendix B – Rituximab Indications, Dosing, and Level of Evidence
Indication Criteria for Use Dosing Regimen Monitoring Level of Evidence
Autoimmune Hemolytic Anemia
(AIHA)
1. Warm AIHA: Unresponsive to
corticosteroids and are deemed to be non-
candidates for splenectomy.
2. A diagnosis of cold autoimmune hemolytic
anemia (CAD).
375 mg/m2 once weekly
for 4 weeks
Monitor therapeutic markers for anemia
(HCT, Hgb, reticulocyte count, serum
lactate dehydrogenase, indirect bilirubin,
etc.)
Class IIa, Level B
Chronic Inflammatory
Demyelinating Polyneuropathy
(CIDP) and other autoimmune
polyneuropathies
Unresponsive to intravenous immunoglobulin
(IVIG) or to decrease the frequency of IVIG
treatments
375 mg/m2 once weekly
for 4 weeks
Monitor objective improvement in muscle
strength, sensory sensation, or nerve
conduction (e.g. Neurological Disability
Score, MRC strength score, adjusted
Inflammatory Neuropathy Cause and
Treatment scale, EMG, etc.)
Class IIb, Level B
Cryoglobulinemic Vasculitis 1. Associated with hepatitis C but patient
unresponsive or intolerant to anti-viral agents
2. Hepatitis with glomerulonephritis or severe
leg ulcerations in combination with anti-viral
agents
3. Mixed cryoglobulinemia with vasculitis
unresponsive to glucocorticoids and
immunosuppressants
375 mg/m2 once weekly
for 4 weeks
Monitor end organ damage
Birmingham Vasculitis Activity Score
(BVAS)
Class IIa, Level B
Dermatomyositis/Polymyositis
(DM/PM)
Unresponsive to at least one trial of a
conventional immunosuppressant
(azathioprine, methotrexate, cyclosporine,
mycophenolate mofetil)
375 mg/m2 once weekly
for 4 weeks or
1000 mg every 14 days
x 2 doses
Monitor objective improvements in
muscle strength, skin manifestation
improvement (rash), and therapeutic
markers of muscle injury (creatine
kinase, etc.)
Class IIb, Level B
Eosinophilic granulomatosis
with polyangiitis (EPGA) –
Churg-Straus
Unresponsive or intolerant to first line therapy
of glucocorticoids.
375 mg/m2 once weekly
for 4 weeks or
1000 mg every 14 days
x 2 doses
Monitor ESR, eosinophil count, end
organ function
Class IIb, Level C
Granulomatosis with
Polyangiitis (GPA) - Wegner's
Use in combination with glucocorticoids. 375 mg/m2 once weekly
for 4 weeks
Evaluate at 6 months for remission of
disease or absence of clinical disease
activity. Birmingham Vasculitis Activity
Score (BVAS)
Class I, Level A
Immune thrombocytopenia
purpura (ITP)
Unresponsive to corticosteroids and deemed
to be a non-candidate for splenectomy
375 mg/m2 once weekly
for 4 weeks
Monitor platelet counts and objective
signs of bleeding
Class IIa, Level B
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22
Indication Criteria for Use Dosing Regimen Monitoring Level of Evidence
Microscopic Polyangiitis (MPA) Use in combination with glucocorticoids.
Consider cyclophosphamide in when
teratogenicity and relapsing disease are not a
consideration.
375 mg/m2 once weekly
for 4 weeks
Birmingham Vasculitis Activity Score
(BVAS)
Class I, Level A
Multiple Sclerosis (MS) 1. Relapsing-remitting MS unresponsive to at
least one disease modifying therapy
(interferon beta, glatiramer, acetate,
fingolimod, etc.)
2. Progressive forms of MS should not be
treated with rituximab
1000 mg every 14 days
x 2 doses
Monitor disability (Expanded Disability
Status Scale), number of symptom
relapses, etc.
Class IIa, Level B
Myasthenia Gravis (MG) Unresponsive to thymectomy (if indicated) and
at least one conventional immunosuppressant
(azathioprine, cyclosporine, mycophenolate
mofetil, tacrolimus)
375 mg/m2 once weekly
for 4 weeks
Monitor symptom improvement (muscle
fatigue, MGFA clinical classification
improvement), relapse rate, etc.)
Class IIa, Level B
Neuromyelitis Optica (NMO) Unresponsive to, or cannot be weaned from,
corticosteroids
375 mg/m2 once weekly
for 4 weeks or
1000 mg every 14 days
x 2 doses
Monitor disability (Expanded Disability
Status Scale), number of symptom
relapses, etc.
Class IIb, Level C
Polyarteritis Nodosa Unresponsive to prednisone and
plasmapheresis
1000 mg every 14 days
x 2 doses
Clinical manifestations, virologic
parameters
Class IIb, Level C
Rheumatoid Arthritis (RA) Moderate to severe active disease with
insufficient responsive or contraindication to
DMARDs and one or more TNF inhibitors or
malignancy diagnosis.
1000 mg every 14 days
x 2 doses
Functionality, radiographic progression,
Simplified Disease Activity Index (SDAI),
Clinical Disease Activity Index (CDAI),
Modified Disease Activity Scores (DAS)
scores
Class I, Level A
Sjögren’s Syndrome Severe, active disease with extraglandular
manifestations
375 mg/m2 every 2
weeks x 2 doses or
weekly for 4 weeks
Clinical manifestations, European
Sjögren’s Syndrome Disease Activity
Index (ESSDAI)
Class I, Level B
Systemic lupus erythematous
(SLE)
Moderate to severe disease refractory to other
therapies
cycle treatment:
rituximab 1000 mg every
14 days x 2 doses
British Isles Lupus Assessment Group
index (BILAG
Class I, Level B
DMARD - disease modifying antirheumatic drugs
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