Rituximab

Identification

Name

Rituximab

Accession Number

DB00073

Description

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light and heavy-chain variable region sequences and human constant region sequences ⁶, ^Label. It was originally approved by the U.S. FDA in 1997 as a single agent to treat patients with B-cell Non-Hodgkin's Lymphoma (NHL) ⁸, however, has now been approved for a variety of conditions ^Label. On November 28, 2018, the US FDA approved Truxima, the first biosimilar to Rituxan (Rituximab) ⁷.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: C₆₄₁₆H₉₈₇₄N₁₆₈₈O₁₉₈₇S₄₄
Protein Average Weight: 143859.7 Da

Sequences

>Rituximab heavy chain chimeric
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSY
NQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS
AASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

>Rituximab light chain chimeric
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVR
FSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

Rituximab - CAS 174722-31-7 [Link]

Download FASTA Format

Synonyms

rituximab-abbs
rituximab-pvvr

External IDs

GP2013
IDEC-102
IDEC-C2B8
PF 05280586
PF-05280586
RG-105

Pharmacology

Indication

Rituximab is indicated in the following conditions ^Label:

Non–Hodgkin’s Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)

Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

Moderate to severe Pemphigus Vulgaris (PV) in adult patients

The biosimilar (approved in November 2018), Truxima, is indicated For the treatment of adult patients with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL) to be used as a single agent or in combination with chemotherapy ⁷.

In September 2019, the rituximab injection was approved along with glucocorticoids to manage granulomatosis with polyangiitis (GPA) in addition to microscopic polyangiitis (MPA) in children of at least 2 years of age ⁹.

Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Rituximab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lymphomas ¹. The antibody leads to selective killing of B-cells. The following are the pharmacodynamic outcomes for various conditions, including non- Hodgkin's Lymphoma ^Label:

Non-Hodgkin’s Lymphoma (NHL) In Non-Hodgkin's Lymphoma patients, the administration of rituximab led to the depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks, showing sustained depletion for up to 6-9 months post-treatment in 83% of treated patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following the completion of treatment ^Label. There were sustained and statistically significant decreases in serum IgM and IgG levels measured from 5-11 months following rituximab administration; 14% of patients showed IgM and/or IgG serum levels below the normal range ^Label.

Rheumatoid Arthritis In rheumatoid arthritis (RA) patients, treatment with rituximab induced the depletion of peripheral B lymphocytes, with the majority of patients showing near complete depletion (CD19 counts below the lower limit of quantification, 20 c-lls/μl) within 2 weeks after the first dose of rituximab. The majority of treated patients showed peripheral B-cell depletion, sustained for a minimum of 6 months. A small percentage of patients (~4%) had peripheral B-cell depletion that was sustained for more than 3 years after one course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were decreased at 6 months with the greatest change observed in IgM. At Week 24 of the first cycle of rituximab treatment, small percentages of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). When rituximab was administered to RA patients during repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab are not clear at this time. Treatment with rituximab in patients with RA was associated with a decreased level of several biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF ^Label and was found to decrease disease symptoms ².

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis In GPA and MPA patients, peripheral blood CD19 B-cells were depleted to less than 10 cells/μl after the first two infusions of rituximab, and remained at the same level in most (84%) patients through Month 6 of the treatment. By Month 12, most patients (81%) demonstrated signs of B-cell return with counts >10 cells/μL. By Month 18, the majority of patients (87%) had counts >10 cells/μL ^Label.

Mechanism of action

Rituximab is a monoclonal antibody that targets the CD20 antigen, which is expressed on the surface of pre-B and mature B-lymphocytes ¹, ², ³, ^Label. After binding to CD20, rituximab mediates B-cell lysis (or breakdown). The possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC) ^Label.

Rituximab belongs to the immunoglobulin G1 (IgG1) sub-class, consisting of a murine variable region (Fab region) and a human constant region (Fc region). The Fab region has variable sections that define a specific target antigen, allowing the antibody to attract and secure its exclusive antigen, specifically the binding of rituximab (IgG1) to CD20 on pre-B and mature B lymphocytes. The Fc region is the tail end of the antibody that communicates with cell surface receptors to activate the immune system, in this case, a sequence of events leading to the depletion of circulating B lymphocytes by complement-dependent cell lysis, antibody-dependent cellular cytotoxicity, as well as apoptosis ⁶.

In regards to the mechanism of action in rheumatoid arthritis, B cells are thought to play a role in the pathogenesis of rheumatoid arthritis (RA) and the associated condition of chronic synovitis. B cells may act at various sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or the production of proinflammatory cytokines ^Label. The administration of rituximab in this condition has been shown to result in significant clinical and symptomatic improvements ², ^Label.

Target	Actions	Organism
AB-lymphocyte antigen CD20	antibody	Humans

Absorption

Following the administration of 2 doses of rituximab in patients with rheumatoid arthritis (RA), the mean (± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were : 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively ^Label.

Volume of distribution

3.1 L in Rheumatoid Arthritis ^Label

4.5 L in Granulomatosis with polyangitis and microscopic polyangitis ^Label

Protein binding

Not Available

Metabolism

Most likely removed by opsonization via the reticuloendothelial system ⁵.

Route of elimination

Likely eliminated through the reticuloendothelial system ⁵.

Half-life

Non-Hodgkin's Lymphoma: Based on a population pharmacokinetic analysis of data from 298 Non-Hodgkin's Lymphoma (NHL) patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days) ^Label.

Rheumatoid Arthritis: Mean terminal elimination half-life was 18.0 days in patients with rheumatoid arthritis ^Label Based on a population pharmacokinetic analysis of data from 2005 RA patients who received rituximab ^Label.

Chronic Lymphocytic Leukemia (CLL): Pharmacokinetics were studied in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14-62 days) ^Label.

Granulomatosis with Polyangitis and Microscopic Polyangitis: Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2 rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days) ^Label.

Clearance

Rheumatoid Arthritis: 0.335 L/day ^Label

Granulomatosis with Polyangitis and Microscopic Polyangitis: 0. 312 L/day ^Label

Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance ^Label.

Adverse Effects

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Toxicity

Oral LD50: 27 mg/kg (mouse and rat) ^MSDS

Inhalation LD50: 32 mg/m3 (mouse) and 37 mg/m3 (rat) ^MSDS

Skin LD50: 20 mg/kg (rabbit) and 50 mg/kg (rat) ^MSDS

Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab or to determine potential effects on fertility in males or females ^Label.

Embryo-Fetal toxicity: Can cause neonatal harm. Advise of potential risk to neonates and use of effective contraception ^Label.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Low affinity immunoglobulin gamma Fc region receptor III-A	FCGR3A	(G;G) / (G;T)	T > G	Effect Directly Studied	Patients with this genotype have increased frequency of anti-tumor response when using rituximab to treat diffuse large B-cell lymphoma, follicular lymphoma, or [follicular non-Hodgkin lymphoma].	Details

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abatacept	Rituximab may increase the immunosuppressive activities of Abatacept.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Rituximab.
Acebutolol	Acebutolol may increase the hypotensive activities of Rituximab.
Acenocoumarol	The risk or severity of bleeding can be increased when Acenocoumarol is combined with Rituximab.
Acetylsalicylic acid	The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Rituximab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Rituximab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Rituximab.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Rituximab.
Alefacept	The risk or severity of adverse effects can be increased when Rituximab is combined with Alefacept.
Alemtuzumab	The risk or severity of adverse effects can be increased when Rituximab is combined with Alemtuzumab.

Additional Data Available

Extended Description

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Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

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A severity rating for each drug interaction, from minor to major.

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Evidence Level

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A rating for the strength of the evidence supporting each drug interaction.

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Action

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An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

Products

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International/Other Brands

MabThera (Roche)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Rituxan	Injection, solution	10 mg/1mL	Intravenous	Genentech, Inc.	1997-11-26	Not applicable
Rituxan	Solution	10 mg	Intravenous	Hoffmann La Roche	2000-03-20	Not applicable
Rituxan	Injection, solution	10 mg/1mL	Intravenous	Genentech, Inc.	1997-11-26	Not applicable
Rituxan Sc	Solution		Subcutaneous	Hoffmann La Roche	2018-04-24	Not applicable
Rituxan Sc	Solution		Subcutaneous	Hoffmann La Roche	2016-11-22	Not applicable
Riximyo	Solution		Intravenous	Sandoz Canada Incorporated	2020-05-22	Not applicable
Ruxience	Injection, solution	500 mg/50mL	Intravenous	Pfizer Laboratories Div Pfizer Inc	2020-01-23	Not applicable
Ruxience	Solution	10 mg	Intravenous	Pfizer Canada Ulc	2020-05-26	Not applicable
Ruxience	Injection, solution	100 mg/10mL	Intravenous	Pfizer Laboratories Div Pfizer Inc	2020-01-23	Not applicable
Truxima	Solution	100 mg	Intravenous	Celltrion	2019-12-11	Not applicable

Additional Data Available

Application Number

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A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

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A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Rituxan Hycela	Rituximab (120 mg/1mL) + Hyaluronidase (human recombinant) (2000 U/1mL)	Injection, solution	Subcutaneous	Genentech, Inc.	2017-06-22	Not applicable
Rituxan Hycela	Rituximab (120 mg/1mL) + Hyaluronidase (human recombinant) (2000 U/1mL)	Injection, solution	Subcutaneous	Genentech, Inc.	2017-06-22	Not applicable

Chemical Identifiers

UNII: 4F4X42SYQ6
CAS number: 174722-31-7

References

General References

McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. [PubMed:9704735]
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. [PubMed:15201414]
Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TM, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, Hasselbalch HC: Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol. 2005 Apr;78(4):275-80. [PubMed:15795920]
Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M: The epitope recognized by rituximab. Blood. 2006 Sep 15;108(6):1975-8. Epub 2006 May 16. [PubMed:16705086]
Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [PubMed:28653357]
Emer JJ, Claire W: Rituximab: a review of dermatological applications. J Clin Aesthet Dermatol. 2009 May;2(5):29-37. [PubMed:20729962]
FDA approves first biosimilar for treatment of adult patients with non-Hodgkin’s lymphoma [Link]
FDA Approves Two New Indications for Rituxan in Patients With Non-Hodgkin's Lymphoma [Link]
FDA approves first treatment for children with rare diseases that cause inflammation of small blood vessels [Link]

External Links

UniProt: P01857
Genbank: J00228
PubChem Substance: 46505820
RxNav: 121191
ChEMBL: CHEMBL1201576
Therapeutic Targets Database: DAP000382
PharmGKB: PA451261
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Rituximab

AHFS Codes

10:00.00 — Antineoplastic Agents

FDA label

Download (257 KB)

MSDS

Download (117 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Prevention	Transplant, Kidney	1
4	Active Not Recruiting	Treatment	Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Granulomatosis With Polyangiitis / Microscopic Polyangiitis	1
4	Active Not Recruiting	Treatment	Function of Renal Transplant	1
4	Completed	Other	Autoimmune Diseases / Transplant, Kidney	1
4	Completed	Prevention	Autoimmune Adrenocortical Failure	1
4	Completed	Prevention	Transplantation, Kidney	1
4	Completed	Treatment	Acute Lymphoblastic Leukaemias (ALL)	1
4	Completed	Treatment	Adult Acute Lymphocytic Leukemia	1
4	Completed	Treatment	Burkitt's Lymphoma / Large Cell Anaplastic Lymphoma / Lymphoma, Lymphoblastic / Mediastinal Neoplasms	1
4	Completed	Treatment	Chronic Lymphocytic Leukaemia (CLL)	1

Pharmacoeconomics

Manufacturers

Roche

Packagers

Biogen Idec Inc.
F Hoffmann-La Roche Ltd.
Genentech Inc.

Dosage Forms

Form	Route	Strength
Solution, concentrate	Intravenous	500 mg
Injection	Intravenous	10 MG/ML
Injection	Intravenous	1400 MG/11.7ML
Injection, solution		1.4 g/11.7mL
Injection, solution	Cutaneous	1400 MG
Injection, solution, concentrate	Intravenous	100 mg/10mL
Injection, solution, concentrate	Intravenous	500 mg/50mL
Injection	Intravenous	100 mg
Injection, solution	Intravenous	120 mg/mL
Injection, solution	Subcutaneous	1400 MG
Injection	Intravenous	500 mg/50ml
Solution, concentrate	Intravenous	10 mg/ml
Solution	Subcutaneous	1400 mg
Injection	Intravenous
Solution	Intravenous	100 mg/10ml
Solution	Intravenous	500 mg/50ml
Injection, solution	Intravenous	10 mg/1mL
Solution	Intravenous	10 mg
Injection, solution	Subcutaneous
Solution	Subcutaneous
Injection, solution, concentrate	Intravenous	100 MG
Injection, solution, concentrate	Intravenous	500 MG
Solution	Intravenous
Injection, solution	Intravenous	100 mg/10mL
Injection, solution	Intravenous	500 mg/50mL
Injection, solution, concentrate	Intravenous; Parenteral	100 MG
Injection, solution, concentrate	Intravenous; Parenteral	500 MG
Solution	Intravenous	100 mg
Solution	Intravenous	500 mg

Prices

Unit description	Cost	Unit
Rituxan 10 mg/ml Concentrate 10ml Vial	708.17USD	vial
Rituxan 10 mg/ml vial	68.09USD	ml

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Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
Unlock Additional Data
CA2149329	No	2008-07-15	2013-11-12
CA1336826	No	1995-08-29	2012-08-29
US5736137	No	1998-04-07	2015-04-07

Additional Data Available

Filed On

Available for Purchase

The date on which a patent was filed with the relevant government.

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Properties

State

Liquid

Experimental Properties

Property	Value	Source
melting point (°C)	61 °C (FAB fragment)	http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062
hydrophobicity	-0.414	http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062
isoelectric point	8.68	http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062

Targets

Details1. B-lymphocyte antigen CD20

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antibody

General Function: Mhc class ii protein complex binding
Specific Function: This protein may be involved in the regulation of B-cell activation and proliferation.
Gene Name: MS4A1
Uniprot ID: P11836
Uniprot Name: B-lymphocyte antigen CD20
Molecular Weight: 33076.99 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
van Meerten T, Hagenbeek A: CD20-targeted therapy: the next generation of antibodies. Semin Hematol. 2010 Apr;47(2):199-210. doi: 10.1053/j.seminhematol.2010.01.007. [PubMed:20350667]
Jaglowski SM, Byrd JC: Rituximab in chronic lymphocytic leukemia. Semin Hematol. 2010 Apr;47(2):156-69. doi: 10.1053/j.seminhematol.2010.01.005. [PubMed:20350663]
McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. [PubMed:9704735]
Rituxan FDA label [File]