Editing Rituximab

{{Short description|Biopharmaceutical drug}}
{{Use dmy dates|date=March 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid = 458438457
| image = Rituximab.png
| width = 300
| alt = 
| caption =

<!-- Monoclonal antibody data -->
| type = mab
| mab_type = mab
| source = xi/o
| target = [[CD20]]

<!-- Clinical data -->
| pronounce = 
| tradename = Rituxan, Mabthera, others
| Drugs.com = {{drugs.com|monograph|rituximab}}
| MedlinePlus = a607038
| DailyMedID = Rituximab
| pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Rituximab Use During Pregnancy | website=Drugs.com | date=16 December 2019 | url=https://www.drugs.com/pregnancy/rituximab.html | access-date=2 February 2020 | archive-date=30 August 2019 | archive-url=https://web.archive.org/web/20190830220734/https://www.drugs.com/pregnancy/rituximab.html | url-status=live }}</ref>
| pregnancy_category= 
| routes_of_administration = [[Intravenous infusion|Intravenous]]
| class = [[Monoclonal antibody]]
| ATC_prefix = L01
| ATC_suffix = FA01
| ATC_supplemental =
| biosimilars = rituximab-abbs,<ref name="Truxima FDA label">{{cite web | title=Truxima- rituximab-abbs injection solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9af3ddc7-4217-417a-ac89-8704edc5bc44 | access-date=26 March 2021 | archive-date=25 March 2021 | archive-url=https://web.archive.org/web/20210325082706/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9af3ddc7-4217-417a-ac89-8704edc5bc44 | url-status=live }}</ref> rituximab-pvvr,<ref name="Ruxience FDA label">{{cite web | title=Ruxience- rituximab-pvvr injection solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f941fc61-f7a3-4e4a-ab7c-87c1667fa05b | access-date=26 March 2021}}</ref> rituximab-arrx,<ref name="Riabni FDA label">{{cite web | title=Riabni- rituximab-arrx injection solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da1c4de7-0e5b-4f72-97ec-7a8d368f085f | access-date=26 March 2021 | archive-date=25 March 2021 | archive-url=https://web.archive.org/web/20210325082725/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da1c4de7-0e5b-4f72-97ec-7a8d368f085f | url-status=live }}</ref> Blitzima<ref>{{cite web | title=Blitzima EPAR | website=[[European Medicines Agency]] | date=13 July 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/blitzima | access-date=1 July 2024 | archive-date=9 September 2021 | archive-url=https://web.archive.org/web/20210909064129/https://www.ema.europa.eu/en/medicines/human/EPAR/blitzima | url-status=live }}</ref> Ituxredi,<ref name="Ituxredi EPAR" /><ref name="Ituxredi PI" /> Riabni,<ref name="Riabni FDA label" /> Rixathon,<ref>{{cite web | title=Rixathon EPAR | website=[[European Medicines Agency]] | date=15 June 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/rixathon | access-date=7 January 2024 | archive-date=9 September 2021 | archive-url=https://web.archive.org/web/20210909064148/https://www.ema.europa.eu/en/medicines/human/EPAR/rixathon | url-status=live }}</ref> Riximyo,<ref>{{cite web | title=Summary Basis of Decision (SBD) for Riximyo | website=[[Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00494&lang=en | access-date=29 May 2022 | archive-date=30 May 2022 | archive-url=https://web.archive.org/web/20220530055258/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00494&lang=en | url-status=live }}</ref> Ruxience,<ref name="Ruxience FDA label" /> Truxima<ref name="Truxima FDA label" />

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref name="MabThera PI">[https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropmabth10415 Rituximab (rch) (CAS registry number: 174722-31-7)] {{webarchive|date=30 November 2015|url=https://web.archive.org/web/20151130164406/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropmabth10415}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = Rx-only
| legal_CA_comment = /&nbsp;Schedule D<ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=[[Health Canada]] | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024 | archive-date=25 March 2024 | archive-url=https://web.archive.org/web/20240325234307/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = <ref name="MabThera SmPC">{{cite web | title=Mabthera 100 mg Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=13 March 2021 | url=https://www.medicines.org.uk/emc/product/3801/smpc | access-date=26 March 2021 | archive-date=21 January 2022 | archive-url=https://web.archive.org/web/20220121012710/https://www.medicines.org.uk/emc/product/3801/smpc | url-status=live }}</ref><ref name="MabThera SC SmPC">{{cite web | title=Mabthera 1400 mg Solution for Subcutaneous Injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=13 March 2021 | url=https://www.medicines.org.uk/emc/product/5333/smpc | access-date=26 March 2021}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Rituxan FDA label" /><ref name="Truxima FDA label" /><ref name="Ruxience FDA label" /><ref name="Riabni FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="MabThera EPAR">{{cite web | title=Mabthera EPAR | website=[[European Medicines Agency]] | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/mabthera | access-date=8 September 2021 | archive-date=9 September 2021 | archive-url=https://web.archive.org/web/20210909063437/https://www.ema.europa.eu/en/medicines/human/EPAR/mabthera | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref>{{cite web | title=Mabthera PI | website=Union Register of medicinal products | date=3 June 1998 | url=https://ec.europa.eu/health/documents/community-register/html/h067.htm | access-date=5 July 2024}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->
| bioavailability = 100% (IV)
| protein_bound =
| metabolism =
| metabolites = 
| onset = 
| elimination_half-life = 30 to 400 hours (varies by dose and length of treatment)
| duration_of_action = 
| excretion = Uncertain: may undergo phagocytosis and catabolism in RES

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 174722-31-7
| CAS_supplemental = 
| PubChem =
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00073
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4F4X42SYQ6
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02994
| ChEBI_Ref = 
| ChEBI = 
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201576
| NIAID_ChemDB = 
| PDB_ligand =

<!-- Chemical and physical data -->
| C=6416 | H=9874 | N=1688 | O=1987 | S=44
}}

<!-- Definition and medical uses -->
'''Rituximab''', sold under the brand name '''Rituxan''' among others, is a [[monoclonal antibody]] medication used to treat certain [[autoimmune diseases]] and types of [[cancer]].<ref name=AHFS2016/> It is used for [[non-Hodgkin lymphoma]], [[chronic lymphocytic leukemia]] (in children and adults, but not recommended in elderly patients), [[rheumatoid arthritis]], [[granulomatosis with polyangiitis]], [[idiopathic thrombocytopenic purpura]], [[pemphigus vulgaris]], [[myasthenia gravis]] and [[Epstein–Barr virus]]-positive [[mucocutaneous ulcer]]s.<ref name=AHFS2016/><ref>{{cite journal | vauthors = Tandan R, Hehir MK, Waheed W, Howard DB | title = Rituximab treatment of myasthenia gravis: A systematic review | journal = Muscle & Nerve | volume = 56 | issue = 2 | pages = 185–196 | date = August 2017 | pmid = 28164324 | doi = 10.1002/mus.25597 | s2cid = 19504332 }}</ref><ref>{{cite journal | vauthors = Singer O, McCune WJ | title = Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis | journal = Current Opinion in Rheumatology | volume = 29 | issue = 3 | pages = 248–253 | date = May 2017 | pmid = 28306595 | doi = 10.1097/BOR.0000000000000382 | s2cid = 35805200 }}</ref><ref name=Doj2018>{{cite journal | vauthors = Dojcinov SD, Fend F, Quintanilla-Martinez L | title = EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts | journal = Pathogens | volume = 7 | issue = 1 | pages = 28 | date = March 2018 | pmid = 29518976 | pmc = 5874754 | doi = 10.3390/pathogens7010028 | doi-access = free | title-link = doi }}</ref> It is given by slow [[intravenous infusion]] (injected slowly through an IV line).<ref name=AHFS2016>{{cite web|title=Rituximab|url=https://www.drugs.com/monograph/rituximab.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-date=27 March 2016|archive-url=https://web.archive.org/web/20160327001117/http://www.drugs.com/monograph/rituximab.html}}</ref>

<!-- Side effects -->
The most common side effects with intravenous infusions are reactions related to the infusion (such as fever, chills and shivering) while most common serious side effects are infusion reactions, infections and heart-related problems.<ref name="MabThera EPAR" /> Similar side effects are seen when it is injected under the skin, with the exception of reactions around the injections site (pain, swelling and rash), which occur more frequently with the skin injections.<ref name="MabThera EPAR" />

Severe side effects include reactivation of [[hepatitis B]] in those previously infected, [[progressive multifocal leukoencephalopathy]], [[toxic epidermal necrolysis]], and death.<ref name=AHFS2016/><ref>{{cite web | title=FDA Drug Safety Communication: Boxed Warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 February 2016 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-boxed-warning-and-new-recommendations-decrease-risk-hepatitis-b | access-date=2 February 2020 | archive-date=28 April 2020 | archive-url=https://web.archive.org/web/20200428213737/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-boxed-warning-and-new-recommendations-decrease-risk-hepatitis-b | url-status=live }}</ref> It is unclear if use during [[pregnancy]] is safe for the developing fetus or newborn baby.<ref name="Drugs.com pregnancy" /><ref name=AHFS2016/>

<!-- Mechanism -->
Rituximab is a [[Fusion protein|chimeric]] [[monoclonal antibody]] against the protein [[CD20]], which is primarily found on the surface of immune system [[B cells]].<ref name=Bos2013/> When it binds to this protein it triggers cell death.<ref name=AHFS2016/>

<!-- History society and culture -->
Rituximab was approved for medical use in 1997.<ref name=Bos2013>{{cite book| vauthors = Bosch X, Ramos-Casals M, Khamashta MA |title=Drugs Targeting B-Cells in Autoimmune Diseases|date=2013|publisher=Springer Science & Business Media|isbn=9783034807067|pages=1–4|url=https://books.google.com/books?id=2l-4BAAAQBAJ&pg=PA4|url-status=live|archive-url=https://web.archive.org/web/20171105200138/https://books.google.com/books?id=2l-4BAAAQBAJ&pg=PA4|archive-date=5 November 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> Rituxan is co-marketed by [[Biogen]] and [[Genentech]] in the US, by [[Hoffmann-La Roche|Roche]] elsewhere except Japan, and co-marketed by [[Chugai Pharmaceuticals]] and Zenyaku Kogyo in Japan.<ref name="Biogen PR 20100218">{{cite press release|url=https://investors.biogen.com/news-releases/news-release-details/fda-approves-rituxan-plus-chemotherapy-most-common-type-adult|title=FDA Approves Rituxan Plus Chemotherapy for the Most Common Type of Adult Leukemia|publisher=Biogen|date=18 February 2010|access-date=30 June 2021|archive-date=9 July 2021|archive-url=https://web.archive.org/web/20210709182746/https://investors.biogen.com/news-releases/news-release-details/fda-approves-rituxan-plus-chemotherapy-most-common-type-adult|url-status=live}}</ref><ref>{{cite press release | title=FDA Approves Genentech's Rituxan (rituximab) in Children With Two Rare Blood Vessel Disorders | publisher=Genentech | via=Business Wire | date=27 September 2019 | url=https://www.businesswire.com/news/home/20190927005432/en/FDA-Approves-Genentech%E2%80%99s-Rituxan-rituximab-in-Children-With-Two-Rare-Blood-Vessel-Disorders | access-date=27 August 2024}}</ref>

== Medical uses ==

Rituximab is a chimeric monoclonal antibody targeted against CD20, a [[cell membrane|surface]] [[antigen]] present on [[B cell]]s. It acts by depleting normal as well as pathogenic B cells while sparing [[plasma cell]]s and [[hematopoietic stem cell]]s, which do not express the CD20 surface antigen.<ref>{{cite journal | vauthors = De A, Ansari A, Sharma N, Sarda A | title = Shifting Focus in the Therapeutics of Immunobullous Disease | journal = Indian Journal of Dermatology | volume = 62 | issue = 3 | pages = 282–290 | date = 2017 | pmid = 28584371 | pmc = 5448263 |doi = 10.4103/ijd.IJD_199_17 | doi-access = free | title-link = doi }}</ref>

In the United States, rituximab is [[Indication (medicine)|indicated]] to treat:

# [[non-Hodgkin lymphoma]]<ref name="Rituxan FDA label" />
# [[chronic lymphocytic leukemia]]<ref name="Rituxan FDA label" />
# [[rheumatoid arthritis]] having inadequate response to one or more [[TNF inhibitor]]s<ref name="Rituxan FDA label" />
# [[vasculitis|vasculitides]] such as [[granulomatosis with polyangiitis]] and [[microscopic polyangiitis]]<ref name="Rituxan FDA label" />
# moderate to severe [[pemphigus vulgaris]]<ref name="Rituxan FDA label" />
# in combination with chemotherapy for children (≥ 6 months to < 18 years) with previously untreated, advanced stage, CD20-positive [[diffuse large B-cell lymphoma]] (DLBCL), [[Burkitt lymphoma]] (BL), Burkitt-like lymphoma (BLL), or mature acute [[B-cell leukemia]] (B-AL).<ref name="Rituxan FDA label" /><ref name="FDA 20211203">{{cite web | title=FDA approves rituximab plus chemotherapy for pediatric cancer indications | website=U.S. Food and Drug Administration | date=3 December 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rituximab-plus-chemotherapy-pediatric-cancer-indications | access-date=4 December 2021 | archive-date=3 December 2021 | archive-url=https://web.archive.org/web/20211203153512/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rituximab-plus-chemotherapy-pediatric-cancer-indications | url-status=live }} {{PD-notice}}</ref>

In the European Union, rituximab is indicated for the treatment of follicular lymphoma and diffuse large B cell non-Hodgkin's lymphoma (two types of non-Hodgkin's lymphoma, a blood cancer);<ref name="MabThera EPAR" /> chronic lymphocytic leukemia (CLL, another blood cancer affecting white blood cells);<ref name="MabThera EPAR" /> severe rheumatoid arthritis (an inflammatory condition of the joints);<ref name="MabThera EPAR" /> two inflammatory conditions of blood vessels known as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA);<ref name="MabThera EPAR" /> moderate to severe pemphigus vulgaris, an autoimmune disease characterised by widespread blistering and erosion of the skin and mucous membranes (the linings of internal organs). 'Autoimmune' means that the disease is caused by the immune system (the body's natural defences) attacking the body's own cells.<ref name="MabThera EPAR" />

=== Blood cancers ===
Rituximab is used to treat [[Hematological malignancy|cancers of the white blood system]] such as [[leukemia]]s and [[lymphoma]]s, including non-Hodgkin's lymphoma, [[chronic lymphocytic leukemia]], and nodular lymphocyte predominant Hodgkin's lymphoma.<ref>{{cite journal | vauthors = Saini KS, Azim HA, Cocorocchio E, Vanazzi A, Saini ML, Raviele PR, Pruneri G, Peccatori FA | title = Rituximab in Hodgkin lymphoma: is the target always a hit? | journal = Cancer Treatment Reviews | volume = 37 | issue = 5 | pages = 385–390 | date = August 2011 | pmid = 21183282 | doi = 10.1016/j.ctrv.2010.11.005 }}</ref><ref>{{cite journal | vauthors = Eichenauer DA, Engert A | title = Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management | journal = Hematology. American Society of Hematology. Education Program | volume = 2017 | issue = 1 | pages = 324–328 | date = December 2017 | pmid = 29222274 | pmc = 6142570 | doi = 10.1182/asheducation-2017.1.324 }}</ref> This also includes [[Waldenström's macroglobulinemia]], a type of non-Hodgkin lymphoma.<ref name=AHFS2016/> Rituximab in combination with [[hyaluronidase]] human, sold under the brand names Mabthera SC<ref name="MabThera SC SmPC" /> and Rituxan Hycela,<ref name="Rituxan Hycela label" /> is used to treat [[follicular lymphoma]], [[diffuse large B-cell lymphoma]], and chronic lymphocytic leukemia.<ref name="Rituxan Hycela label">{{cite web|date=3 December 2019|title=Rituxan Hycela- rituximab and hyaluronidase injection, solution|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e5b7e82-f018-4eaf-ae78-d6145a906b20|access-date=2 February 2020|website=DailyMed|archive-date=27 March 2021|archive-url=https://web.archive.org/web/20210327083228/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e5b7e82-f018-4eaf-ae78-d6145a906b20|url-status=live}}</ref> It is used in combination with [[fludarabine]] and [[cyclophosphamide]] to treat previously untreated and previously treated CD20-positive chronic lymphocytic leukemia.<ref name="Rituxan FDA label">{{cite web|date=6 November 2019|title=Rituxan- rituximab injection, solution|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563|access-date=2 February 2020|website=DailyMed|archive-date=4 August 2020|archive-url=https://web.archive.org/web/20200804180021/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563|url-status=live}}</ref>

=== Autoimmune diseases ===

Rituximab has been shown to be an effective [[rheumatoid arthritis]] treatment in three [[randomised controlled trials]] and is now licensed for use in [[refractory]] rheumatoid disease.<ref>{{cite journal | vauthors = Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T | title = Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis | journal = The New England Journal of Medicine | volume = 350 | issue = 25 | pages = 2572–2581 | date = June 2004 | pmid = 15201414 | doi = 10.1056/NEJMoa032534 | doi-access = free | title-link = doi }}</ref> In the United States, it has been [[FDA approval|FDA approved]] for use in combination with [[methotrexate]] for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-[[TNF-alpha]] therapy. In the European Union, the license is slightly more restrictive: it is licensed for use in combination with methotrexate in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy.<ref>{{cite journal | vauthors = Tak PP, Kalden JR | title = Advances in rheumatology: new targeted therapeutics | journal = Arthritis Research & Therapy | volume = 13 | issue = Suppl 1 | pages = S5 | date = May 2011 | pmid = 21624184 | pmc = 3123966 | doi = 10.1186/1478-6354-13-S1-S5 | doi-access = free | title-link = doi }}</ref>

There is some evidence for efficacy, but not necessarily [[Pharmacovigilance|safety]], in a range of other autoimmune diseases, and rituximab is widely used [[off-label]] to treat difficult cases of [[multiple sclerosis]],<ref name=McGinley2017rev>{{cite journal | vauthors = McGinley MP, Moss BP, Cohen JA | title = Safety of monoclonal antibodies for the treatment of multiple sclerosis | journal = Expert Opinion on Drug Safety | volume = 16 | issue = 1 | pages = 89–100 | date = January 2017 | pmid = 27756172 | doi = 10.1080/14740338.2017.1250881 | s2cid = 36762194 }}</ref><ref>{{cite journal | vauthors = He D, Guo R, Zhang F, Zhang C, Dong S, Zhou H | title = Rituximab for relapsing-remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD009130 | date = December 2013 | pmid = 24310855 | doi = 10.1002/14651858.CD009130.pub3 | pmc = 11972833 }}</ref> [[systemic lupus erythematosus]], [[chronic inflammatory demyelinating polyneuropathy]] and autoimmune [[anemia]]s.<ref name=NWU>{{cite web|url=http://www.northwestern.edu/newscenter/stories/2009/05/bennett.html|title=Popular Cancer Drug Linked to Often Fatal 'Brain Eating' Virus| vauthors = Paul M |date=20 May 2009|publisher=Northwestern University News and Information|access-date=22 May 2009|url-status=dead |archive-url=https://web.archive.org/web/20100529073721/http://www.northwestern.edu/newscenter/stories/2009/05/bennett.html|archive-date=29 May 2010}}</ref><ref>{{cite web | title=Popular Cancer Drug Linked To Often Fatal Brain Virus | website=ScienceDaily | date=9 May 2009 | url=https://www.sciencedaily.com/releases/2009/05/090518161158.htm | access-date=5 July 2024}}</ref> The most dangerous, although among the most rare, side effect is [[progressive multifocal leukoencephalopathy]] infection, which is usually fatal; however, only a very small number of cases have been recorded occurring in autoimmune diseases.<ref name=NWU /><ref>{{cite press release |url=https://www.fda.gov/bbs/topics/NEWS/2006/NEW01532.html |title=FDA Warns of Safety Concern Regarding Rituxan in New Patient Population |website=U.S. [[Food and Drug Administration]] (FDA) |date=18 December 2006 |access-date=29 April 2013 |url-status=dead |archive-date=13 May 2009 |archive-url=https://web.archive.org/web/20090513023924/https://www.fda.gov/bbs/topics/NEWS/2006/NEW01532.html}}</ref>

Other autoimmune diseases that have been treated with rituximab include [[autoimmune hemolytic anemia]], [[pure red cell aplasia]], [[thrombotic thrombocytopenic purpura]] (TTP),<ref>{{cite journal | vauthors = Froissart A, Veyradier A, Hié M, Benhamou Y, Coppo P | title = Rituximab in autoimmune thrombotic thrombocytopenic purpura: A success story | journal = European Journal of Internal Medicine | volume = 26 | issue = 9 | pages = 659–665 | date = November 2015 | pmid = 26293834 | doi = 10.1016/j.ejim.2015.07.021 | doi-access = free | title-link = doi }}</ref> [[idiopathic thrombocytopenic purpura]] (ITP),<ref>{{cite journal | vauthors = 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 | title = Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura | journal = American Journal of Hematology | volume = 78 | issue = 4 | pages = 275–280 | date = April 2005 | pmid = 15795920 | doi = 10.1002/ajh.20276 | s2cid = 42218074 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Patel V, Mihatov N, Cooper N, Stasi R, Cunningham-Rundles S, Bussel JB | year = 2007 | title = Long-term responses seen with rituximab in patients with ITP | url = http://www.communityoncology.net/journal/articles/0402107.pdf | journal = Community Oncology | volume = 4 | issue = 2 | page = 107 | doi = 10.1016/s1548-5315(11)70061-4 | url-status = dead | archive-url = https://web.archive.org/web/20070929061010/http://www.communityoncology.net/journal/articles/0402107.pdf | archive-date = 29 September 2007 | access-date = 18 April 2007 | department=Correspondence }}</ref> [[Evans syndrome]],<ref>{{cite journal | vauthors = Shanafelt TD, Madueme HL, Wolf RC, Tefferi A | title = Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome | journal = Mayo Clinic Proceedings | volume = 78 | issue = 11 | pages = 1340–1346 | date = November 2003 | pmid = 14601692 | doi = 10.4065/78.11.1340 }}</ref> vasculitis (e.g., [[granulomatosis with polyangiitis]]), [[bulla (dermatology)|bullous]] skin disorders (for example, [[pemphigus]], [[pemphigoid]]—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study),<ref>{{cite journal | vauthors = Ahmed AR, Spigelman Z, Cavacini LA, Posner MR | title = Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin | journal = The New England Journal of Medicine | volume = 355 | issue = 17 | pages = 1772–1779 | date = October 2006 | pmid = 17065638 | doi = 10.1056/nejmoa062930 | doi-access = free | title-link = doi }}</ref> type 1 [[diabetes mellitus]], [[Sjögren syndrome]], [[anti-NMDA receptor encephalitis]] and [[Devic's disease]]([[Anti-AQP4 disease]], [[MOG antibody disease]]),<ref>{{cite journal | vauthors = Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, Wingerchuk DM, Boggild M, Constantinescu CS, Miller A, De Angelis T, Matiello M, Cree BA | title = Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients | journal = Archives of Neurology | volume = 65 | issue = 11 | pages = 1443–1448 | date = November 2008 | pmid = 18779415 | doi = 10.1001/archneur.65.11.noc80069 | doi-access = free | title-link = doi }}</ref> [[Graves' ophthalmopathy]],<ref>{{cite web |url=http://www.ophthalmologyjournaloftheaao.com/article/S0161-6420%2809%2900548-X/abstract |title=Rituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy |access-date=19 October 2011 |url-status=dead |archive-url=https://web.archive.org/web/20170822220531/http://www.ophthalmologyjournaloftheaao.com/article/S0161-6420(09)00548-X/abstract |archive-date=22 August 2017 }}</ref> [[autoimmune pancreatitis]],<ref>{{cite journal |title=Immunomodulators and Rituximab in the Management of Autoimmune Pancreatitis |journal=Pancreapedia |date=11 June 2013 |doi=10.3998/panc.2013.20 | doi-access = free | title-link = doi | vauthors = Hart PA, Chari ST }}</ref> [[Opsoclonus myoclonus syndrome]] (OMS),<ref>{{cite journal | vauthors = Pranzatelli MR, Tate ED, Travelstead AL, Longee D | title = Immunologic and clinical responses to rituximab in a child with opsoclonus-myoclonus syndrome | journal = Pediatrics | volume = 115 | issue = 1 | pages = e115–e119 | date = January 2005 | pmid = 15601813 | doi = 10.1542/peds.2004-0845 | doi-access = free | title-link = doi }}</ref> and [[IgG4-related disease]].<ref>{{cite journal | vauthors = Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, Löhr M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH | title = International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease | journal = Arthritis & Rheumatology | volume = 67 | issue = 7 | pages = 1688–1699 | date = July 2015 | pmid = 25809420 | doi = 10.1002/art.39132 | s2cid = 39750214 }}</ref> There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.<ref>{{cite journal | vauthors = He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E | title = Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab | journal = JAMA Dermatology | volume = 151 | issue = 6 | pages = 646–650 | date = June 2015 | pmid = 25901938 | doi = 10.1001/jamadermatol.2015.59 | doi-access = free | title-link = doi }}</ref>

== Adverse events ==

Serious adverse events, which can cause death and disability, include:<ref name="Rituxan FDA label" /><ref name=AHFS2016 />

* Severe [[Intravenous infusion#Adverse effects|infusion reaction]]
* [[Cardiac arrest]]
* [[Cytokine release syndrome]]
* [[Tumor lysis syndrome]], causing [[acute kidney injury]]
* Infections<ref>{{cite journal | vauthors = Kyriakidis I, Mantadakis E, Stiakaki E, Groll AH, Tragiannidis A | title = Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas | journal = Cancers | volume = 14 | issue = 20 | pages = 5022 | date = October 2022 | pmid = 36291806 | pmc = 9599435 | doi = 10.3390/cancers14205022 | doi-access = free | title-link = doi }}</ref>
** [[Progressive multifocal leukoencephalopathy]] caused by [[JC virus]] reactivation<ref>{{cite journal | vauthors = Molloy ES, Calabrese LH | title = Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies | journal = Arthritis and Rheumatism | volume = 64 | issue = 9 | pages = 3043–3051 | date = September 2012 | pmid = 22422012 | doi = 10.1002/art.34468 }}</ref>
**[[Hepatitis B]] reactivation
** Other viral infections<ref>{{cite journal | vauthors = Grammatikos A, Donati M, Johnston SL, Gompels MM | title = Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies | journal = Frontiers in Immunology | volume = 12 | pages = 731643 | date = 30 August 2021 | pmid = 34527001 | pmc = 8435594 | doi = 10.3389/fimmu.2021.731643 | doi-access = free | title-link = doi }}</ref>
* Immune toxicity, with depletion of B cells in 70% to 80% of [[lymphoma]] patients
* [[human lung|Pulmonary]] toxicity<ref>{{cite journal | vauthors = Burton C, Kaczmarski R, Jan-Mohamed R | title = Interstitial pneumonitis related to rituximab therapy | journal = The New England Journal of Medicine | volume = 348 | issue = 26 | pages = 2690–1; discussion 2690–1 | date = June 2003 | pmid = 12826649 | doi = 10.1056/NEJM200306263482619 }}</ref>
* [[Bowel obstruction]] and [[Gastrointestinal perforation|perforation]]<ref>{{cite web |url=http://rochecanada.com/portal/servlet/staticfilesServlet?type=data&communityId=re753001&id=static/attachedfile/re7300002/re77300002/AttachedFile_04801.pdf |title=Reports of Bowel Obstruction and Perforation with Rituxan (rituximab) |date=10 November 2006 |publisher=Roche Canada |url-status=dead |archive-url=https://web.archive.org/web/20140327221239/http://rochecanada.com/portal/servlet/staticfilesServlet?type=data&communityId=re753001&id=static%2Fattachedfile%2Fre7300002%2Fre77300002%2FAttachedFile_04801.pdf |archive-date=27 March 2014 }}</ref>
A concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response.<ref>{{cite journal | vauthors = Oren S, Mandelboim M, Braun-Moscovici Y, Paran D, Ablin J, Litinsky I, Comaneshter D, Levartovsky D, Mendelson E, Azar R, Wigler I, Balbir-Gurman A, Caspi D, Elkayam O | title = Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response | journal = Annals of the Rheumatic Diseases | volume = 67 | issue = 7 | pages = 937–941 | date = July 2008 | pmid = 17981914 | doi = 10.1136/ard.2007.077461 | s2cid = 21878513 | doi-access = free | title-link = doi }}</ref>{{Unreliable medical source|date=October 2024|reason=primary source study}} This was brought into focus during the [[COVID-19 pandemic]], where persons with [[multiple sclerosis]] and rituximab treatment had higher risk of severe COVID-19.<ref>{{cite journal |vauthors=Spelman T, Forsberg L, McKay K, Glaser A, Hillert J |date=June 2022 |title=Increased rate of hospitalisation for COVID-19 among rituximab-treated multiple sclerosis patients: A study of the Swedish multiple sclerosis registry |journal=Multiple Sclerosis |volume=28 |issue=7 |pages=1051–1059 |doi=10.1177/13524585211026272 |pmid=34212816 |s2cid=235710318 | doi-access = free | title-link = doi }}</ref>{{Unreliable medical source|date=October 2024|reason=primary source study}}<ref>{{cite journal | vauthors = Reyes S, Ramsay M, Ladhani S, Amirthalingam G, Singh N, Cores C, Mathews J, Lambourne J, Marta M, Turner B, Gnanapavan S, Dobson R, Schmierer K, Giovannoni G | display-authors = 6 | title = Protecting people with multiple sclerosis through vaccination | journal = Practical Neurology | volume = 20 | issue = 6 | pages = 435–445 | date = December 2020 | pmid = 32632038 | doi = 10.1136/practneurol-2020-002527 | doi-access = free }}</ref> In persons previously treated with rituximab for multiple sclerosis, nine of ten patients who delayed re-dosing until B cell counts passed 40/μL developed protective levels of antibodies after vaccination with the [[Pfizer–BioNTech COVID-19 vaccine]].<ref>{{cite journal | vauthors = Tolf A, Wiberg A, Müller M, Nazir FH, Pavlovic I, Laurén I, Mangsbo S, Burman J | title = Factors Associated With Serological Response to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Treated With Rituximab | journal = JAMA Network Open | volume = 5 | issue = 5 | pages = e2211497 | date = May 2022 | pmid = 35544139 | doi = 10.1001/jamanetworkopen.2022.11497 | pmc = 9096596 | s2cid = 248695128 }}</ref>{{Unreliable medical source|date=October 2024|reason=primary source study}}

== Mechanisms of action ==
[[File:Rituximab mechanisms of action.jpg|thumbnail|right|Rituximab mechanisms of action; the three major independent mechanisms are (1) antibody dependent cellular cytotoxicity (ADCC), (2) complement mediated cytotoxicity (CMC), and (3) apoptosis; subset panel illustrates a schematic view of CD20 structure and rituximab.<ref name="pmid26443686">{{cite journal | vauthors = Seyfizadeh N, Seyfizadeh N, Hasenkamp J, Huerta-Yepez S | title = A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections | journal = Critical Reviews in Oncology/Hematology | volume = 97 | pages = 275–290 | date = January 2016 | pmid = 26443686 | doi = 10.1016/j.critrevonc.2015.09.001 }}</ref>]]

[[File:Rituxan in action.jpg|thumbnail|right|Rituximab binding to CD20. The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins.]]

The antibody binds to the cell surface protein [[CD20]]. CD20 is widely expressed on B cells, from early pre-B cells to later in [[Cellular differentiation|differentiation]], but it is absent on terminally differentiated [[plasma cell]]s. Although the function of CD20 is unknown, it may play a role in [[calcium|Ca<sup>2+</sup>]] influx across plasma membranes, maintaining intracellular Ca<sup>2+</sup> concentration and allowing activation of B cells.

Rituximab is relatively ineffective in elimination of cells with low CD20 cell-surface levels.<ref name="pmid32482755">{{cite journal | vauthors = Pavlasova G, Borsky M, Svobodova V, Oppelt J, Cerna K, Novotna J, Seda V, Fojtova M, Fajkus J, Brychtova Y, Doubek M, Pospisilova S, Mayer J, Mraz M | title = Rituximab primarily targets an intra-clonal BCR signaling proficient CLL subpopulation characterized by high CD20 levels | journal = Leukemia | volume = 32 | issue = 9 | pages = 2028–2031 | date = September 2018 | pmid = 30030508 | doi = 10.1038/s41375-018-0211-0 | doi-access = free | title-link = doi }}</ref> It tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changes the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time.<ref name="pmid23613524">{{cite journal | vauthors = Rudnicka D, Oszmiana A, Finch DK, Strickland I, Schofield DJ, Lowe DC, Sleeman MA, Davis DM | title = Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity | journal = Blood | volume = 121 | issue = 23 | pages = 4694–4702 | date = June 2013 | pmid = 23613524 | doi = 10.1182/blood-2013-02-482570 | doi-access = free | title-link = doi }}</ref>

The following effects have been found:<ref>{{cite journal | vauthors = Shaw T, Quan J, Totoritis MC | title = B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience | journal = Annals of the Rheumatic Diseases | volume = 62 | issue = Suppl 2 | pages = ii55–ii59 | date = November 2003 | pmid = 14532151 | pmc = 1766758 | doi = 10.1136/ard.62.suppl_2.ii55 }}</ref>

* The [[Fragment crystallizable region|Fc]] portion of rituximab mediates [[antibody-dependent cellular cytotoxicity]] (ADCC) and [[complement-dependent cytotoxicity]] (CDC).<ref name="pmid34438120">{{cite journal | vauthors = Borsky M, Hrabcakova V, Novotna J, Brychtova Y, Doubek M, Panovska A, Muller P, Mayer J, Trbusek M, Mraz M | title = Rituximab induces rapid blood repopulation by CLL cells mediated through their release from immune niches and complement exhaustion | journal = Leukemia Research | volume = 111 | pages = 106684 | date = December 2021 | pmid = 34438120 | doi = 10.1016/j.leukres.2021.106684 }}</ref>
* Rituximab has a general regulatory effect on the [[cell cycle]].
* Preferential elimination of malignant B cells with high CD20 levels and high BCR signaling propensity, especially in chronic lymphocytic leukemia (CLL).<ref name="pmid32482755" />
* It increases [[MHC II]] and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
* It elicits shedding of [[CD23]].
* It downregulates the [[B cell receptor]].
* It induces [[apoptosis]] of CD20+ cells.
* Rituximab also induces a release of some chronic lymphocytic leukemia cells from immune niches, which might make them more sensitive to chemotherapy used in combination with an anti-CD20 antibody.<ref name="pmid34438120" />

The combined effect results in the elimination of B cells (including the cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid [[stem cell]]s.

Rituximab binds to [[amino acid]]s 170–173 and 182–185 on CD20, which are physically close to each other as a result of a [[disulfide bond]] between amino acids 167 and 183.<ref>{{cite journal | vauthors = Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M | title = The epitope recognized by rituximab | journal = Blood | volume = 108 | issue = 6 | pages = 1975–1978 | date = September 2006 | pmid = 16705086 | doi = 10.1182/blood-2006-04-014639 | doi-access = free | title-link = doi }}</ref>

== History ==
Rituximab was developed by [[Biogen Idec|IDEC Pharmaceuticals]] under the name IDEC-C2B8. The US patent for the drug was issued in 1998 and expired in 2015.<ref name=patentNPriceData>{{cite web|url=https://go.drugbank.com/drugs/DB00073|archiveurl=https://web.archive.org/web/20140105002750/http://www.drugbank.ca/drugs/DB00073|url-status=dead|title=Rituximab|archive-date=5 January 2014|website=go.drugbank.com|access-date=14 March 2023}}</ref>

Based on its safety and effectiveness in [[clinical trial]]s,<ref>{{cite journal | vauthors = Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R | title = IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma | journal = Blood | volume = 90 | issue = 6 | pages = 2188–2195 | date = September 1997 | pmid = 9310469 | doi = 10.1182/blood.V90.6.2188 | doi-access = free | title-link = doi }}</ref> rituximab was approved by the US [[Food and Drug Administration]] (FDA) in 1997 to treat B-cell [[non-Hodgkin lymphoma]]s resistant to other [[chemotherapy]] regimens.<ref name="Rituximab Product Approval">{{cite web | title=Rituximab Product Approval Information | website=U.S. [[Food and Drug Administration]] (FDA) | date=20 February 2009 | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm093345.htm | archive-url=https://web.archive.org/web/20170210011738/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm093345.htm | archive-date=10 February 2017 | url-status=dead | access-date=27 August 2024 }}</ref><ref>{{cite journal | vauthors = Scott SD | title = Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma | journal = Cancer Practice | volume = 6 | issue = 3 | pages = 195–197 | year = 1998 | pmid = 9652253 | doi = 10.1046/j.1523-5394.1998.006003195.x }}</ref> Rituximab, in combination with [[CHOP (chemotherapy)|CHOP chemotherapy]], is superior to CHOP alone in the treatment of [[diffuse large B-cell lymphoma]] and many other B-cell lymphomas.<ref>''Harrison's Principles of Internal Medicine'', Longo et al. ''McGraw Hill Medical'' 2011 page 931</ref> In 2010, it was authorized by the [[European Commission]] for maintenance treatment after initial treatment of [[follicular lymphoma]].<ref>{{cite news |url=https://www.genengnews.com/news/roche-gets-ec-nod-for-follicular-lymphoma-maintenance-therapy/ |title=Roche Gets EC Nod for Follicular Lymphoma Maintenance Therapy |date=29 October 2010 |url-status=live |archive-url=https://web.archive.org/web/20101031202519/http://www.genengnews.com/gen-news-highlights/roche-gets-ec-nod-for-follicular-lymphoma-maintenance-therapy/81244149/ |archive-date=31 October 2010 }}</ref>

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd" />

Originally available for intravenous injection (e.g. over 2.5 hrs), in 2016, it gained EU approval in a formulation for subcutaneous injection for [[B-cell CLL/lymphoma]] (CLL).<ref>{{cite web | vauthors = Stanton D |url=https://www.biopharma-reporter.com/Article/2016/06/01/EU-approves-indication-for-subcutaneous-form-of-Roche-s-MabThera |title=EU approves second indication for subcutaneous form of Roche's rituximab |access-date=9 June 2016 |url-status=live |archive-url=https://web.archive.org/web/20160607225341/http://www.biopharma-reporter.com/Bio-Developments/EU-approves-indication-for-subcutaneous-form-of-Roche-s-MabThera |archive-date=7 June 2016 | website=BioPharma-Reporter | date=31 May 2016 }}</ref>

In June 2017, the US FDA granted regular approval to the combination of rituximab and hyaluronidase human (brand name Rituxan Hycela) for adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.<ref name="FDA 20170622">{{cite web | title=FDA approves rituximab plus hyaluronidase combination for Treatment of FL, DLBCL and CLL | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 June 2017 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rituximab-plus-hyaluronidase-combination-treatment-fl-dlbcl-and-cll | access-date=5 July 2024}} {{PD-notice}}</ref> The combination is not indicated for the treatment of non-malignant conditions.<ref name="Rituxan Hycela label" /><ref name="FDA 20170622" /> The combination was approved based on clinical studies SABRINA/NCT01200758 and MabEase/NCT01649856.<ref name="Rituxan Hycela label" />

In September 2019, the US FDA approved rituximab injection to treat granulomatosis with polyangiitis and microscopic polyangiitis in children two years of age and older in combination with glucocorticoids (steroid hormones).<ref name="FDA PR 20190927" /> It is the first approved treatment for children with these rare vasculitis diseases, in which a person's small blood vessels become inflamed, reducing the amount of blood that can flow through them.<ref name="FDA PR 20190927" /> This can cause serious problems and damage to organs, most notably the lungs and the kidneys.<ref name="FDA PR 20190927" /> It also can impact the sinuses and skin.<ref name="FDA PR 20190927">{{cite press release | title=FDA approves first treatment for children with rare diseases that cause inflammation of small blood vessels | website=U.S. [[Food and Drug Administration]] (FDA) | date=27 September 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-rare-diseases-cause-inflammation-small-blood-vessels | archive-url=https://web.archive.org/web/20190928014215/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-rare-diseases-cause-inflammation-small-blood-vessels | url-status=dead | archive-date=28 September 2019 | access-date=5 July 2024}} {{PD-notice}}</ref> Rituximab was approved by the FDA to treat adults with granulomatosis with polyangiitis and microscopic polyangiitis in 2011.<ref name="FDA PR 20190927" />

In December 2021, the US FDA approved rituximab in combination with chemotherapy for children aged 6 months to 18 years with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia.<ref name="FDA 20211203" /><ref name="FDA DISCO 20211217">{{cite web | title=FDA D.I.S.C.O. Burst Edition: FDA approvals of Rituxan (rituximab) plus chemotherapy for pediatric cancer indications, and Keytruda (pembrolizumab) for adjuvant treatment of Stage IIB or IIC melanoma | website=U.S. [[Food and Drug Administration]] (FDA) | date=2 December 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-rituxan-rituximab-plus-chemotherapy-pediatric-cancer | archive-url=https://web.archive.org/web/20221220074246/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-rituxan-rituximab-plus-chemotherapy-pediatric-cancer | url-status=dead | archive-date=20 December 2022 | access-date=5 July 2024}} {{PD-notice}}</ref> Efficacy was evaluated in Inter-B-NHL Ritux 2010, a global multicenter, open-label, randomized 1:1 trial of participants six months in age or older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or B-cell acute leukemia.<ref name="FDA DISCO 20211217" /> Advanced stage was defined as stage III with elevated lactose dehydrogenase level (lactose dehydrogenase greater than twice the institutional upper limit of normal values) or stage IV B-cell non-Hodgkin's lymphoma or B-cell acute leukemia.<ref name="FDA DISCO 20211217" /> Participants were randomized to Lymphome Malin B chemotherapy that consisted of corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple drug (methotrexate/cytarabine/corticosteroid) intrathecal therapy alone or in combination with rituximab or non-US licensed rituximab, administered as six infusions of rituximab IV at a dose of 375 mg/m2 as per the Lymphome Malin B scheme.<ref name="FDA DISCO 20211217" />

== Society and culture ==

=== Legal status ===
Rituximab was approved for medical use in the United States in November 1997.<ref name="Rituxan FDA label" /><ref name="Rituximab Product Approval" />

==== Biosimilars ====
[[Biosimilar]]s are approved in the United States, India, the European Union, Switzerland, Japan, and Australia.{{cn|date=August 2024}} The US FDA approved rituximab-abbs (Truxima) in 2018,<ref name="Truxima FDA label" /><ref name="FDA PR 20181128" /><ref name="FDA Truxima" /> rituximab-pvvr (Ruxience) in 2019,<ref name="Ruxience FDA label" /> and rituximab-arrx (Riabni) in 2020.<ref name="Riabni FDA label" />

In July 2024, the [[Committee for Medicinal Products for Human Use]] of the [[European Medicines Agency]] recommended marketing authorization for the rituximab biosimilar Ituxredi produced by [[Dr. Reddy's Laboratories|Dr. Reddy's Laboratories / Holding GmbH]]. Ituxredi is intended for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris.<ref name="Ituxredi EPAR">{{cite web |date=25 July 2024 |title=Ituxredi EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/ituxredi |access-date=27 July 2024 |website=European Medicines Agency}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Ituxredi was authorized for medical use in the European Union in September 2024.<ref name="Ituxredi EPAR" /><ref name="Ituxredi PI">{{cite web | title=Ituxredi Product information | website=Union Register of medicinal products | date=23 September 2024 | url=https://ec.europa.eu/health/documents/community-register/html/h1861.htm | access-date=24 September 2024}}</ref>

A Rituximab biosimilar was approved in India in 2007.<ref>{{Cite web |date=13 March 2018 |title=Rituximab Biosimilar to Launch in Turkish Market |url=https://www.centerforbiosimilars.com/view/rituximab-biosimilar-to-launch-in-turkish-market |access-date=24 October 2024 |website=Center for Biosimilars }}</ref>

=== Economics ===
In 2014, Genentech reclassified Rituxan as a [[specialty drug]], a class of drugs that are only available through specialty distributors in the US.<ref name="Time_2014">{{cite magazine |date=27 October 2014 |title=Hospitals Furious at Cancer-Drug Price Hikes |url=https://time.com/3541484/cancer-drug-price-hikes/ |url-status=live |archive-url=https://web.archive.org/web/20151020062334/http://time.com/3541484/cancer-drug-price-hikes/ |archive-date=20 October 2015 |access-date=26 October 2015 |magazine=Time |vauthors=Saporito B}}</ref> Because wholesalers discounts and rebates no longer apply, hospitals would pay more.<ref name="Time_2014" />

Patents on rituximab have expired in the European Union<ref>{{cite web |date=24 July 1992 |title=Recombinant antibodies for human therapy |url=https://patents.google.com/patent/EP0605442A4/en |access-date=27 July 2024 |website=Google Patents}}</ref><ref>{{cite web |date=9 November 1999 |title=Chimeric anti-CD20 antibody, rituxan, for use in the treatment of chronic lymphocytic leukemia |url=https://patents.google.com/patent/EP1616572B1/en |access-date=27 July 2024 |website=Google Patents}}</ref><ref>{{cite journal |vauthors=Storz U |date=2014 |title=Rituximab: how approval history is reflected by a corresponding patent filing strategy |journal=mAbs |volume=6 |issue=4 |pages=820–37 |doi=10.4161/mabs.29105 |pmc=4171018 |pmid=24866199}}</ref> and in the United States.<ref>{{cite web |date=9 November 1999 |title=Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody |url=https://patents.google.com/patent/US7682612B1/en |access-date=27 July 2024 |website=Google Patents}}</ref><ref>{{cite web |date=31 May 2013 |title=Methods related to rituximab |url=https://patents.google.com/patent/US20150141620A1/en |access-date=27 July 2024 |website=Google Patents}}</ref><ref>{{cite web | vauthors = Inserro A |date=25 March 2019 |title=Roche Settles With Pfizer Over Rituximab Patent |url=https://www.centerforbiosimilars.com/view/roche-settles-with-pfizer-over-rituximab-patent |access-date=27 July 2024 |website=Center for Biosimilars}}</ref> [[Biosimilar]]s were approved in the United States, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved rituximab-abbs (Truxima) in 2018,<ref name="Truxima FDA label" /><ref name="FDA PR 20181128">{{cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treatment-adult-patients-non-hodgkins-lymphoma|title=FDA approves first biosimilar for treatment of adult patients with non-Hodgkin's lymphoma|date=28 November 2018|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=11 November 2019|archive-date=15 December 2019|archive-url=https://web.archive.org/web/20191215164843/https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treatment-adult-patients-non-hodgkins-lymphoma|url-status=dead}}</ref><ref name="FDA Truxima">{{cite web | title=FDA approves Truxima as biosimilar to Rituxan for non-Hodgkin's lympho | website=U.S. [[Food and Drug Administration]] (FDA) | date=28 November 2018 | url=https://www.fda.gov/drugs/fda-approves-truxima-biosimilar-rituxan-non-hodgkins-lymphoma | access-date=5 July 2024}}</ref> rituximab-pvvr (Ruxience) in 2019,<ref name="Ruxience FDA label" /> and rituximab-arrx (Riabni) in 2020.<ref name="Riabni FDA label" /><ref name="GABI">{{cite web|url=https://gabionline.net/biosimilars/general/Biosimilars-of-rituximab |title=Biosimilars of Rituximab|publisher=Generics and Biosimilars Initiative|archive-url=https://web.archive.org/web/20240224193418/https://gabionline.net/biosimilars/general/Biosimilars-of-rituximab|archive-date=24 February 2024|url-status=live|access-date=29 April 2017|date=14 April 2017}}</ref><ref>{{cite news|url=https://www.reuters.com/article/us-novartis-rituximab/novartis-abandons-effort-for-u-s-approval-of-biosimilar-rituximab-idUSKCN1N72NA|title=Novartis abandons effort for U.S. approval of biosimilar rituximab|vauthors=Lahiri D, Osterman C|date=2 November 2018|access-date=3 November 2018|publisher=Reuters|archive-date=3 November 2018|archive-url=https://web.archive.org/web/20181103034312/https://www.reuters.com/article/us-novartis-rituximab/novartis-abandons-effort-for-u-s-approval-of-biosimilar-rituximab-idUSKCN1N72NA|url-status=live}}</ref> Truxima and Riabni are approximately $3600 per 500&nbsp;mg, wholesale - 10% less than Rituxan, while Ruxience is 24% less than Rituxan.<ref>{{Cite web |date=4 May 2020 |title=Teva, Celltrion Maintain Slender Discount to Rituxan |url=https://www.centerforbiosimilars.com/view/teva-celltrion-maintain-slender-discount-to-rituxan |url-status=live |archive-url=https://web.archive.org/web/20240330194608/https://www.centerforbiosimilars.com/view/teva-celltrion-maintain-slender-discount-to-rituxan |archive-date=30 March 2024 |access-date=30 March 2024 |website=Center for Biosimilars}}</ref><ref name="Center4Biosimilars">{{cite web |date=17 December 2020 |title=Amgen Rituximab Biosimilar Gains FDA Approval |url=https://www.centerforbiosimilars.com/view/fda-approves-rituximab-biosimilar-from-amgen |url-status=live |archive-url=https://web.archive.org/web/20210423043501/https://www.centerforbiosimilars.com/view/fda-approves-rituximab-biosimilar-from-amgen |archive-date=23 April 2021 |access-date=23 April 2021 |website=The Center For Biosimilars |quote=The pharmaceutical company said Riabni will be marketed at a discount to the reference product of 23.7% below wholesale acquisition cost (WAC), or a WAC of $716.80 per 100 mg and $3584 per 500 mg single-dose vial. These costs are 15.2% less than the WAC for the biosimilar rituximab Truxima, Amgen said. The company added that Riabni's average sales price will be 16.7% below the current average for Rituxan.}}</ref> The Indian biosimilar ''ituxredi'' retails for about 1/6 the price.<ref>{{cite news |title=Dr Reddy's launches half-price version of MabThera - PharmaTimes |url=https://pharmatimes.com/news/dr_reddys_launches_half-price_version_of_mabthera_989813/ |access-date=19 November 2024 |work=pharmatimes.com |date=3 May 2007}}</ref>

==== Tailored-dosing ====
Tailored-dose rituximab is more cost-effective than fixed-dose. It is both more effective and less expensive.<ref>{{cite journal | vauthors = Contreras K, Orozco V, Puche E, González CA, García-Padilla P, Rodríguez MP, Rosselli D | title = Cost-Effectiveness of Rituximab (Fixed Schedule vs Tailored Dose) Compared With Azathioprine Maintenance Therapy in Adults With Generalized Antineutrophil Cytoplasm Antibody-Associated Vasculitis in Colombia | journal = Value in Health Regional Issues | volume = 28 | pages = 98–104 | date = March 2022 | pmid = 34922060 | doi = 10.1016/j.vhri.2021.08.002 }}</ref><ref>{{cite journal | vauthors = Romero G, Ticchioni M, Cohen M, Rosenthal-Allieri MA, Mondot L, Lebrun Frenay C | title = Neuromyelitis optica: Contribution of therapeutic responses markers monitoring in patients given rituximab | journal = Revue Neurologique | volume = 172 | issue = 3 | pages = 220–224 | date = March 2016 | pmid = 26915311 | doi = 10.1016/j.neurol.2015.12.004 }}</ref>

==Research==
Rituximab has been reported as a possible cofactor in a chronic [[hepatitis E]] infection in a person with lymphoma. Hepatitis E infection is normally an [[Acute (medicine)|acute]] infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus.<ref>{{cite journal | vauthors = Kriston L, Härter M, Hölzel L | title = Challenges in reporting meta-analyses of diagnostic accuracy studies | journal = Annals of Internal Medicine | volume = 150 | issue = 6 | pages = 430 | date = March 2009 | pmid = 19293085 | doi = 10.7326/0003-4819-150-6-200903170-00025 | department=Letters }}</ref>

===Myalgic encephalomyelitis/chronic fatigue syndrome===
In 2009, a patient receiving methotrexate-induced B-cell depletion for cancer treatment, experienced a transient remittal of their [[myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) symptoms. While initial trials using Rituximab were promising, a phase 3 trial published in 2019 did not find an association between Rituximab treatment and improvements in ME/CFS.<ref name=":0">{{cite journal | vauthors = Fluge Ø, Rekeland IG, Lien K, Thürmer H, Borchgrevink PC, Schäfer C, Sørland K, Aßmus J, Ktoridou-Valen I, Herder I, Gotaas ME, Kvammen Ø, Baranowska KA, Bohnen LM, Martinsen SS, Lonar AE, Solvang AH, Gya AE, Bruland O, Risa K, Alme K, Dahl O, Mella O | title = B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial | journal = Annals of Internal Medicine | volume = 170 | issue = 9 | pages = 585–593 | date = May 2019 | pmid = 30934066 | doi = 10.7326/M18-1451 | s2cid = 91186383 }}</ref><ref>{{cite journal | vauthors = Seton KA, Espejo-Oltra JA, Giménez-Orenga K, Haagmans R, Ramadan DJ, Mehlsen J | title = Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives | journal = Journal of Clinical Medicine | volume = 13 | issue = 2 | page = 325 | date = January 2024 | pmid = 38256459 | pmc = 10816159 | doi = 10.3390/jcm13020325 | collaboration = European ME Research Group for Early Career Researchers (Young EMERG) | doi-access = free }}</ref>

===Intrathecal===

For CNS diseases, rituximab could be administered [[intrathecal]]ly and this possibility is under study.<ref>{{cite journal | vauthors = Bonnan M, Ferrari S, Bertandeau E, Demasles S, Krim E, Miquel M, Barroso B | title = Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials | journal = Current Drug Targets | volume = 15 | issue = 13 | pages = 1205–1214 | date = 2014 | pmid = 25355180 | doi = 10.2174/1389450115666141029234644 }}</ref>

=== Other anti-CD20 monoclonals ===

The efficacy and success of rituximab has led to some other anti-CD20 monoclonal antibodies being developed:

* [[ocrelizumab]], humanized (90%-95% human) B cell-depleting agent.
* [[ofatumumab]] (HuMax-CD20) a fully human B cell-depleting agent.<ref name="titleGenmab.com / HuMax-CD20 (ofatumumab)">{{cite web |url=http://www.genmab.com/ScienceAndResearch/ProductsinDevelopment/HuMax-CD20.aspx |title=Genmab.com / HuMax-CD20 (ofatumumab) |access-date=3 December 2007 |archive-url = https://web.archive.org/web/20070911144653/http://www.genmab.com/ScienceAndResearch/ProductsinDevelopment/HuMax-CD20.aspx <!-- Bot retrieved archive --> |archive-date = 11 September 2007}}</ref>
* Third-generation anti-CD20s such as [[obinutuzumab]] have a glycoengineered [[Fc fragment]] (Fc)<ref name="titleFc-structure">{{cite web |url=http://www.healthvalue.net/Fc-structure.html |title=Fc-structure |access-date=3 December 2007 |url-status=live |archive-url=https://web.archive.org/web/20071110011928/http://www.healthvalue.net/Fc-structure.html |archive-date=10 November 2007 }}</ref> with enhanced binding to [[Fc gamma receptor]]s, which increase ADCC ([[antibody-dependent cellular cytotoxicity]]).<ref name="titleMonoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?">{{cite journal | vauthors = Eccles SA | title = Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger? | journal = Breast Cancer Research | volume = 3 | issue = 2 | pages = 86–90 | year = 2001 | pmid = 11250751 | pmc = 138676 | doi = 10.1186/bcr276 | doi-access = free | title-link = doi }}</ref> This strategy for enhancing a monoclonal antibody's ability to induce ADCC takes advantage of the fact that the displayed Fc glycan controls the antibody's affinity for Fc receptors.<ref>{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}</ref>

== References ==
{{reflist}}

== Further reading ==
* {{cite report | title=Non-Hodgkin's lymphoma: rituximab subcutaneous injection | publisher=NICE | date=September 2014 | url=https://www.nice.org.uk/advice/esnm46/chapter/full-evidence-summary }}
* {{cite journal | vauthors = Salles G, Barrett M, Foà R, Maurer J, O'Brien S, Valente N, Wenger M, Maloney DG | title = Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience | journal = Advances in Therapy | volume = 34 | issue = 10 | pages = 2232–2273 | date = October 2017 | pmid = 28983798 | pmc = 5656728 | doi = 10.1007/s12325-017-0612-x }}
* {{cite journal | vauthors = Smith MR | title = Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance | journal = Oncogene | volume = 22 | issue = 47 | pages = 7359–68 | date = October 2003 | pmid = 14576843 | doi = 10.1038/sj.onc.1206939 }}

== External links ==
* {{cite web | title=Discovery – Development of Rituximab | website=National Cancer Institute | date=7 March 2014 | url=https://www.cancer.gov/research/progress/discovery/blood-cancer }}

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