Common side effects which often occur within two hours of the medication being given include rash, itchiness, low blood pressure, and shortness of breath.[medical citation needed] Infections are also common.[16]
Rituximab is a chimericmonoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells.[21] When it binds to this protein it triggers cell death.[16]
Rituximab is a chimeric monoclonal antibody targeted against CD20, a surfaceantigen present on B cells. It acts by depleting normal as well as pathogenic B cells while sparing plasma cells and hematopoietic stem cells, which do not express the CD20 surface antigen.[24]
In the United States, rituximab is indicated to treat:
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.[29] In the United States, it has been 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.[30]
At least one patient with rheumatoid arthritis developed PML after treatment with rituximab.[53]
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 infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus.[54]
A major concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response.[55] 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.[56] In persons previously treated with rituximab for multiple sclerosis, 9 of 10 patients who delayed re-dosing until B cell counts passed 40/μL developed protective levels of antibodies after vaccination with tozinameran.[57]
The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.
Rituximab is relatively ineffective in elimination of cells with low CD20 cell-surface levels.[59] 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.[60]
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).[59]
It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen).
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.[62]
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 cells.
Rituximab binds to amino acids 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.[63]
In 2014, Genentech reclassified rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US.[69] Because wholesalers discounts and rebates no longer apply, hospitals would pay more.[69]
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).[70]
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.[71] The combination is not indicated for the treatment of non-malignant conditions.[28][71] The combination was approved based on clinical studies SABRINA/NCT01200758 and MabEase/NCT01649856.[28]
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).[72] 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.[72] This can cause serious problems and damage to organs, most notably the lungs and the kidneys.[72] It also can impact the sinuses and skin.[72] Rituximab was approved by the FDA to treat adults with granulomatosis with polyangiitis and microscopic polyangiitis in 2011.[72]
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.[25][73] 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.[73] 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.[73] 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.[73]
Patents on rituximab expired in the European Union in February 2013, and in the United States in September 2016.[failed verification][74] By November 2018[update], several biosimilars had been approved in the US, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved Truxima (rituximab-abbs) in 2018,[75][76] Ruxience (rituximab-pvvr) in 2019,[2] and Riabni (rituximab-arrx) in 2020. The Riabni is about $3600 per 500 mg, wholesale, list. Truxima is about the same price as Riabni - 10% less than Rituxan, while Ruxience is 24% less than Rituxan. [3][74][77][78][79]
Rituximab did not improve symptoms in patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in a trial published in 2019.[80][81] Twenty-two percent of participants had serious events.[80] This potential use was investigated after improvements in ME/CFS was seen in two cancer patients treated with rituximab.[82]
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.[84]
Third-generation anti-CD20s such as obinutuzumab have a glycoengineered Fc fragment (Fc)[85] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity).[86] 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.[87]
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^Tandan R, Hehir MK, Waheed W, Howard DB (August 2017). "Rituximab treatment of myasthenia gravis: A systematic review". Muscle & Nerve. 56 (2): 185–196. doi:10.1002/mus.25597. PMID28164324. S2CID19504332.
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^ abBorsky M, Hrabcakova V, Novotna J, Brychtova Y, Doubek M, Panovska A, et al. (December 2021). "Rituximab induces rapid blood repopulation by CLL cells mediated through their release from immune niches and complement exhaustion". Leukemia Research. 111: 106684. doi:10.1016/j.leukres.2021.106684. PMID34438120.
^ ab"Biosimilars of Rituximab". Generics and Biosimilars Initiative. 14 April 2017. Archived from the original on 24 February 2024. Retrieved 29 April 2017.
^"Amgen Rituximab Biosimilar Gains FDA Approval". The Center For Biosimilars. 17 December 2020. Archived from the original on 23 April 2021. Retrieved 23 April 2021. 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.{{cite web}}: line feed character in |quote= at position 304 (help)
^Bonnan M, Ferrari S, Bertandeau E, Demasles S, Krim E, Miquel M, et al. (2014). "Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials". Current Drug Targets. 15 (13): 1205–1214. doi:10.2174/1389450115666141029234644. PMID25355180.