Rituximab (DB00073) Approved Drug Chemical Formula: C6416H9874N1688O1987S44 Molecular Weight: 143859.7 Rituxan 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. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids Indication/Usage For treatment of CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Pharmacodynamics Rituximab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lympohomas. The antibody leads to selective killing of B-cells. Mechanism Of Action The Fab regions of rituximab binds to the CD20 antigen on B lymphocytes, while the Fc domain recruits antibodies and complements to mediate cell lysis.

Volume of Distribution Metabolism Most likely removed by opsonization via the reticuloendothelial system when bound to B lymphocytes, or by human antimurine antibody production. Half-Life 0.8 hours (mammalian reticulocytes, in vitro) Volume of Distribution * 3.1 L Clearance * 0.34 L/day [RA patients] Category Antineoplastic Agents, Immunologic Factors and Antirheumatic Agents Affected Organisms Human and other Mammals Patents Patent no. 2149329, Canada, approved: 2008-07-15 expired: 2013-11-12 Patent no. 1336826, Canada, approved: 1995-08-29 expired: 2012-08-29 Patent no. 5736137, USA, approved : 1998-04-07 expired: 2015-04-07 Drug Interactions DB08822 (Azilsartan medoxomil): Azilsartan medoxomil used in combination with rituximab may lead to hypotension. DB00195 (Betaxolol), DB00880 (Chlorothiazide): Antihypertensives like may enhance the hypotensive effect of rituximab. Consider temporarily withholding antihypertensive medications for 12 hours prior to rituximab infusion to avoid excessive hypotension during or immediately after infusion.

DB08904 (Certolizumab pegol): Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. DB00966 (Telmisartan): Telmisartan may increase the hypotensive effect of Rituximab. Telmisartan should be withheld prior to and throughout Rituximab administration. DB01162 (Terazosin), DB00214 (Torasemide), DB01021 (Trichlormethiazide): Additive antihypertensive effects may occur. Increased risk of hypotension. Consider withholding drug for 12 hours prior to administration of Rituximab. DB08895 (Tofacitinib): Avoid combination due to the potential increase in tofacitinib related adverse effects. DB00839 (Tolazamide), DB00177 (Valsartan), DB00661 (Verapamil): Additive hypotensive effects may occur. Consider withholding drug for 12 hours prior to administration of Rituximab. DB00519 (Trandolapril): Trandolapril may increase the hypotensive effect of Rituximab. DB00072 (Trastuzumab): Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. Sequence Heavy chain: chimericQVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Light chain: chimericQIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Experimental Properties Melting Point- 61 °C for FAB Fragment; 71 °C for whole mAb Hydrophobicity: -0.414 Isoelectric Point: 8.68 Targets B-lymphocyte antigen CD20, Low affinity immunoglobulin gamma Fc region receptor III-B, Complement C1r subcomponent, Complement C1q subcomponent subunit A, Complement C1q subcomponent subunit B, Complement C1q subcomponent subunit C, Low affinity immunoglobulin gamma Fc region receptor III-A, Complement C1s subcomponent, High affinity immunoglobulin gamma Fc receptor I, Low affinity immunoglobulin gamma Fc region receptor II-a, Low affinity immunoglobulin gamma Fc region receptor II-b, Low affinity immunoglobulin gamma Fc region receptor II-c 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":http://www.ncbi.nlm.nih.gov/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":http://www.ncbi.nlm.nih.gov/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":http://www.ncbi.nlm.nih.gov/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":http://www.ncbi.nlm.nih.gov/pubmed/16705086

Burton C, Kaczmarski R, Jan-Mohamed R: Interstitial pneumonitis related to rituximab therapy. N Engl J Med. 2003 Jun 26;348(26):2690-1; discussion 2690-1. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/12826649 http://www.google.com/patents/EP2231183A2?cl=en http://planetorbitrap.com/data/uploads/528fce2e395be.pdf Brands Rituxan – Biogen Idec Inc., and Genentech USA, Inc

RITUXAN Formulation Used/Prescribed for Dosage Contraindications Rituxan (rituximab) is a genetically engineered chimeric murine/humanmonoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kDa. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Rituxan is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration Formulation Rituxan is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials. The product is formulated in polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL), sodium chloride (9 mg/mL) and Water for Injection. The pH is 6.5. Used/Prescribed for Used in Non–Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Dosage Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. In NHL the recommended dose is 375 mg/m2 as an intravenous infusion. In CLL 375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days). Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks. Administer Rituxan as a 375 mg/m2 intravenous infusion once weekly for 4 weeks. Contraindications None

Side- effects Drug Interactions References Infusion reactions, Mucocutaneous reactions, Hepatitis B reactivation with fulminant hepatitis, Progressive multifocal leukoencephalopathy , Tumor lysis syndrome , Infections, Cardiac arrhythmias, Renal toxicity, Bowel obstruction and perforation Drug Interactions In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. References http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563 http://www.rxlist.com/rituxan-drug.htm