DOCSLIB.ORG

NMSHP Presentation 2018 Final

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
NMSHP Presentation 2018 Final 10/4/18 Objectives PHARMACIST TECHNICIAN Kidney Transplantation: • Describe mechanisms of • Identify medications used transplant in transplant recipients What Pharmacists & Technicians immunosuppression • Identify common adverse • Outline documentation Need to Know effects to transplant requirements for Amanda J. Condon, PharmD, BCPS immunosuppression transplant medications Solid Organ Transplant Pharmacist • Modify transplant University of New Mexico Hospitals regimens to ensure safety and efficacy 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 1 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 2 Epidemiology – U.S. Epidemiology – New Mexico 95,124 13,992 24,213 522 52 2,310 people need lifesaving kidney kidney transplants have been Donors recovered so far in people need lifesaving kidney kidney transplants have been Patients have been transplanted transplants (total waitlist performed so far in 2018 2018 transplants in New Mexico performed in New Mexico since 1988 candidates) (January to August 2018) (January to August 2018) 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 3 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 4 Epidemiology Indications for Transplant Modifiable • Diabetes • Hypertension • NSAID overuse Non-Modifiable • Genetics (polycystic kidney disease, etc) • Congenital Abnormalities (obstructive uropathy, etc) • Glomerular Disease (anti-GBM, IgA Nephropathy, etc) 10/4/18 NMSHP: KIDNEYhttps://optn.transplant.hrsa.gov/ TRANSPLANTATION 5 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 6 1 10/4/18 Transplant Course Goals oF Immunosuppression Infection Rejection Malignancy Monthly Adherence (ACR vs AMR) Weekly Visits Visits Toxicity Listing Transplant! ~ 1 month ~ 6 months Pre- Waiting on List Biweekly Bimonthly q6-12 month Transplant ~ Months to Years Visits Visits Visits Graft Work Up ~ 1 month ~ 3 months ..Forever Patient & ~6 mos – 1 year Failure Graft Survival 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 7 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 8 Sensitization & Risk Factors For Rejection Phases of Immunosuppression Transplant Rejection HLA DCD Organ Sensitizing Mismatch Delayed Risk Factors Events Previous Graft Transplant Function Blood Rejection Transfusion Episodes Induction Previous Graft African Pregnancy Loss American Desensitization Maintenance 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 9 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 10 Determination oF Regimens Induction Agents • Evaluation of Immunologic Risk Goal: To prevent early acute allograft rejection immediately • HLA mismatch • Blood group post-transplant using intense, prophylactic • Younger recipient and incompatibility immunosuppressive therapy older donor • Delayed onset of graft • African-American function (DGF) – Basiliximab (Simulect®) • Panel Reactive Antibody • Cold ischemia time > 24 ◦ 20 mg IV POD0 and POD4 (PRA) > 0 hours • Donor-specific Antibody – Antithymocyte Globulin (Thymoglobulin®) (DSA) ◦ 2 mg/kg (IBW) IV starting POD0 up to 6mg/kg total • Evaluation of Infectious Risk • Elderly • Previous chemotherapy – Alemtuzumab (Campath®) • HBV exposure • ganR CMV ◦ 30 mg IV POD0 • HCV exposure 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 11 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 12 2 10/4/18 Basiliximab (Simulect®) • Mechanism of Action: – Blocks T-cell proliferation via Interleukin-2 (IL-2) receptor antagonism (anti-CD25 antibodies) • Used in lowest immunologic risk patients • Decreased infection rates when compared to thymoglobulin • Does not lead to sustained depletion of lymphocytes and related CD4 helper T cells N Engl J Med. 2004 Dec 23;351(26):2715-29. 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 13 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 14 Antithymocyte Globulin Antithymocyte Globulin (Thymoglobulin®) (Thymoglobulin®) • Mechanism of Action: • Infusion reactions common – Binds to T-cell surface antigens leading to the elimination of T-cells – Associated with previous rabbit exposure – Premedicate: APAP 650mg PO, Benadryl 25mg IV, Steroids • Used in moderate to high immunologic risk patients • Can cause serum sickness • Increased risk for CMV and BKV – Occurs 10-21 days after administration • PJP and other invasive fungal pathogens have been associated with – Presentation: Myalgias, fever, fatigue, jaw pain thymoglobulin • Monitoring: – WBC, Platelets – Reduction if WBC < 3 or PLT < 75 – Hold if WBC < 2 or PLT < 50 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 15 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 16 Alemtuzumab (Campath®) Phases of Immunosuppression • Mechanism of Action: Transplant Rejection – Binds to CD52 on T-cells, B-cells, NK cells, and monocytes/macrophages causing complement activation and antibody-dependent cellular toxicity • “AIDS” in a bottle that can result in pan-T-cell depletion • CD4/CD8 counts nadir at 4 weeks, 1 year for recovery • Associated with many opportunistic infections Induction Desensitization Maintenance 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 17 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 18 3 10/4/18 Maintenance Agents Goal: To prevent early and late allograft rejection post- transplant using long-term prophylactic immunosuppressive therapy • Corticosteroids • CTLA-4 Blockade (Belatacept) (Methylprednisolone, Prednisone) • mTOR Inhibitors (Sirolimus, • Calcineurin Inhibitors (Tacrolimus, Everolimus) Cyclosporine) • Antimetabolites (Mycophenolate, Azathioprine) N Engl J Med. 2004 Dec 23;351(26):2715-29. 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 19 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 20 Corticosteroids (Prednisone, Corticosteroids (Prednisone, Methylprednisolone) Methylprednisolone) • Mechanism of Action: •Adverse Effects….. are plenty – Profound immune system augmentation including inhibition of IL-1, 2, 3, 4, 5, 6, 8, TNF involved in T-cell proliferation; decreased B-cell SHORT TERM LONG TERM clone expansion, and decreased antibody synthesis • Mood Change • Osteoporosis • Increased risk of bacterial, mycobacterial, viral and fungal infections • Hyperglycemia* • Adrenal Insufficiency • Hypertension* • Ulcerative Esophagitis • Routinely used to treat rejection • Increased Appetite • Hirsutism • Insomnia • Pacreatitis • Acne • Amenorrhea • Leukocytosis* • Diabetes Mellitus 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 21 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 22 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Mechanism of Action: – Binds to immunophilins and block the function of calcineurin at different enzymatic sites, resulting in downstream impairment of T-cell IL-2 synthesis • Tacrolimus is broader in inhibitory effect (IL-3, IL-4, IL-5, IFN-γ, other cytokines) • CsA has antiviral properties – HIV, HSV, HCV • Increased risk of CMV and BKV 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 23 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 24 4 10/4/18 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Drug Interactions GUT – Primarily through hepatic metabolism (CYP3A4 inhibition or induction) ◦ ↑ Drug Level: ketoconazole, diltiazem, fluconazole, grapefruit juice ◦ ↓ Drug Level: phenytoin, rifampin – P-gp Substrate – Drug interactions have high inter- and intra-patient variability – Consistent administration with or without food BLOOD 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 25 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 26 When to Check Troughs? Tacrolimus Preparations • Depends on the clinical situation and when last trough was checked • Prograf – Immediate release capsule • Recommend erring on side of caution and checking a trough when in doubt – IV preparation ◦ Dose reduce to 1/3 of oral dose as a continuous infusion • Any AKI ◦ Please don’t do this – use sublingual instead (if possible) – Tacrolimus can be the cause of AKI – Can be used for SL administration – Tacrolimus is NOT renally excreted ◦ Dose reduce 1 mg PO : 0.5 mg SL • Any diarrhea • Astagraf – Tacrolimus levels are increased during episodes of diarrhea – Once-daily long-acting capsule – Really only used for tacrolimus-sensitive patients (ie, 0.5mg once a day = 0.25mg Prograf BID) 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 27 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 28 Calcineurin Inhibitors (Tacrolimus, Tacrolimus Preparations Cyclosporine) • Envarsus XR • Tacrolimus Adverse Effects – Once-daily long-acting tablet – Fantastic pharmacokinetics! • Hypertension • Hyperglycemia* – Significantly less neurotoxicity • Diarrhea • Pruritis • Nephrotoxicity • Hyperkalemia • Headache • Hypomagnesemia • Hepatotoxicity • Infection • Neurotoxicity • Alopecia 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 29 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 30 5 10/4/18 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Cyclosporine Adverse Effects • Adverse Effects Tacrolimus Cyclosporine LESS COMMON MORE COMMON Nephrotoxicity +++ ++ • Migraine • Hyperlipidemia Hyperglycemia & DM +++ ++ • • Nephrotoxicity Acne Neurotoxicity +++ ++ • GI effects • Tremor Electrolyte abnormalities +++ ++ • Gynecomastia • Hypertension • • Hyperkalemia Hyperglycemia Hypertension +++ +++ • Gingival hyperplasia • Hypomagnesemia Other Alopecia Hirsutism, • • Hepatotoxicity Hirsutism hyperlipidemia, gingival hyperplasia, hyperuricemia 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 31 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 32 Antimetabolites (Mycophenolate, Antimetabolites (Mycophenolate, Azathioprine) Azathioprine) • Mechanism of Action: – Targets enzymes involved in de novo synthesis of purines leading to impairment of DNA replication in B- and T-cells • Potential for bone marrow suppression • Significantly increased risk for major viral, fungal and parasitic infections • Usually
Load more

Recommended publications
  • Alemtuzumab Comparison with Rituximab and Leukemia Whole
    Mechanism of Action of Type II, Glycoengineered, Anti-CD20 Monoclonal Antibody GA101 in B-Chronic Lymphocytic Leukemia Whole Blood Assays in This information is current as Comparison with Rituximab and of September 27, 2021. Alemtuzumab Luca Bologna, Elisa Gotti, Massimiliano Manganini, Alessandro Rambaldi, Tamara Intermesoli, Martino Introna and Josée Golay Downloaded from J Immunol 2011; 186:3762-3769; Prepublished online 4 February 2011; doi: 10.4049/jimmunol.1000303 http://www.jimmunol.org/content/186/6/3762 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/02/04/jimmunol.100030 Material 3.DC1 References This article cites 44 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/186/6/3762.full#ref-list-1 by guest on September 27, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American
    [Show full text]
  • Alemtuzumab Comparison with Rituximab and Leukemia Whole
    Mechanism of Action of Type II, Glycoengineered, Anti-CD20 Monoclonal Antibody GA101 in B-Chronic Lymphocytic Leukemia Whole Blood Assays in This information is current as Comparison with Rituximab and of September 29, 2021. Alemtuzumab Luca Bologna, Elisa Gotti, Massimiliano Manganini, Alessandro Rambaldi, Tamara Intermesoli, Martino Introna and Josée Golay Downloaded from J Immunol 2011; 186:3762-3769; Prepublished online 4 February 2011; doi: 10.4049/jimmunol.1000303 http://www.jimmunol.org/content/186/6/3762 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/02/04/jimmunol.100030 Material 3.DC1 References This article cites 44 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/186/6/3762.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American
    [Show full text]
  • Horizon Scanning Status Report June 2019
    Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors.
    [Show full text]
  • Structure–Function Relationships of the Variable Domains of Monoclonal
    Critical Reviews in Oncology/Hematology 64 (2007) 210–225 Structure–function relationships of the variable domains of monoclonal antibodies approved for cancer treatment Charlotte Magdelaine-Beuzelin a,b, Quentin Kaas c, Vanessa Wehbi a, Marc Ohresser a, Roy Jefferis d, Marie-Paule Lefranc c, Herve´ Watier a,b,∗ a Universit´eFran¸cois Rabelais de Tours, EA 3853 “Immuno-Pharmaco-G´en´etique des Anticorps th´erapeutiques”, France b CHRU de Tours, Laboratoire d’Immunologie, France c IMGT, Laboratoire d’ImmunoG´en´etique Mol´eculaire, LIGM, Institut de G´en´etique Humaine, UPR CNRS 1142, Montpellier, France d Immunity and Infection, University of Birmingham, United Kingdom Accepted 20 April 2007 Contents 1. Chimeric and humanized antibodies .................................................................................... 211 2. IMGT Collier de Perles ............................................................................................... 217 3. Antibody/antigen interactions.......................................................................................... 219 4. Variable domain genetic analysis....................................................................................... 220 5. Immunogenicity...................................................................................................... 222 Reviewers ........................................................................................................... 223 Acknowledgements..................................................................................................
    [Show full text]
  • Monoclonal Antibodies
    MONOCLONAL ANTIBODIES ALEMTUZUMAB ® (CAMPATH 1H ) I. MECHANISM OF ACTION Antibody-dependent lysis of leukemic cells following cell surface binding. Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody that is directed against surface glycoprotein CD52. CD52 is expressed on the surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, a subpopulation of granulocytes, and tissues of the male reproductive system (CD 52 is not expressed on erythrocytes or hematopoietic stem cells). The alemtuzumab antibody is an IgG1 kappa with human variable framework and constant regions, and complementarity-determining regions from a murine monoclonal antibody (campath 1G). II. PHARMACOKINETICS Cmax and AUC show dose proportionality over increasing dose ranges. The overall average half-life is 12 days. Peak and trough levels of Campath rise during the first weeks of Campath therapy, and approach steady state by week 6. The rise in serum Campath concentration corresponds with the reduction in malignant lymphocytes. III. DOSAGE AND ADMINISTRATION Campath can be administered intravenously or subcutaneously. Intravenous: Alemtuzumab therapy should be initiated at a dose of 3 mg administered as a 2-hour IV infusion daily. When the 3 mg dose is tolerated (i.e., ≤ Grade 2 infusion related side effects), the daily dose should be escalated to 10mg and continued until tolerated (i.e., ≤ Grade 2 infusion related side effects). When the 10 mg dose is tolerated, the maintenance dose of 30 mg may be initiated. The maintenance dose of alemtuzumab is 30 mg/day administered three times a week on alternate days (i.e. Monday, Wednesday, and Friday), for up to 12 weeks.
    [Show full text]
  • A Novel Raji-Burkitt's Lymphoma Model for Preclinical and Mechanistic Evaluation of CD52-Targeted Immunotherapeutic Agents
    Cancer Therapy: Preclinical A Novel Raji-Burkitt’s Lymphoma Model for Preclinical and Mechanistic Evaluation of CD52-Targeted Immunotherapeutic Agents Rosa Lapalombella,1Xiaobin Zhao,1, 2 Georgia Triantafillou,1Bo Yu,3,4 Yan Jin, 4 Gerard Lozanski,5 Carolyn Cheney,1Nyla Heerema,5 David Jarjoura,6 Amy Lehman,6 L. James Lee,3,4 Guido Marcucci,1Robert J. Lee,2,4 Michael A. Caligiuri,1 Natarajan Muthusamy,1and John C. Byrd1, 2 Abstract Purpose:Todate, efforts to study CD52-targeted therapies, such as alemtuzumab, have beenlim- ited due to the lack of stable CD52 expressing transformed B-cell lines and animal models.We describe generation and utilization of cell lines that stably express CD52 both in vitro and in vivo. Experimental Design: By limiting dilution, we have established several clones of Raji-Burkitt’s lymphoma cell line that express surface CD52. Immunophenotype and cytogenetic charac- terizationof these clones was done. In vivo usefulness of the CD52high cell line to evaluate the ther- apeuticefficacyofCD52-directedantibody wasinvestigatedusingaSCIDmousexenograftmodel. Results: Stable expression of CD52 was confirmed in cells cultured in vitro up to 52 weeks of continuous growth. The functional integrity of the expressed CD52 molecule was shown using alemtuzumab, which induced cytotoxic effects in vitro in the CD52high but not the CD52low clone. Compared with control antibody, alemtuzumab treatment in CD52high inoculated mice resulted in significantly increased median survival. Comparable levels of CD52-targeted direct cyto- toxicity, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity and anti-CD52 immunoliposome-mediated delivery of synthetic oligodeoxyribo nucleotides in CD52high clone and primary B-chronic lymphocytic leukemia cells implicated potential in vivo application of this model for evaluation of CD52-targeted antibody and immunoliposomes encapsulating therapeutic agents.
    [Show full text]
  • Cetuximab Promotes Anticancer Drug Toxicity in Rhabdomyosarcomas with EGFR Amplificationin Vitro
    ONCOLOGY REPORTS 30: 1081-1086, 2013 Cetuximab promotes anticancer drug toxicity in rhabdomyosarcomas with EGFR amplificationin vitro YUKI YAMAMOTO1*, KAZUMASA FUKUDA2*, YASUSHI FUCHIMOTO4*, YUMI MATSUZAKI3, YOSHIRO SAIKAWA2, YUKO KITAGAWA2, YASUHIDE MORIKAWA1 and TATSUO KURODA1 Departments of 1Pediatric Surgery, 2Surgery and 3Physiology, Keio University School of Medicine, Tokyo 160-858; 4Division of Surgery, Department of Surgical Subspecialities, National Center for Child Health and Development, Tokyo 157-8535, Japan Received January 15, 2013; Accepted April 2, 2013 DOI: 10.3892/or.2013.2588 Abstract. Overexpression of human epidermal growth factor i.e., t(2;13) (q35;q14) in 55% of cases and t(1;13) (p36;q14) in receptor (EGFR) has been detected in various tumors and is 22% of cases (1). Current treatment options include chemo- associated with poor outcomes. Combination treatment regi- therapy, complete surgical resection and radiotherapy (3). mens with EGFR-targeting and cytotoxic agents are a potential However, the prognosis for patients with advanced-stage RMS therapeutic option for rhabdomyosarcoma (RMS) with EGFR is quite poor (4). The main problems with clinical treatments amplification. We investigated the effects of combination include metastatic invasion, local tumor recurrence and multi- treatment with actinomycin D and the EGFR-targeting agent drug resistance. Therefore, more specific, effective and less cetuximab in 4 RMS cell lines. All 4 RMS cell lines expressed toxic therapies are required. wild-type K-ras, and 2 of the 4 overexpressed EGFR, as Numerous novel anticancer agents are currently in early determined by flow cytometry, real-time PCR and direct phase clinical trials. Of these, immunotherapy with specific sequencing.
    [Show full text]
  • Antibodies for the Treatment of Brain Metastases, a Dream Or a Reality?
    pharmaceutics Review Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Marco Cavaco, Diana Gaspar, Miguel ARB Castanho * and Vera Neves * Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal * Correspondence: [email protected] (M.A.R.B.C.); [email protected] (V.N.) Received: 19 November 2019; Accepted: 28 December 2019; Published: 13 January 2020 Abstract: The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.
    [Show full text]
  • National Drug Monograph Ofatumumab Arzerra September
    Ofatumumab Monograph National Drug Monograph Ofatumumab (Arzerra™) September 2010, Updated August 2014 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Outcome in clinically significant area CLL Relapsed/Refractory (R/R ): ORR CLL (previously untreated): PFS Effect Size CLL (R/R): ORR 58%, PFS 5.7 months, OS 13.7 months CLL (previously untreated): PFS 22 vs 13 months; HR 0.57 (0.45, 0.72); p< 0.001 Potential Harms Neutropenia (all grades) 66%; (gr 3, 4) 42% Infections (all grades) 70%; (gr 3,4) 29% Infusion-related reactions w/first infusion: 38% Net Clinical Benefit CLL (R/R): Moderate CLL (previously untreated): Moderate Definitions Outcome in clinically significant area: morbidity, mortality, symptom relief, emotional/physical functioning, or health-related quality of life Effect Size: odds ratio, relative risk, NNT, absolute risk reduction, relative risk reduction, difference in size of outcomes between groups, hazard ratio Potential Harms: Low risk (Grade 3 or 4 toxicity in <20%) versus High risk (Grade 3 or 4 toxicity in ≥20%) Net Clinical Benefit: Substantial (high benefit with low risk of harm), moderate (high benefit with high risk of harm), minimal (low benefit with low risk of harm), negative (low benefit with high risk of harm) Executive Summary: Ofatumumab is a monoclonal antibody that is directed against CD-20 positive cells.
    [Show full text]
  • 125486Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 125486Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Risk Evaluation and Mitigation Strategy (REMS) Review Date: September 19, 2013 Reviewer(s): Bob Pratt, Pharm.D. Division of Risk Management Team Leader: Cynthia LaCivita, Pharm.D. Division of Risk Management Division Director: Claudia Manzo, Pharm.D. Division of Risk Management Subject: Evaluation to determine if a REMS is necessary Drug Name(s): obinutuzumab (Gazyva) Therapeutic Class: Antineoplastic agent Dosage and Route: 1,000 mg intravenous infusion that follows a 28-day treatment cycle for six cycles Application Type/Number: BLA 125486 Applicant/sponsor: Genentech, Inc. OSE RCM #: 2013-1007 Reference ID: 3376001 1 INTRODUCTION This review by the Division of Risk Management (DRISK) evaluates if a risk evaluation and mitigation strategy (REMS) is needed for the new molecular entity obinutuzumab. On April 22, 2013, Genentech submitted an original Biologics License Application (BLA) for obinutuzumab in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia. The sponsor did not submit a proposed REMS or risk management plan. 1-4 1.1 BACKGROUND Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of a functionally incompetent monoclonal lymphocyte. CLL is considered to be a disease of the elderly with a median age at diagnosis of 70 years. It is the most common leukemia in Western countries.
    [Show full text]
  • Lemtrada, INN-Alemtuzumab
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT LEMTRADA 12 mg concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 12 mg alemtuzumab in 1.2 ml (10 mg/ml). Alemtuzumab is a monoclonal antibody produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium by recombinant DNA technology. Excipients with known effect This medicine contains less than 1 mmol potassium (39 mg) per infusion, i.e. it is essentially ‘potassium- free’. This medicine contains less than 1 mmol sodium (23 mg) per infusion, i.e. it is essentially ‘sodium- free’. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate). A clear, colourless to slightly yellow concentrate with pH 7.0 – 7.4. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications LEMTRADA is indicated as a single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis (RRMS) for the following patient groups: • Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT) or • Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
    [Show full text]
  • Mabcampath, INN-Alemtuzumab
    authorised ANNEX I SUMMARY OF PRODUCT CHARACTERISTICSlonger no product Medicinal 1 1. NAME OF THE MEDICINAL PRODUCT MabCampath 10 mg/ml concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml contains 10 mg of alemtuzumab. Each ampoule contains 30 mg of alemtuzumab. Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for a 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. authorised Colourless to slightly yellow concentrate. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications MabCampath is indicated for the treatment of patients with B-celllonger chronic lymphocytic leukaemia (B- CLL) for whom fludarabine combination chemotherapy is not appropriate. 4.2 Posology and method of administration no MabCampath should be administered under the supervision of a physician experienced in the use of cancer therapy. Posology During the first week of treatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of 12 weeks. product In most patients, dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moderate to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills, rashes and bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4).
    [Show full text]