Transplantation Drug Manual Fourth Edition John Pirsch, MD Professor of Medicine and Surgery Director of Medical Transplantation University of Wisconsin Madison, Wisconsin, USA William D. Simmons, RPH Senior Clinical Pharmacist School of Pharmacy Instructor Transplantation Specialist University of Wisconsin Madison, Wisconsin, USA Hans Sollinger, MD, PhD Folkert O. Belzer Professor of Surgery Chairman, Division of Organ Transplantation University of Wisconsin Madison, Wisconsin, USA LANDES BIOSCIENCE AUSTIN, TEXAS U.S.A. TRANSPLANTATION DRUG MANUAL, 4TH EDITION LANDES BIOSCIENCE Austin, Texas, U.S.A. U.S. and World Copyright © 2003 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publishers: Landes Bioscience, 810 South Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 www.landesbioscience.com International and U.S. ISBN 1-57059-678-6 Although this pocket reference guide summarizes pertinent drug information, full Prescribing Information should be consulted before prescribing any product. The contents of this publication are the sole responsibility of the medical editors and not of Sangstat Medical Corporation or the Publisher. While the authors, editors, and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein. Library of Congress Cataloging-in-Publication Data CIP applied for, but not available at time of publication. Table of Contents 1. Working Guide to Immunosuppression................ 1 Current Agents Overview...................................................3 Antithymocyte Globulin (Equine).......................................5 Antithymocyte Globulin (Rabbit) .......................................6 Azathioprine......................................................................7 Cyclophosphamide............................................................8 Cyclosporine-A (Non-Modified).........................................9 Cyclosporine-A................................................................10 Cyclosporine Capsules and Oral Solution (Modified)........................................................................11 Methylprednisolone.........................................................13 Muromonab-CD3............................................................15 Mycophenolate Mofetil....................................................17 Prednisone.......................................................................18 Tacrolimus.......................................................................19 Basiliximab......................................................................21 Daclizumab.....................................................................22 Sirolimus..........................................................................23 2. Antimicrobials .................................................... 25 Antivirals Overview.........................................................27 Acyclovir.........................................................................28 Valacyclovir.....................................................................31 Famciclovir......................................................................33 Ganciclovir......................................................................34 Valganciclovir..................................................................36 Immunoglobulin..............................................................37 CMV Hyperimmune Globulin..........................................38 Foscarnet Sodium............................................................39 Antibiotics Overview.......................................................41 Trimethoprim and Sulfamethoxazole (TMP-SMX).............43 Penicillins with Beta-Lactamase Inhibitor.........................45 Quinolones......................................................................47 Cephalosporins................................................................50 Aminoglycosides..............................................................53 Linezolid..........................................................................55 Antifungals Overview......................................................56 Nystatin Suspension.........................................................57 Clotrimazole Troche.........................................................58 Fluconazole.....................................................................59 Amphotericin B................................................................60 Amphotericin B Lipid Complex Injection.........................62 Miconazole Vaginal Cream 2%........................................63 Ketoconazole...................................................................64 Caspofungin.....................................................................65 3. Cardiovascular Agents......................................... 66 Cardiovascular Agents Overview.....................................68 Calcium Channel Blockers...............................................71 Alpha-Adrenergic Receptor Blockers................................74 Central Alpha-Adrenergic Agonist....................................75 Beta-Blockers...................................................................76 ACE Inhibitors..................................................................77 Angiotensin II Receptor Antagonists.................................79 Cholesterol-Lowering Agents ...........................................80 4. Antiosteoporosis Agents...................................... 83 Antiosteoporosis Agents Overview...................................85 Alendronate Sodium........................................................86 Etidronate Disodium........................................................87 Calcitonin-Salmon...........................................................88 5. Antiplatelets........................................................ 89 Antiplatelets Overview.....................................................91 Antiosteoporosis Agents Overview...................................91 Aspirin.............................................................................92 6. Diabetes Agents................................................... 93 Diabetes Agents Overview...............................................95 Insulin..............................................................................97 Glyburide......................................................................100 Glipizide........................................................................102 Metformin Hydrochloride..............................................103 Pioglitazone...................................................................104 Rosiglitazone.................................................................105 7. Ulcer Prophylaxis and Treatment...................... 107 Ulcer Prophylaxis and Treatment Overview...................109 Magnesium/Aluminum Hydroxide Suspension, Aluminum Hydroxide Suspension, Calcium Carbonate........................................................110 Histamine H2-Receptor Antagonists...............................112 Proton Pump Inhibitors..................................................114 Pantoprazole..................................................................116 Sucralfate.......................................................................117 8. Diuretics ........................................................... 119 Diuretics Overview........................................................121 Diuretics........................................................................122 9. Other Concomitant Agents............................... 125 Other Concomitant Agents Overview ............................127 Other Cardiovascular Agents .........................................131 Levothyroxine................................................................134 Sodium Bicarbonate.......................................................135 Aquaphor® Ointment....................................................136 Octreotide .....................................................................137 Metoclopramide ............................................................138 Bethanechol...................................................................140 Phenytoin......................................................................141 Warfarin.........................................................................142 Pentoxifylline.................................................................144 Fludrocortisone..............................................................145 Potassium......................................................................146 Introduction The field of transplantation continues to evolve. In the years since the first publication of the Transplantation Drug Pocket Reference Guide, the therapeutic armamen- tarium for transplantation has grown. The introduction of new agents continues to enhance our ability to im- prove the short- and long-term success of transplantation. The third edition of the guide, now entitled Transplanta- tion Drug Manual, includes information on agents approved for use in transplant recipients. As in the first and second editions, we compiled practical information on the wide array of pharmaceutical agents currently available—both those used for immunosuppression and those used to minimize posttransplant complications. The agents described here are the most frequently prescribed drugs in the Transplant Service at the University of Wisconsin. We hope you find this information to be useful and practical in managing the transplant patient. Chapter 1 Working Guide to Immunosuppression Current Agents Overview • Antithymocyte globulin (equine) - ATGAM • Antithymocyte globulin (rabbit) -Thymoglobulin • Azathioprine • Cyclophosphamide • Cyclosporine-A • Cyclosporine Capsules and Oral Solution (Modified) • Methylprednisolone • Muromonab-CD3 • Mycophenolate Mofetil • Prednisone • Tacrolimus • Basiliximab • Daclizumab • Sirolimus 3 Current Agents Overview n -o nosi ues Agent Dosage mr p mp Antithymocyte Delaying Onset of Allograft Rejection Iu s Globulin (ATGAM) •Fixed dose of 15 mg/kg for 14 days, then every other day for 14 days s for a total of 21 doses in 28 days al •First dose should be administered within 24 hours before or after bi o transplantation cr mi Treatment of Rejection nti A •10-15 mg/kg/d IV for 8-14 days, then every other day up to 21 doses Antithymocyte Treatment of Rejection ar ul Globulin (rabbit) • 1.5 mg/kg/d for 7 to 14 days IV cs asnt Azathioprine •3 mg/kg/d to 5 mg/kg/d single dose given at time of transplantation ve og •1 mg/kg/d to 3 mg/kg/d for maintenance diA •Dose usually adjusted depending on WBCs Car •Lower doses should be considered in presence of renal dysfunction s Cyclophosphamide •2 mg/kg/d to 3 mg/kg/d is initial recommended dose, but is rapidly o-ent reduced due to toxicity ostes Ag Cyclosporine-A Gelatin Capsules & Oral Solution ntiosi •15 mg/kg single dose given 4 to 12 hours prior to transplantation Aor •Usual starting dose in 4-10 mg/kg in bid dosing. Dose is titrated to p achieve whole blood levels of 200-300 mg/ml s et el IV Infusion at •5 mg/kg to 6 mg/kg single dose given 4 to 12 hours prior to pl transplantation nti •Single daily IV dose continued postoperatively until patient can tolerate A oral formulations Cyclosporine NOTE: Neoral, Gengraf, and Sandimmune are not bioequivalent and ess Capsules and Oral should not be used interchangeably. Neoral has increased etnt be Solution bioavailability and this should be taken into consideration ag (Modified) when making dosing decisions. DiA •Daily dose should be given as two divided doses on a consistent schedule nt re em Newly Transplanted Patients Ulcat •Initial dose of Neoral should be the same as a Sandimmune dose. e Suggested initial doses include: Tr – 9 ± 3 mg/kg/day for kidney transplant patients – 8 ± 4 mg/kg/day for liver transplant patients s •–Th e 7 d ±o s3e m isg t/hkgen/d sauyb fsoer qhueeanrttl ytr aandsjupslatendt ptoa taiecnhtiseve a predefined etic r cyclosporine blood concentration u Di Conversion from Sandimmune to Neoral •Neoral should be started with the same daily dose as was previously •uTsheed N weoitrha lS daonsdeim smhouunlde (th1e:1n dboes aed cjuosntveedr stoio nac)hieve preconversion herents cyclosporine blood trough concentrations Otg A •Until cyclosporine blood trough concentrations reach preconversion levels, monitoring should be undertaken every 4 to 7 days Continued … 4 -on Current Agents Overview nosi ues mpr Agent Dosage mp Isu Methylprednisolone Induction •250 mg to 1000 mg at time of transplantation and for next 2 to 3 doses s al obi Taper cr •Start at 2 mg/kg/d, taper to a range of 0.15 mg/kg/d to 0.2 mg/kg/d after mi one year nti A Attenuation of Cytokine Release Syndrome ular •8 mg/kg given 1 to 4 hours prior to first injection of muromonab-CD3 ascnts Muromonab-CD3 •5 mg/d IV for 10 to 14 days ve dioAg Mycophenolate Initial dose should be given within 72 hours following transplantation ar Mofetil •1.0 g twice a day used in combination with corticosteroids and C cyclosporine s eo-gent Prednisone M•a0i.n1t emnga/nkcge/—d tAod 2u lmtsg/kg/d usually given once daily osts A ntiosi Maintenance—Pediatric Aor •0.25 mg/kg/d to 2 mg/kg/d or 25 mg/m2 to 60 mg/m2 usually given p daily or on alternate days s et Tacrolimus IV Infusion el •0.03 to 0.05 mg/kg/d as a continuous infusion at pl nti Capsules A •0.15 mg/kg/d to 0.30 mg/kg/d administered in 2 divided daily doses every 12 hours s •First dose should be given 8 to 12 hours after discontinuing IV infusion es etnt Basiliximab • 20 mg within 2 hours of transplantation surgery and repeated 4 days be ag after transplantation DiA Daclizumab • 1 mg/kg/dose for 5 doses. The first dose within 24 hours of transplanta- tion, then at intervals of 14 days for 4 doses nt re em c Ulat e Tr s c eti r u Di ernts he Otg A 5 Antithymocyte Globulin (Equine) n -o nosi ues Brand Name ATGAM® mpr mp Company Pharmacia & Upjohn, Inc. Iu s Class •Immunosuppressant gamma globulin, primarily monomeric IgG, from s hyperimmune serum of horses immunized with human thymic al lymphocytes bi o Mechanism of •Antibodies of multiple specificities interact with lymphocyte surface cr mi Action antigens, depleting numbers of circulating, thymus-dependent lympho- cytes and interfering with cell-mediated and humoral immune responses nti A Indications •Management of renal allograft rejection •Adjunct to other immunosuppressive therapy to delay the onset of the ular first rejection episode cs asnt Contraindication •Hypersensitivity to ATGAM or any other equine gamma globulin ovge preparation diA ar Warnings •Should be administered in facilities equipped and staffed with adequate C laboratory and supportive medical resources s •Immunosuppressive activity may vary from lot to lot o-ent •Potential for the transmission of infectious agents eg •Treatment should be discontinued if the following occur: osts A • Symptoms of anaphylaxis • Thrombocytopenia • Leukopenia ntiosi Special •Risk of infection, leukopenia, and thrombocytopenia Aor p Precautions •Safety and effectiveness demonstrated only in patients who received s concomitant immunosuppression et •Pregnancy Category C el at Adverse Reactions •Fever (1 patient in 3) pl •Chills (1 patient in 7) nti •Leukopenia (1 patient in 7) A •Dermatologic reactions (1 patient in 8) •Thrombocytopenia (1 patient in 9) s Reported in >1%, but <5% of Patients etents •Arthralgia •Chest and/or back pain be •Clotted A/V fistula •Nausea and/or vomiting DiaAg •Night sweats •Pain at infusion site •Peripheral thrombophlebitis •Stomatitis Drug Interaction •Dextrose Injection, USP nt Formulation •5 mL ampule containing 50 mg/mL erme c Dosage Delaying Onset of Allograft Rejection Ulat •Fixed dose of 15 mg/kg for 14 days, then every other day for 14 days for Tre a total of 21 doses in 28 days •First dose should be administered within 24 hours before or after transplantation s c Treatment of Rejection eti •10 mg/kg/d IV for 8-14 days, then every other day up to 21 doses r u Dose should be infused at least over 4 hours, through a 0.2-1 micron filter Di Editors’ Notes: ATGAM® and Thymoglobulin® are the only two polyclonal antilymphocyte preparations which are currently avail- aAbTleG. AAMTG®A cMau®se si sle assn leimukmopuennoigal othbaunle T ahgyaminostg lloybmuplihno®cy. tBeos tphr eapgeanretds hinav eh obreseens; uTsehdy mtoo pgrleovbeunltin a®cu ties rperjeepctairoend aifnt erra tbrbanitss-. herents plantation and to treat acute rejection episodes. Otg A