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Plumb's V eterinary Drug Handbook Sixth Edition Donald C. Plumb, Pharm. D. distributed by Blackwell Publishing

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COPyri GHt © 2008 by d onald C. Plumb All rights reserved. No part of this book may be reproduced or transmitted in any form or any means, electronic or mechanical, including recording, photocopying, or by any information stor age and retrieval system, without the written permission of the copyright owner. worldwide print distribution by: Blackwell Publishing Professional 2121 s outh state Avenue Ames, i owa 50014-8300 (800) 862-6657www. blackwellpublishing. com/Vet/ published by Pharma V et Inc. stockholm, Wisconsin design and typesetting Peregrine Graphics s ervices st. Paul, Minnesota isb N: 978-0-8138-1097-3 Last digit is the print number 9 8 7 6 5 4 3 2 1

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For Shirley, Whose efforts, support, and love make this reference a reality * * *

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Contributors to the Sixth Edition C. A. t ony b uffington, d VM, Phd, d ACVN Professor of Veterinary Clinical sciences the Ohio state u niversity Veterinary Hospital Columbus, OH Dog and Cat Therapeutic Diets Andrea G. Cannon, d VM, d ACVd Animal d ermatology & Allergy rocklin, CA; Modesto, CA; b oise, id Dermatological Agents, Topical Gigi davidson, di CVP North Carolina state u niversity raleigh, NC Ophthalmology Products, Topical Principles of Compounding Ophthalmic Products Camille d e Clementi, VMd, d Abt As PCA Animal Poison Control Center urbana, i L Overdose and Toxin Exposure Decontamination Guidelines, ASPCA Animal Poison Control Center Data for Drug Monographs Michelle d u Mond, r Vt Nutrition s upport specialist the Ohio state u niversity Veterinary Hospital Columbus, OH Dog and Cat Therapeutic Diets dinah Jordan, Pharmd, di CVP Mississippi state u niversity Mississippi state, Ms Insulin, Maropitant, & Mirtazapine Monographs sandra Koch, d VM, Ms, d ACVd College of Veterinary Medicine, u niversity of Minnesota st. Paul, MNDermatological Agents, Topical elaine Lust, Pharmd, di CVP Creighton u niversity Omaha, Ne Ceftiofur (Free Acid, Sodium and HCl), Danofloxacin, Tulathromycin Monographs to sign up for e-mail notifi cation of updates and errata, or get information on ordering information for additional versions, visit Plumb's Veterinary Drug Handbook's web site at: www. vetdruginfo. com

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Preface to the Sixth Edition in this edition, Plumb's Veterinary Drug Handbook continues to evolve with the addition of more drugs, more types of drugs (topical dermatology drugs), and a new look; however, the basic premise remains to serve as a single volume reference to assist veterinarians, other health professionals, and animal caretakers in providing optimal drug therapy for veterinary patients. t he changes to this edition include a new design and layout; the addition of 75 new drug monographs; updates to the older monographs, with a listing for rapid-scanning for potential drug interactions and overdose information for 50 drugs from the As PCA Animal Poison Control Center; and new sections on topical dermatologic agents and products, Principles of Compounding Ophthalmic Products, and Overdose and t oxin exposure d econtamination Guidelines in the appendix. donald C. Plumb About the Author donald C. Plumb, Pharm. d., was formerly d irector of Pharmacy s ervices and Hospital d irector at the university of Minnesota's Veterinary Medical Center. Now retired from the u niversity of Minnesota, he focuses full-time on providing veterinary drug information to veterinarians, other health professionals, and animal caretakers.

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Notes and Cautions Dosages and Extra-Label Use of Medications dosages for the various species for the drugs listed in this reference come from a variety of sources and are referenced to their source in the appendix. While a sincere effort has been made to assure that the dosages and information in cluded in this book are accurate and reflect the original source's information, errors can occur; it is recommended that the reader refer to the original reference or the approved labeling information of the product for addi tional information and verification of all dosages. except for labeled dosages for veterinary-approved products (for a given species and indication,) dosages listed in this reference should be considered “extra-label” and are not necessarily endorsed by the manufacturer, the Food and drug Administration (Fd A) or this author. Veterinarians are responsible as per the Animal Medical drug u se Clarification Act (AMdu CA) for the appropriate use of medications. t he Animal Medicinal drug u se Clarification Act of 1994 (AMdu CA) allows veterinarians to prescribe extralabel uses of certain approved animal drugs and approved human drugs for animals under certain conditions. e xtralabel (or extra-label) use refers to the use of an approved drug in a manner that is not in accordance with the approved label directions. t he key constraints of AMdu CA are that any extralabel use must be by or on the order of a veterinarian within the context of a veterinarian-client-patient relationship, must not result in violative residues in food-producing animals, and the use must be in conformance with the implementing regulations published at 21 CFr Part 530. A list of drugs specifically prohibited from extra-label use appears in the Code of Federal r egulations. For additional information go to the Fd A-Center for Veterinary Medicine Website at: http://www. fda. gov/cvm/ Abbreviations: OTC & Rx in addition to the abbreviations used in writing prescriptions (e. g., tid, q8h, etc. —see the abbreviation list in the appendix), the terms O t C or rx are found in parentheses after a listed dosage form. i f rx, the drug is considered to be a prescription or legend product, and requires a prescription. O t C denotes that the item is available “over-the-counter” and does not require a prescription for purchase. Trade and Proprietary Names the notation used to signify trade names or proprietary names is an italicized, capitalized name followed by a ® (e. g., Amoxi-Tabs®). this notation may not accurately represent the drug's official registered copyright, trademark, or licensed status (e. g., ™, etc. ) Drug Interactions drug interaction identification and evaluation is in its infancy in veterinary medicine, as relatively little specific information is known on the subject for the variety of species treated. While drug interactions can be clinically significant and potentially life-threatening in veterinary patients, most of the interactions listed in the monographs are derived from human medicine (which is only slightly more informed than veterinary medicine on this topic) and are often included primarily to serve as cautions to the prescriber to be alert for unforeseen outcomes, or to enhance monitoring associated with the drug therapy. Additionally, it is likely there are potentially many other clinically significant interactions between drugs that are not listed; prescribers are reminded that the risk for adverse drug interactions occurring increases with the number of different drugs given to an individual patient. Disclaimer the author/publisher/distributor assume no responsibility for and make no warranty with respect to results that may be obtained from the uses, procedures, or dosages listed, and do not necessarily endorse such uses, procedures, or dosages. t he author/publisher shall not be liable to any person whatsoever for any dam ages, or equivalencies, or by reason of any misstatement or error, negligent or otherwise obtained in this work. should the pur chaser not wish to be bound by the above, he/she may return the reference to the distributor for a full refund.

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Contents Sy STEMIC MONOg RAPh S Acarbose 1 Acemannan 2 Acepromazine Maleate 3 Acetaminophen 6 Acetazolamide 7 Acetic Acid 9 Acetohydroxamic Acid 9 Acetylcysteine 10 Acitretin 12 Acyclovir 14 Aglepristone 15 Albendazole 17 Albuterol s ulfate 19 Alendronate s odium 21 Alfentanil HCl 22 Allopurinol 24 Alprazolam 26 Altrenogest 27 Aluminum Hydroxide 29 Amantadine HCl 30 Amikacin s ulfate 32 Aminocaproic Acid 35 Aminopentamide Hydrogen s ulfate 36 Aminophylline/t heophylline 37 Amiodarone HCl 40 Amitriptyline HCl 42 Amlodipine b esylate 44 Ammonium Chloride 46 Ammonium Molybdate 47 Ammonium t etrathiomolybdate 47 Amoxicillin 48 Amoxicillin/Clavulanate Potassium 51 Amphotericin b d esoxycholate 53 Amphotericin b Lipid-b ased 53 Ampicillin 57 Ampicillin s odium/s ulbactam s odium 60 Amprolium Hydrochloride 62 Antivenin (Crotalidae) Polyvalent (e quine Origin) 63 Antivenin (Crotalidae) Polyvalent i mmune Fab (Ovine Origin) 63 Antivenin (Micrurus Fulvias) eastern and t exas Coral s nake 65Antivenin (Latrodectus Mactans) b lack Widow spider 66 Apomorphine HCl 67 Apramycin s ulfate 69 Ascorbic Acid 70 Asparaginase 71 Aspirin 73 Atenolol 77 Atipamezole HCl 79 Atovaquone 80 Atracurium b esylate 81 Atropine s ulfate 83 Auranofin 86 Azaperone 87 Azathioprine 88 Azithromycin 91 Aztreonam 92 baclofen 94 barbiturate Pharmacology 95 benazepril HCl 96 betamethasone 97 bethanechol Chloride 99 bisacodyl 101 bismuth s ubsalicylate 102 bleomycin s ulfate 104 boldenone u ndecylenate 106 bromide, Potassium 107 bromide, s odium 107 bromocriptine Mesylate 109 budesonide 110 buprenorphine HCl 112 buspirone HCl 114 busulfan 115 butorphanol t artrate 116 Cabergoline 120 Calcitonin s almon 121 Calcitriol 122 Calcium Acetate 124 Calcium s alts 125 Captopril 129 Carbenicillin i ndanyl s odium 130 Carbimazole 132 Carboplatin 133 Carnitine 135 Carprofen 136 Carvedilol 139 Caspofungin Acetate 140

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Cefaclor 141 Cefadroxil 143 Cefazolin s odium 144 Cefepime HCl 147 Cefixime 148 Cefoperazone s odium 149 Cefotaxime s odium 151 Cefotetan d isodium 153 Cefoxitin s odium 154 Cefpodoxime Proxetil 156 Ceftazidime 157 Ceftiofur Crystalline Free Acid 159 Ceftiofur HCl 161 Ceftiofur s odium 164 Ceftriaxone s odium 166 Cefuroxime 168 Cephalexin 170 Cephapirin 172 Cetirizine HCl 173 Charcoal, Activated 174 Chlorambucil 176 Chloramphenicol 178 Chlordiazepoxide ± Clidinium b r 181 Chlorothiazide 183 Chlorpheniramine Maleate 185 Chlorpromazine HCl 186 Chlorpropamide 188 Chlortetracycline 190 Chorionic Gonadotropin (HCG) 191 Chromium 193 Cimetidine 194 Ciprofloxacin 197 Cisapride 199 Cisplatin 200 Citrate s alts 202 Clarithromycin 204 Clemastine Fumarate 206 Clenbuterol HCl 207 Clindamycin 209 Clofazimine 212 Clomipramine HCl 213 Clonazepam 215 Clonidine 217 Clopidogrel b isulfate 218 Cloprostenol s odium 219 Clorazepate d ipotassium 221 Clorsulon 223 Cloxacillin 224Codeine 225 Colchicine 227 Corticotropin (ACt H) 229 Cosyntropin 230 Cromolyn s odium 232 Cyanocobalamin (Vitamin b-12) 233 Cyclophosphamide 234 Cyclosporine 237 Cyproheptadine HCl 240 Cytarabine 241 dacarbazine (dti C) 243 dactinomycin 245 dalteparin s odium 246 danazol 248 danofloxacin Mesylate 249 dantrolene s odium 250 dapsone 252 darbepoetin Alfa 254 decoquinate 255 deferoxamine Mesylate 256 deracoxib 257 deslorelin Acetate 259 desmopressin Acetate 260 desoxycorticosterone Pivalate 262 detomidine HCl 263 dexamethasone 265 dexmedetomidine 270 dexpanthenol 271 dexrazoxane 272 dextran-70 273 diazepam 275 diazoxide, Oral 278 dichlorphenamide 280 dichlorvos 281 diclazuril 282 diclofenac s odium 283 dicloxacillin 284 diethylcarbamazine Citrate 286 diethylstilbestrol 287 difloxacin HCl 289 digoxin 291 dihydrotachysterol 294 diltiazem HCl 296 diminazene Aceturate 298 dimenhydrinate 299 dimercaprol 301 dimethyl s ulfoxide 303 dinoprost t romethamine 305

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diphenhydramine HCl 308 diphenoxylate HCl + Atropine s ulfate 310 dirlotapide 312 disopyramide Phosphate 314 dobutamine HCl 316 docusate 317 dolasetron Mesylate 319 domperidone 320 dopamine HCl 321 doramectin 323 doxapram HCl 325 doxepin HCl 327 doxorubicin HCl 328 doxycycline 331 edetate Calcium d isodium 334 edrophonium Chloride 336 emodepside + Praziquantel 337 enalapril 338 enoxaparin s odium 340 enrofloxacin 342 ephedrine s ulfate 345 epinephrine 347 epoetin Alfa/erythropoietin 349 eprinomectin 351 epsiprantel 352 ergocalciferol 352 ertapenem s odium 354 erythromycin 355 esmolol HCl 358 estradiol Cypionate 360 ethacrynic Acid 362 ethambutol HCl 363 ethanol 365 etidronate d isodium 366 etodolac 367 etomidate 369 euthanasia Agents with Pentobarbital 370 Famciclovir 371 Famotidine 372 Fatty Acids, essential/Omega 374 Felbamate 375 Fenbendazole 376 Fentanyl 379 Fentanyl Citrate, i njectable 379 Ferrous s ulfate 382 Filgrastim 384 Finasteride 385 Firocoxib 386Flavoxate HCl 388 Florfenicol 389 Fluconazole 391 Flucytosine 393 Fludrocortisone Acetate 394 Flumazenil 396 Flumethasone 397 Flunixin Meglumine 400 Fluorouracil 402 Fluoxetine 404 Fluticasone Propionate 405 Fluvoxamine Maleate 407 Folic Acid 409 Fomepizole 410 Furazolidone 411 Furosemide 413 Gabapentin 415 Gemcitabine HCl 417 Gemfibrozil 418 Gentamicin s ulfate 419 Glimepiride 423 Glipizide 424 Glucagon 425 Glucocorticoid Agents, General i nformation 427 Glucosamine/Chondroitin s ulfate 429 Glutamine 431 Glyburide 432 Glycerin, Oral 433 Glycopyrrolate 434 Gold s alts, i njectable 436 Gonadorelin 438 Granisetron HCl 440 Griseofulvin 441 Guaifenesin 443 Halothane 445 Hemoglobin Glutamer-200 (b ovine) 446 Heparin 448 Hetastarch 451 Hyaluronate s odium 452 Hydralazine HCl 453 Hydrochlorothiazide 455 Hydrocodone b itartrate 458 Hydrocortisone 459 Hydrogen Peroxide 3% (Oral) 462 Hydromorphone 464 Hydroxyurea 466 Hydroxyzine 467 Hyoscyamine s ulfate 469

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ibafloxacin 470 ifosfamide 471 imidocarb d ipropinate 473 imipenem-Cilastatin s odium 474 imipramine 476 inamrinone Lactate 478 insulin 479 interferon Alfa, Human r ecombinant 484 interferon Omega, Feline 486 iodide, s odium 487 iodide, Potassium 487 ipecac s yrup 488 ipodate s odium 490 ipratropium b romide 491 irbesartan 492 iron d extran 493 isoflupredone Acetate 494 isoflurane 496 isoniazid (i NH) 497 isoproterenol HCl 499 isosorbide d initrate 500 isosorbide Mononitrate 500 isotretinoin 502 isoxsuprine HCl 504 itraconazole 505 ivermectin 508 Kaolin/Pectin 512 Ketamine HCl 513 Ketoconazole 517 Ketoprofen 521 Ketorolac t romethamine 523 Lactulose 524 Leflunomide 526 Leucovorin Calcium 527 Leuprolide 528 Levamisole 529 Levetiracetam 532 Levothyroxine s odium 534 Lidocaine HCl 536 Lincomycin HCl 539 Liothyronine s odium 541 Lisinopril 542 Lomustine 544 Loperamide HCl 545 Lorazepam 547 Lufenuron 548 Lysine 550 Magnesium Hydroxide 551Magnesium/Aluminum Antacids 551 Magnesium (Parenteral) 553 Mannitol 555 Marbofloxacin 557 Maropitant Citrate 558 Mechlorethamine HCl 560 Meclizine HCl 561 Medetomidine HCl 562 Medium Chain t riglycerides 564 Medroxyprogesterone Acetate 565 Megestrol Acetate 567 Meglumine Antimoniate 570 Melarsomine 571 Melatonin 572 Meloxicam 574 Melphalan 575 Meperidine HCl 577 Mercaptopurine 579 Meropenem 581 Metformin HCl 582 Methadone HCl 584 Methazolamide 585 Methenamine Mandelate 587 Methimazole 588 Methionine 589 Methocarbamol 591 Methohexital s odium 592 Methotrexate 594 Methoxyflurane 596 Methylene b lue 597 Methylphenidate 599 Methylprednisolone 600 Methyltestosterone 604 Metoclopramide HCl 606 Metoprolol 608 Metronidazole 610 Mexiletine HCl 613 Mibolerone 614 Midazolam HCl 616 Milbemycin Oxime 618 Mineral Oil 620 Minocycline HCl 621 Mirtazapine 623 Misoprostol 625 Mitotane 627 Mitoxantrone HCl 629 Morantel t artrate 631 Morphine s ulfate 632

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Moxidectin 635 Mycobacterial Cell Wall Fraction i mmunomodulator 637 Mycophenolate Mofetil 639 Naloxone HCl 641 Naltrexone HCl 642 Nandrolone d ecanoate 643 Naproxen 645 Narcotic (Opiate) Agonist Analgesics, Pharmacology of 647 N-butylscopolammonium b romide 647 Neomycin s ulfate 648 Neostigmine 651 Niacinamide 652 Nitazoxanide 653 Nitenpyram 655 Nitrofurantoin 656 Nitroglycerin 658 Nitroprusside s odium 659 Nizatidine 661 Novobiocin s odium 662 Nystatin 664 Octreotide Acetate 665 Olsalazine s odium 666 Omeprazole 667 Ondansetron 669 Orbifloxacin 670 Oseltamivir Phosphate 671 Oxacillin s odium 673 Oxazepam 675 Oxfendazole 676 Oxibendazole 677 Oxybutynin Chloride 678 Oxymorphone HCl 679 Oxytetracycline 682 Oxytocin 685 Pamidronate d isodium 688 Pancrelipase 689 Pancuronium b romide 690 Pantoprazole 692 Parapox Ovis Virus i mmunomodulator 693 Paregoric 694 Paromomycin s ulfate 695 Paroxetine HCl 696 Penicillamine 698 Penicillins, General i nformation 699 Penicillin G 701 Penicillin V Potassium 705 Pentazocine 707 Pentobarbital s odium 709Pentosan Polysulfate s odium 712 Pentoxifylline 714 Pergolide Mesylate 715 Phenobarbital 717 Phenoxybenzamine HCl 720 Phenylbutazone 722 Phenylephrine HCl 724 Phenylpropanolamine HCl 726 Phenytoin s odium 727 Pheromones 730 Phosphate, Parenteral 731 Physostigmine s alicylate 733 Phytonadione 734 Pimobendan 736 Piperacillin s odium 738 Piperacillin s odium + t azobactam 739 Piperazine 741 Pirlimycin HCl 743 Piroxicam 744 Polysulfated Glycosaminoglycan 746 Ponazuril 747 Potassium 748 Pralidoxime Chloride 750 Praziquantel 751 Prazosin HCl 754 Prednisolone 755 Prednisone 755 Primaquine Phosphate 762 Primidone 764 Probenecid 766 Procainamide HCl 767 Procarbazine HCl 770 Prochlorperazine 771 Promethazine HCl 773 Propantheline b romide 775 Propionibacterium Acnes i njection 777 Propofol 778 Propranolol HCl 780 Protamine s ulfate 783 Pseudoephedrine HCl 784 Psyllium Hydrophilic Mucilloid 785 Pyrantel Pamoate 786 Pyridostigmine b romide 788 Pyridoxine HCl (Vitamin b-6) 790 Pyrilamine Maleate 791 Pyrimethamine 792 Pyrimethamine + s ulfadiazine 794 Quinacrine HCl 796

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Quinidine 797 ramipril 800 ranitidine HCl 801 rifampin 803 romifidine HCl 805 ronidazole 807 s-Adenosyl-Methionine (s AMe) 809 saline/Hyperosmotic Laxatives 810 selamectin 812 selegiline HCl 814 sertraline HCl 815 sevelamer HCl 817 sevoflurane 818 sildenafil Citrate 820 silymarin; Milk t histle 821 sodium b icarbonate 822 sodium Polystyrene s ulfonate 825 sodium stibogluconate; s odium Antimony Gluconate 826 sodium s ulfate 827 sodium t hiosulfate 827 somatotropin 828 sotalol HCl 829 spectinomycin HCl 831 spinosad 1015 spironolactone 832 stanozolol 834 staphylococcal Phage Lysate 836 streptokinase 837 streptozocin 838 succimer 839 succinylcholine Chloride 841 sucralfate 843 sufentanil Citrate 844 sulfachlorpyridazine s odium 846 sulfadiazine/t rimethoprim 847 sulfamethoxazole/t rimethoprim 847 sulfadimethoxine 851 sulfadimethoxine/Ormetoprim 853 sulfasalazine 854 taurine 856 tepoxalin 857 terbinafine HCl 858 terbutaline s ulfate 859 testosterone 861 tetracycline HCl 863 theophylline 37 thiabendazole 867 thiamine HCl 869thioguanine 870 thiopental s odium 872 thiotepa 874 thyrotropin 875 tiamulin 876 ticarcillin d isodium 877 ticarcillin d isodium + Clavulanate Potassium 880 tiletamine HCl/Zolazepam HCl 882 tilmicosin 884 tiludronate d isodium 885 tiludronic Acid 885 tinidazole 887 tiopronin 888 tobramycin s ulfate 889 tocainide HCl 892 tolazoline HCl 893 tolfenamic Acid 895 toltrazuril 896 topiramate 897 torsemide 898 tramadol HCl 900 triamcinolone Acetonide 901 triamterene 905 trientine HCl 906 trilostane 907 trimeprazine t artrate With Prednisolone 909 tripelennamine HCl 910 tulathromycin 911 tylosin 913 ursodiol 915 Valproic Acid 916 Vanadium 918 Vancomycin HCl 919 Vasopressin 920 Vecuronium b romide 922 Verapamil HCl 923 Vinblastine s ulfate 925 Vincristine s ulfate 927 Vitamin e/s elenium 929 Voriconazole 931 Warfarin s odium 933 Xylazine HCl 935 yohimbine HCl 938 Zafirlukast 939 Zidovudine (AZt ) 940 Zinc 942 Zonisamide 943

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APPENDIx Ophthalmic Products, t opical 945 routes of Administration For Ophthalmic drugs 945 diagnostic Agents 946 Fluorescein s odium 946 Lissamine Green 946 Phenol r ed t hread 947 Proparacaine 947 rose b engal 947 schirmer t ear t est 947 tetracaine 948 Glaucoma, t opical Agents 948 Parasmpathomimetics (Miotics) 949 Pilocarpine 949 demecarium 949 echothiophate i odide 949 sympathomimetics 950 Apraclonidine 950 brimonidine 950 beta-Adrenergic Antagonists 950 betaxolol 950 Carteolol 951 Levobunolol 951 Metipranolol 951 timolol 951 Carbonic Anhydrase i nhibitors 952 brinzolamide 952 dorzolamide 952 Prostaglandins 952 Latanaprost 952 bimatoprost 952 travoprost 952 Miscellaneous Agents for t reatment of Glaucoma 953 epinephrine 953 Mydriatic-Cycloplegic Vasoconstrictors 953 Cyclopentolate 953 Phenylephrine 953 Atropine 954 tropicamide 954 Anti-inflammatory/Analgesic Ophthalmic Agents 955 Mast Cell stabilizers, Antihistamines, d econgestants 955 Cromolyn s odium 955 Lodoxamine 955 Olopatadine 955 Non-steroidal Antiinflammatory Agents 955 bromfenac 955 diclofenac 956 Flurbiprofen 956Ketorolac 956 Nepafenac 957 suprofen 957 steroidal Anti-inflammatory Agents 957 Prednisolone Acetate 957 dexamethasone 957 Loteprednol e tabonate 957 Corticosteroids, t opical 957 Ophthalmic Analgesics 959 Morphine s ulfate 959 Nalbuphine 959 Antimicrobial Ophthalmic t herapy 959 Antibiotics, s ingle & Combination Agents 959 Chloramphenicol 960 Ciprofloxacin 960 Gatifloxacin 960 Levofloxacin 960 Moxifloxacin 960 Norfloxacin 960 Ofloxacin 960 Gentamicin 961 tobramycin 961 sulfacetamide 961 tetracycline 961 Oxytetracycline 961 Antibiotic Combinations 962 Antibiotic and Corticosteroid Combinations 962 Antifungals 963 Amphotericin b 963 Povidone i odine 963 Natamycin 964 Miconazole 964 silver s ulfadiazine 964 itraconazole 965 Voriconazole 965 Antivirals 966 trifluridine 966 idoxuridine 967 interferon Alpha 967 Acyclovir 967 Valacyclovir 967 Famciclovir 967 Ganciclovir 967 Cidofovir 967 Penciclovir 967 Keratoconjunctivitis s icca 968 Cyclosporine 968 tacrolimus 969

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Artificial t ear Products/Ocular Lubricants 969 Ophthalmic i rrigants 969 topical Hyperosmotic Agents 970 Polysulfonated glycosaminoglycan 970 Hypertonic s odium Chloride 970 Viscoelastic s ubstances 970 Hyaluronic Acid 971 Cytotoxic Ophthalmic Agents 971 Cisplatin beads 971 5-Fluorouracil 971 Mitomycin-C 971 sympathomimetics 972 Hydroxyamphetamine 972 Cocaine 972 Anticollagenase Agent 972 Acetylcysteine 972 edetate d isodium 972 Principles of Compounding Ophthalmic Products 973 dermatological Agents, t opical 976 Non-Corticosteroid Antipruritics 976 Aluminum Acetate s olution 976 diphenhydramine HCl 977 Pramoxine HCl 977 Colloidal Oatmeal 978 Phenol/Menthol/Camphor 979 Lidocaine 979 Lidocaine/Prilocaine (e MLA Cream) 979 Antiinflammatory Agents 980 Corticosteroids 980 Hydrocortisone 980 triamcinolone Acetonide 982 betamethasone 983 isoflupredone Acetate 984 Antiinfectives, t opical 985 Antibacterial Agents 985 Gentamicin s ulfate 985 bacitracin and b acitracin Combinations 986 benzoyl Peroxide 987 Clindamycin 988 Mupirocin 988 Nitrofurazone 989 silver s ulfadiazine (ssd) 990 Antiseptics 990 Chlorhexidine 990 ethyl Lactate 992 Povidone i odine 992 triclosan 993Antifungal Agents 994 Clotrimazole 994 enilconazole 994 Ketoconazole 995 Lime s ulfur 995 Miconazole 996 Nystatin 997 selenium s ulfide 998 terbinafine HCl 999 Keratolytic Agents 1000 salicylic Acid 1000 sulfur, Precipitated 1001 Coal t ar 1002 Antiseborrheic Products 1003 Phytosphingosine 1003 immunomodulators, t opical 1003 imiquimod 1003 tacrolimus 1004 Pimecrolimus 1004 retinoids 1005 tretinoin 1005 Antiparasitic Agents, t opical 1006 Amitraz 1006 Crotamiton 1007 Fipronil ± (s)-Methoprene 1008 imidacloprid 1009 imidacloprid with Permethrin 1009 imidacloprid with Moxidectin 1009 Metaflumizone 1010 (s)-Methoprene Combinations 1010 Pyriproxyfen & Pyriproxyfen Combinations 1011 Permethrin 1012 Pyrethrins and Pyrethrin Combinations 1013 spinosad 1015 Oti C Preparations 1016 ear Cleaners/Flushes/Antiseptic/d isinfectants 1016 Corticosteroid/Antiinflammatory 1017 Antimicrobial (Antibacterial) 1018 Antimicrobial (Antifungal) 1018 Corticosteroid + Antimicrobial 1018 Antiparasitic Preparations 1019 small Animal t herapeutic d iets 1020 therapeutic d iets for d ogs 1021 Modified Fiber d iets for d ogs 1021 Novel Protein d iets for d ogs 1021 Nutrient d ense d iets for d ogs 1024 reduced Fat d iets for d ogs 1026 reduced s odium d iets for d ogs 1028

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reduced Protein/Phosphorus d iets for d ogs 1029 reduced energy d iets for d ogs 1030 restricted Mineral d iets for d ogs 1032 Geriatric d iets for d ogs 1032 dental d iets for d ogs 1034 Other t herapeutic d iets for d ogs 1034 therapeutic d iets for Cats 1035 Modified Fiber d iets for Cats 1035 Novel Protein d iets for Cats 1036 Nutrient d ense d iets for Cats 1037 reduced Fat d iets for Cats 1038 restricted Mineral d iets for Cats 1040 reduced energy d iets for Cats 1041 reduced Phosphorus/Protein for Cats 1043 reduced s odium for Cats 1044 Geriatric d iets for Cats 1045 Other t herapeutic and Hairball d iets for Cats 1046 Overdose and t oxin e xposure d econtamination Guidelines 1047 Ar Ci u CGFs Classifications 1049 Chemotherapy Protocols for t reatment of Neoplastic d iseases in small Animals 1050 Canine Lymphoma Protocols 1050 Prednisone ± Chlorambucil Protocol 1050 COP (Cyclophosphamide-Vincristine-Prednisone) Protocol 1050 doxorubicin Protocol 1050 Wisconsin-Madison Protocol—short 1051 Ve LCAP-s Protocol 1051 Other Canine Protocols 1051 Canine s arcoma & Carcinoma t reatment Protocol “AC” 1051 Canine Osteogenic s arcoma Adjuvant Protocol 1051 Mast Cell t umor Protocol 1052 Feline Lymphoma Protocols 1052 COPLA Protocol 1052 COP Protocol 1052 COAP Protocol 1052 Ferret Lymphoma Protocols 1052 Ferret Ls A Protocol 1052 Conversion t ables for Weight in Kilograms to b ody s urface Area (m2) 1052 tables of Parenteral Fluids 1053 Abbreviations u sed i n Prescription Writing 1054 solubility d efinitions 1055 Conversion: Weights; t emperature; Liquids 1055 Milliequivalents & Molecular Weights 1055 “Normal” Vital s igns 1055 estrus and Gestation Periods for d ogs & Cats 1056 Conversion of Conventional Chemistry u nits to si u nits 1056 reference Laboratory r anges 1057 Chemistry: Canine, Feline, b ovine, e quine 1057Hematology: Canine, Feline, b ovine, e quine 1057 Coagulation: Canine, Feline, b ovine, e quine 1058 urinalysis: Canine, Feline 1058 Cerebral spinal Fluid: Canine, Feline 1058 Ferret: Male Albino 1059 rabbit: Female New Zealand White 1059 Avian: Macaws 1059 Avian: Parrots, African Grey 1059 Hematology: sheep, Goats, s wine 1060 Chemistry: sheep, Goats, s wine 1060 Phone Numbers and Websites 1061 Food and drug Administration Center for Veterinary Medicine (Fd A-CVM) 1061 u. s. d epartment of Agriculture (usd A) 1061 u. s. environmental Protection Agency (e PA) 1061 Food Animal r esidue Avoidance databank (FAr Ad) 1061 drug enforcement Administration (de A) 1061 Animal Poison Centers 1061 Animal b lood b anks 1061 Veterinary Pharmaceutical Manufacturers & s uppliers 1062 Legally i mporting drugs for Compassionate u se into the us A 1065 references 1066 systemic drugs s orted by t herapeutic Class or Major i ndication 1099 Antihistamines 1099 Central Nervous s ystem drugs 1099 euthanasia Agents 1099 Cardiovascular Agents 1099 respiratory drugs 1100 renal And u rinary t ract Agents 1100 Gastrointestinal Agents 1100 Hormones/endocrine/r eproductive Agents 1100 Anti-i nfective drugs 1101 blood Modifying Agents 1102 Fluid & electrolyte Modifiers 1102 Antineoplastics 1102 immunomodulators 1102 Antidotes 1102 bone/Joint Agents 1102 dermatologic Agents (s ystemic) 1103 Vitamins And Minerals/Nutrients 1103 Cholinergic Muscle stimulants 1103 systemic Acidifiers 1103 systemic Alkalinizers 1103 unclassified 1103 index 1104

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Ac Arbose (ay-kar-bose) Precose® Oral antidiabetic Prescriber Highlights Antihyperglycemic agent that reduces the rate & amount T T of glucose absorbed from the gut after a meal; may be use ful for mild reductions in blood glucose in dogs or cats Contraindications: Underweight animals, known hyper-T T sensitivity, diabetic ketoacidosis, inflammatory bowel dis-ease, colonic ulceration, partial intestinal obstruction or predis position to obstruction, chronic intestinal disease with marked disorders of digestion or absorption & when excessive gas formation would be detrimental Dose-dependent diarrhea & flatulence are the adverse T T effects most likely to be noted Give with meals (preferably right before) T T Expense may be an issue T T Uses/Indications May be useful for mild reduc tions in blood glucose concentrations (250-350 mg/dl range) in dogs and cats with non-insulin-depen-dent diabetes mellitus and as adjunctive treat ment of insulin de-pendent diabetes mellitus. Pharmacology/Actions Acarbose competitively inhibits pancreatic alpha-amylase and alpha-glucosidases found in the small intestine. This delays the diges tion of complex carbohydrates and disaccharides to glucose and other monosaccharides. Glucose is absorbed lower in the GI tract in lesser amounts than is normal thereby reducing insulin re-quirements during the postprandial hyperglycemic phase. Acarbose has no effect on lactase. Pharmacokinetics In dogs about 4% of an oral dose is absorbed; in humans only about 2% of an oral dose is absorbed from the gut which is then ex creted by the kidneys. Practically all remaining drug in the gut is metabo-lized in the GI tract by intestinal bacteria. Patients with severe re-nal dys function attain serum levels approximately 5 times those of normal subjects. Contraindications/Precautions/Warnings Acarbose is contraindicated in patients with known hypersensitiv-ity to the drug, diabetic ketoacidosis, inflammatory bowel disease, colonic ul ceration, partial intestinal obstruction or predis position to obstruction, chronic intestinal disease with marked disorders of digestion or absorption, and when excessive gas formation would be detrimental. Acarbose is not indicated in patients of low body weight (some say normal body weight as well) as it may have delete-rious effects on nutrition status. Use caution in patients with re nal dysfunction or severe liver disease. Adverse Effects Adverse effects re ported in cats include flatulence, soft stools and diar rhea; in dogs, diarrhea and weight loss. Ad verse effects are more likely at higher doses. While acarbose alone does not cause hypo glycemia, it may con-tribute to it by reducing the rate and amount of glucose absorbed when the patient is receiving other hypoglycemic agents (insulin, oral hypoglycemics). Reproductive/Nursing Safety Safety in pregnancy has not been established; weigh any potential risks versus benefits in preg nant animals. In humans, the FDA cat-egorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Overdosage/Acute Toxicity Acute overdosages are likely to cause only diarrhea and flatulence. No treatment should be necessary. Should acute hypoglycemia occur secondary to other antihy po glycemics, parenteral glucose should be admin istered. If treating orally, use glucose (do not use sucrose). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acarbose and may be of significance in veterinary patients: CHARCOAl T! : Intestinal adsorbents may reduce the efficacy of acarbose DIg Ox INT! : Acarbose may reduce digoxin blood concentrations Hy PERgly CEm IC Ag ENTS T! (corticosteroids, thiazides, estrogens, phe­ nothiazines, thyroid hormones, and calcium chan nel blockers ): May negate the effects of acarbose PANCREATINT!, PANCREl IPASE, or Amyl ASE : Exogenous enzyme for-mulations may reduce the efficacy of acarbose laboratory Considerations Increased T! serum aminotransferase levels have been noted in some humans taking high dosages for a long period Doses DOg S:T! a) For dogs poorly controlled with insulin and dietary therapy when another reason for the poor control cannot be identi-fied: Initially 12. 5-25 mg total dose per dog PO with each meal. Give only at the time of feeding. May increase dose after two weeks to 50 mg per dog and then to 100 mg per dog (in large dogs, >25 kg) if response has been inadequate. Greater chance of diarrhea at the higher dosages. (Nelson 2005) b) 12. 5-20 mg (total dose) per meal PO (Daminet 2003) CATS:T! a) 12. 5-25 mg (total dose) PO with meals. When acarbose is used with a low carbohydrate diet it may improve glycemic control and reduce insulin dependence. (Scherk 2005c) 1

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b) 12. 5 mg per cat PO twice daily with meals. May be able to reduce insulin dosage and thereby reduce hypoglycemia oc-currence. (Greco 2002b) c) 12. 5-20 mg (total dose) per meal PO (Daminet 2003) monitoring Serum glucose T! Adverse effects (diarrhea)T! Client Information Give immedi ately prior to feeding for best results T! If diarrhea be comes a problem, contact veterinarian T! Acarbose does not cause low blood sugar, but it may contribute T! to it if the animal is receiving other hypoglycemic agents (insulin, oral hypoglycemics) May take up to two weeks for maximal effect T! Chemistry/Synonyms A complex oligosaccharide antihy perglycemic agent, acarbose oc-curs as white to off-white powder, is soluble in water and has a p Ka of 5. 1. Acarbose may also be known as: Bay-g-5421, Precose®, Asucrose ®, Glicobase®, Glucobay®, Glucor®, Glumida®, or Prandase®. Storage/Stability Do not store tablets above 25°C (77°F); protect from moisture. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Acarbose Tablets: 25 mg, 50 mg & 100 mg; Precose® (Bayer); (Rx) Acem Ann An (ase-man-in) n On-specific immun Ostimulant/ antiviral Prescriber Highlights Non-specific injectable immunostimulant that has been T T tried in Fe LV-, FIV, or FIP-positive cats, & vaccine-induced fibrosarcomas (intralesional) Use is controversial; little, if any controlled study docu-T T mentation supporting efficacy in veterinary medicine Adverse effects include: Possible hypersensitivity reac-T T tions; bolus IV administration can cause salivation, weak-ness, collapse, tachycardia, tachypnea; intralesional in-jection can cause prolonged pain at site; intraperitoneal injection can cause monocyte infiltrates on peritoneal surfaces, liver, & spleen Topical products available; potentially can reduce wound T T healing time Uses/Indications Veterinary acemannan injection is labeled for use in dogs or cats as an aid in the treatment (i. e., surgery) and clinical management of fibrosarcoma. It has been used to treat Fe LV, FIV, and FIP infections in cats but clinical efficacy has not been adequately proven by con-trolled clinical studies. It reportedly has been used in horses, but no specific information on this was located. Pharmacology/Actions Acemannan's immunostimulant activity is thought as a result of in-ducing increases in TNF-alpha and IL-1. At injection sites, increased lymphocytic infiltration and accumulation have been noted. In tis-sue cultures, acemannan has suppressed HIV replication. Pharmacokinetics No information was located. Contraindications/Precautions/Warnings The manufacturer lists no contraindications to using acemannan, however, it should not be used in patients who have demonstrated past severe hypersensitivity reactions to it. Adverse Effects While the manufacturer does not list any specific adverse effects associated with use, hypersensitivity or localized injection re-actions are possible. Bolus IV administration can cause saliva-tion, weakness, collapse, hypotension, tachycardia and tachypnea. Intralesional injection can cause prolonged pain at the injection site. Intraperitoneal injection can cause monocyte infiltrates on peritoneal surfaces, liver, and spleen. Reproductive/Nursing Safety No specific information was located on reproductive or nursing safety. The product label states, “The effects of this compound have not been studied in pregnant animals” and, also, “... the chemical nature of acemannan and the absence of significant toxicity in sev-eral animal species suggest the compound is not a teratogen. ” Overdosage/Acute Toxicity Single IP injections of 50 mg/kg in dogs resulted in no significant signs of toxicity. Acemannan fed orally to dogs at rates of up to 1. 5 g/kg/day for 90 days showed no significant effects. Drug Interactions None were identified. laboratory Considerations None were identified. Doses DOg S/CATS:T! For labeled indications (aid in treatment and management of fibrosarcoma): a) Prior to use, reconstitute with 10 m L sterile diluent. Five to 10 minutes may be necessary for complete dissolution. Shake well before using. Use within 4 hours after rehydration. Ad-minister by concurrent intraperitoneal (IP) and intralesional injections weekly for a minimum of 6 treatments. Recom-mended IP dose is 1 mg/kg. Recommended intralesional dose is 2 mg injected deep into each tumor mass. When used as a prelude to surgery, give concurrent IP and intralesional injections weekly. Continue until delineation, necrosis or maximum tumor enlargement due to edema and immune cellular infiltration occur. Rapid necrosis, which accompa-nies this response, may happen within 2 to 4 weeks. Surgical excision is recommended immediately upon delineation, ne-crosis or maximum tumor enlargement. (Label Information; Acemannan Immunostimulant—VPL) monitoring Clinical efficacy T! Adverse effects (most likely local reactions)T!2 ACEm ANNAN

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Client Information This compound is recommended for use by veterinary profes-T! sionals only Clients should be made aware of the “investigational” nature of T! using acemannan systemically; adverse effects are possible Chemistry Acemannan is a complex carbohydrate polymer that is derived from Aloe vera. It is a long-chained polydispersed beta-(1,4)-acetylated polymannose with interspersed O-acetyl groups with a mannose: acetyl ratio of approximately 1:1. Storage/Stability Acemannan injection should be stored at temperatures less than 35°C (95°F); protect from extremes of heat or light. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Acemannan 10 mg vial with 10 m L vial of diluent (sterile saline) in kits of two vials (one of each) or eight vials (4 of each): Acemannan Immunostimulant® (VPL); OTC Biologic. Labeled for use in dogs or cats. Note : This product is a USDA-licensed biologic and is not an FDA-approved product. Note : There are also topical products labeled for veterinary use that contain acemannan including a wound dressing and cleansing foam. Trade name is Carra Vet® (VPL). HUm AN­l Ab El ED PRODUCTS: No systemic products located Aceprom Azine m Ale A te (ase-pro-ma-zeen) Prom Ace®, Aceproject® phen O thiazine sedative/tranquilizer Prescriber Highlights Negligible analgesic effects T T Dosage may need to be reduced in debilitated or geri-T T atric animals, those with hepatic or cardiac disease, or when combined with other agents Inject IV slowly; do not inject into arteries T T Certain dog breeds (T T e. g., giant breeds, sight hounds) may be overly sensitive to effects May cause significant hypotension, cardiac rate abnor-T T malities, hypo-or hyperthermia May cause penis protrusion in large animals (esp. horses) T T Uses/Indications Acepromazine is approved for use in dogs, cats, and horses. Labeled indica tions for dogs and cats include: “... as an aid in controlling intractable animals... alleviate itching as a result of skin irritation; as an antiemetic to control vomiting associated with motion sick-ness” and as a preanesthetic agent. The use of acepromazine as a sedative/tranquilizer in the treatment of adverse behaviors in dogs or cats has largely been supplanted by newer, effective agents that have fewer adverse effects. Its use for sedation during travel is con-troversial and many no longer recommend drug therapy for this purpose. In horses, acepromazine is labeled “... as an aid in controlling fractious animals,” and in conjunction with local anesthesia for various procedures and treatments. It is also commonly used in horses as a pre-anesthetic agent at very small doses to help control behavior. Although not approved, it is used as a tranquilizer (see doses) in other species such as swine, cattle, rabbits, sheep and goats. Acepromazine has also been shown to reduce the incidence of ha-lothane-induced malignant hyperthermia in susceptible pigs. Pharmacology/Actions Acepromazine is a phenothiazine neuroleptic agent. While the exact mechanisms of action are not fully understood, the phenothiazines block post-synaptic dopamine receptors in the CNS and may also inhibit the release of, and increase the turnover rate of dopamine. They are thought to depress portions of the reticular activating sys-tem that assists in the control of body temperature, basal metabolic rate, emesis, vasomotor tone, hormonal balance, and alertness. Addi tionally, phenothiazines have varying degrees of anticholin-ergic, antihistaminic, antispasmodic, and alpha-adrenergic block-ing effects. The primary desired effect for the use of acepromazine in veteri-nary medicine is its tranquilizing ac tion. Additional pharmacologic actions that acepromazine possess, include antiemetic, antispas-modic, and hypothermic actions. Some researchers have reported that acepromazine has anticonvul sant activity, but in veterinary medicine it is generally felt that phenothiazines should not be used in epileptic animals or those susceptible to seizures (e. g., post-my-elography) as it may precipitate seizures. Acepromazine may decrease respiratory rates, but studies have demonstrated that little or no effect occurs with regard to the blood gas picture, p H or oxyhemoglobin saturation. A dose dependent de crease in hematocrit is seen within 30 minutes after dosing in horses and dogs. Hema tocrit values in horses may decrease up to 50% of pre-dose values; this is probably due to increased splenic sequestration of red cells. Besides lowering arterial blood pressure in dogs, acepromaz-ine causes increases in central venous pressure, a vagally induced bradycardic effect and transient sinoatrial arrest. The bradycardia may be negated by a reflex tachycardic effect secondary to decreases in blood pressure. Acepro mazine also has antidysrhythmic effects. Acepromazine has been demonstrated to inhibit the ar rhythmias induced by ultra-short acting barbiturates, and protect against the ventricular fibrilla tory actions of halothane and epinephrine. Other pharmacologic actions are discussed in the adverse effects section below. Pharmacokinetics The pharmacokinetics of acepromazine have been studied in the horse (Ballard et al. 1982). The drug has a fairly high volume of distribution (6. 6 L/kg), and is more than 99% pro tein bound. The onset of action is fairly slow, requiring up to 15 minutes following IV administra tion, with peak effects seen in 30-60 minutes. The elimination half-life in horses is approximately 3 hours. Acepromazine is metabolized in the liver with both conjugated and unconjugated metabolites eliminated in the urine. Metabolites may be found in equine urine up to 96 hours after dosing. Contraindications/Precautions/Warnings Animals may require lower dosages of general anesthetics follow-ing acepromazine. Use cautiously and in smaller doses in animals with hepatic dysfunction, cardiac disease, or general debilitation. Because of its hypotensive effects, ace promazine is relatively con-traindicated in patients with hypovolemia or shock. Phenothiazines are relatively contraindicated in patients with tetanus or strychnine intoxication due to effects on the ex trapyramidal system. Intravenous injections should be made slowly. Do not administer intra-arterially in horses since it may cause severe CNS excitement/ACEPROm Az INE m Al EATE 3

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depression, seizures and death. Because of its effects on thermoregu-lation, use cautiously in very young or debilitated animals. Acepromazine has no analgesic effects; treat animals with ap-propriate analgesics to control pain. The tranquilization effects of acepromazine can be overridden and it cannot always be counted upon when used as a restraining agent. Do not administer to racing animals within 4 days of a race. In dogs, acepromazine's effects may be individually variable and breed dependent. Dogs with MDR1 mutations (many Collies, Australian shepherds, etc. ) may develop a more pronounced seda-tion that persists longer than normal. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identified or suspected of having this mutation. Acepromazine should be used very cautiously as a restraining agent in aggressive dogs as it may make the animal more prone to startle and react to noises or other sensory inputs. In geriatric pa-tients, very low doses have been associated with prolonged effects of the drug. Giant breeds and greyhounds may be ex tremely sensitive to the drug while terrier breeds are somewhat resistant to its effects. Atropine may be used with ace promazine to help negate its brady-cardic effects. In addition to the legal aspects (not approved) of using acepro-mazine in cattle, the drug may cause regurgitation of ruminal con-tents when inducing general anesthesia. Adverse Effects Acepromazine's effect on blood pressure (hypotension) is well de-scribed and an important consideration in therapy. This effect is thought to be mediated by both cen tral mechanisms and through the alpha-adrenergic actions of the drug. Cardiovascular collapse (secondary to bradycardia and hypotension) has been described in all major species. Dogs may be more sensitive to these effects than other animals. In male large animals acepromazine may cause protrusion of the penis; in horses, this effect may last 2 hours. Stallions should be given acepromazine with caution as injury to the penis can occur with resultant swelling and permanent paralysis of the penis retrac-tor muscle. Other clinical signs that have been reported in horses include excitement, restlessness, sweating, trembling, tachypnea, tachy cardia and, rarely, seizures and recumbency. Its effects of causing penis extension in horses, and pro lapse of the membrana nictitans in horses and dogs, may make its use unsuitable for show animals. There are also ethical considerations regarding the use of tranquilizers prior to showing an animal or having the animal examined before sale. Occasionally an animal may develop the contradictory clinical signs of aggressiveness and generalized CNS stimulation after re-ceiving acepromazine. IM injections may cause transient pain at the injec tion site. Reproductive/Nursing Safety In humans, the FDA categorizes phenothiazines as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncovered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Overdosage/Acute Toxicity The LD 50 in mice is 61 mg/kg after IV dosage and 257 mg/kg af-ter oral dose. Dogs receiving 20-40 mg/kg over 6 weeks apparently demonstrated no adverse effects. Dogs gradually receiving up to 220 mg/kg orally exhibited signs of pulmonary edema and hyperemia of internal or gans, but no fatalities were noted. There were 128 exposures to acepromazine maleate reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases, 89 were dogs with 37 show-ing clinical signs and the remaining 39 reported cases were cats with 12 cats showing clinical signs. Common findings in dogs recorded in decreasing frequency included ataxia, lethargy, sedation, depression, and recumbency. Common findings in cats recorded in decreasing frequency included lethargy, hypothermia, ataxia, protrusion of the third eyelid, and anorexia. Because of the apparent relatively low toxicity of acepromaz-ine, most overdoses can be handled by monitoring the animal and treating clinical signs as they occur; massive oral overdoses should definitely be treated by emptying the gut if possible. Hypotension should not be treated with epinephrine; use either phenylephrine or norepinephrine (levarterenol). Seizures may be controlled with barbiturates or diazepam. Doxapram has been suggested as an an-tagonist to the CNS depressant effects of ace promazine. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acepromazine or other phenothiazines and may be of significance in veterinary patients: ACETAm INOPHEN!! : Possible increased risk for hypothermia ANTACIDS!! : May cause reduced GI absorption of oral phenothiazines ANTIDIARRHEAl m Ix TURES!! (e. g., Kaolin/pectin, bismuth subsalicylate mixtures ): May cause reduced GI absorption of oral phenothiazines CNS DEPRESSANT Ag ENTS!! (barbiturates, narcotics, anesthetics, etc. ): May cause additive CNS depression if used with ace promazine EPINEPHRINE!! : Phenothiazines block alpha-adrenergic receptors; concomitant epinephrine can lead to unop posed beta-activity causing vasodilation and increased cardiac rate OPIATES:T! May enhance the hypotensive effects of acepromazine; dosages of acepromazine are generally reduced when used with an opiate ORg ANOPHOSPHATE Ag ENTS !! : Acepromazine should not be given within one month of worming with these agents as their effects may be potentiated PHENy TOIN!! : Metabolism may be decreased if given concurrently with phenothiazines PROCAINE!! : Activity may be enhanced by phenothiazines PROPRANOl Ol!! : Increased blood levels of both drugs may result if administered with phenothiazines QUINIDINE!! : With phenothiazines may cause additive cardiac depression Doses Note : The manufacturer's dose of 0. 5-2. 2 mg/kg for dogs and cats is considered by many clinicians to be 10 times greater than is nec-essary for most indications. Give IV doses slowly; allow at least 15 minutes for onset of action. DOg S:T! a) Premedication: 0. 03-0. 05 mg/kg IM or 1-3 mg/kg PO at least one hour prior to surgery (not as reliable) (Hall and Clarke 1983) b) Restraint/sedation: 0. 025-0. 2 mg/kg IV; maximum of 3 mg or 0. 1-0. 25 mg/kg IM; Preanesthetic: 0. 1-0. 2 mg/kg IV or IM; maximum of 3 mg; 0. 05-1 mg/kg IV, IM or SC (Morgan 1988)4 ACEPROm Az INE m Al EATE

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c) T o reduce anxiety in the painful patient (not a substitute for analgesia): 0. 05 mg/kg IM, IV or SC; do not exceed 1 mg total dose (Carroll 1999) d) 0. 55-2. 2 mg/kg PO or 0. 55-1. 1 mg/kg IV, IM or SC (Pack-age Insert; Prom Ace ® —Fort Dodge) e) As a premedicant with morphine: acepromazine 0. 05 mg/kg IM; morphine 0. 5 mg/kg IM (Pablo 2003b) CATS:T! a) Restraint/sedation: 0. 05-0. 1 mg/kg IV, maximum of 1 mg (Morgan 1988) b) T o reduce anxiety in the painful patient (not a substitute for analgesia): 0. 05 mg/kg IM, IV or SC; do not exceed 1 mg total dose (Carroll 1999) c) 1. 1-2. 2 mg/kg PO, IV, IM or SC (Package Insert; Prom Ace ® —Fort Dodge) d) 0. 11 mg/kg with atropine (0. 045-0. 067 mg/kg) 15-20 min-utes prior to ketamine (22 mg/kg IM). (Booth 1988a) FERRETS:T! a) As a tranquilizer: 0. 25-0. 75 mg/kg IM or SC; has been used safely in pregnant jills, use with caution in dehydrated ani-mals. (Finkler 1999) b) 0. 1-0. 25 mg/kg IM or SC; may cause hypotension/hypo-thermia (Williams 2000) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: As a tranquilizer: 1 mg/kg IM, effect should begin in 10 minutes and last for 1-2 hours (Booth 1988a) b) Rabbits: As a premed: 0. 1-0. 5 mg/kg SC; 0. 25-2 mg/kg IV, IM, SC 15 minutes prior to induction. No analgesia; may cause hypotension/hypothermia. (Ivey and Morrisey 2000) c) Mice, Rats, Hamsters, Guinea pigs, Chinchillas: 0. 5 mg/kg IM. Do not use in Ger bils. (Adamcak and Otten 2000) CATTl E:T! a) Sedation: 0. 01-0. 02 mg/kg IV or 0. 03-0. 1 mg/kg IM (Booth 1988a) b) 0. 05-0. 1 mg/kg IV, IM or SC (Howard 1986) c) Sedative one hour prior to local anesthesia: 0. 1 mg/kg IM (Hall and Clarke 1983) HORSES:T! (Note : ARCI UCGFS Class 3 Drug) a) For mild sedation: 0. 01-0. 05 mg/kg IV or IM. Onset of ac-tion is about 15 minutes for IV; 30 minutes for IM (Taylor 1999) b) 0. 044-0. 088 mg/kg (2-4 mg/100 lbs. body weight) IV, IM or SC (Package Insert; Pro m Ace ® —Fort Dodge) c) 0. 02-0. 05 mg/kg IM or IV as a preanesthetic (Booth 1988a) d) Neuroleptanalgesia: 0. 02 mg/kg given with buprenorphine (0. 004 mg/kg IV) or xylazine (0. 6 mg/kg IV) (Thurmon and Benson 1987) e) For adjunctive treatment of laminitis (developmental phase): 0. 066-0. 1 mg/kg 4-6 times per day (Brumbaugh, Lopez et al. 1999) SWINE:T! a) 0. 1-0. 2 mg/kg IV, IM, or SC (Howard 1986) b) 0. 03-0. 1 mg/kg (Hall and Clarke 1983) c) For brief periods of immobilization: acepromazine 0. 5 mg/kg IM followed in 30 minutes by ketamine 15 mg/kg IM. At-ropine (0. 044 mg/kg IM) will reduce salivation and bronchial secretions. (Lumb and Jones 1984) SHEEP & g OATS:T! a) 0. 05-0. 1 mg/kg IM (Hall and Clarke 1983)monitoring Cardiac rate/rhythm/blood pressure if indicated and possible to T! measure Degree of tranquilization T! Male horses should be checked to make sure penis retracts and T! is not injured Body temperature (especially if ambient temperature is very hot T! or cold) Client Information May discolor the urine to a pink or red-brown color; this is not T! abnormal Acepromazine is approved for use in dogs, cats, and horses not T! intended for food Chemistry/Synonyms Acepromazine maleate (formerly acetylpromazine) is a phenothi-azine derivative that occurs as a yellow, odorless, bitter tasting pow-der. One gram is soluble in 27 m L of water, 13 m L of alcohol, and 3 m L of chloroform. Acepromazine Maleate may also be known as: acetylpromazine maleate, “ACE”, ACP, Aceproject ®, Aceprotabs®, Prom Ace ®, Plegicil®, Noten sil®, and Atravet ®. Storage/Stability/Compatibility Store protected from light. Tablets should be stored in tight con-tainers. Acepromazine injection should be kept from freezing. Although controlled studies have not documented the compat-ibility of these combinations, acepro mazine has been mixed with atropine, buprenorphine, chloral hydrate, ketamine, meperidine, oxy morphone, and xylazine. Both glycopyrrolate and diazepam have been reported to be physically in compatible with phenothiaz-ines, however, glycopyrrolate has been demonstrated to be compat­ ible with promazine HCl for injection. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Acepromazine Maleate for Injection: 10 mg/m L for injection in 50 m L vials; Aceproject ® (Butler), Prom Ace ® (Fort Dodge); generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food. Acepromazine Maleate Tablets: 5, 10 & 25 mg in bottles of 100 and 500 tablets; Prom Ace ® (Fort Dodge); Aceprotabs® (Butler) generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food. When used in an extra-label manner in food animals, it is recom-mended to use the withdrawal periods used in Canada: Meat: 7 days; Milk: 48 hours. Contact FARAD (see appendix) for further guidance. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: None ACEPROm Az INE m Al EATE 5

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6 ACETAm INOPHEN Acet Aminophen (ah-seet-a-min-a-fen) Tylenol®, APAP, Paracetamol Oral analgesic, antipyretic Prescriber Highlights Contraindicated in cats at any dosage; ferrets may be as T T sensitive to acetaminophen as cats At recommended dosages, not overly toxic to dogs, ro-T T dents, or rabbits Often used in combined dosage forms with codeine; see T T codeine monograph for more information Uses/Indications Acetaminophen is occasionally used as an oral analgesic in dogs. In conditions of more severe pain, it may be used in combination with oral codeine phosphate. See the codeine monograph for more infor-mation on the use of acetaminophen-codeine combi nation prepara-tions. Pharmacology/Actions Acetaminophen produces analgesia and antipyresis via a weak, re-versible, isoform-nonspecific inhibition of cyclooxygenase. Unlike aspirin, it does not possess significant antiinflammatory activity nor inhibit platelet function. Pharmacokinetics Specific pharmacokinetic information in domestic animals was not located. In humans, acetaminophen is rapidly and nearly completely absorbed from the gut and is rapidly dis tributed into most tissues. Approximately 25% is plasma protein bound. Dogs apparently ex-hibit dose dependent metabolism (saturable). Contraindications/Precautions/Warnings Acetaminophen is contraindicated in cats at any dosage. Severe methemoglobinemia, hematuria, and icterus can be seen. Cats are un able to significantly glucuronidate acetaminophen leading to tox-ic metabolites being formed and re sultant toxicity. Acetaminophen should not be used in ferrets as they may be as sensitive to it as are cats. At this time, acetaminophen should not be used in Sugar Gliders or Hedgehogs as its safety has not been determined. Dogs do not metabolize acetaminophen as well as humans and its use must be judicious. In dogs, it is generally not recommended to use acetaminophen during the immediate post-operative phase (first 24 hours) due to an increased risk of hepatotoxicity. Adverse Effects Because acetaminophen is not routinely used in veterinary medi-cine, experience on its adverse effect profile is limited. At suggested dosages in dogs, there is some po tential for renal, hepatic, GI, and hematologic effects occurring. Reproductive/Nursing Safety Absolute reproductive safety has not been established, but acet-aminophen is apparently relatively safe for occasional use in preg-nancy (no documented problems in humans). Animal data was not located. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimes-ters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the benefit of therapy clearly out-weighs the risks. ) Acetaminophen is excreted in milk in low concentrations with reported milk:plasma ratios of 0. 91 to 1. 42 at 1 and 12 hours, re-spectively. In nursing human infants, no adverse effects have been reported. Overdosage/Acute Toxicity Because of the potentially severe toxicity associated with acetamino-phen, consultation with an animal poison control center is recom-mended (see appendix). For overdosage in dogs or cats, stan dard gut emptying techniques and supportive care should be administered when applicable. Further treatment with acetylcysteine may be war-ranted (see acetylcysteine monograph for more informa tion). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acetaminophen and may be of significance in veterinary patients: OTHER ANAlg ESICS!! : Chronic use with acetaminophen may lead to renal pathologies b ARb ITURATES!! : Increased conversion of acetaminophen to hepato-toxic metabolites; potentially increased risk for hepatotoxicity DOx ORUb ICIN!! : May deplete hepatic glutathione, thereby leading to increased hepatic toxicity HAl OTHANE!! : Acetaminophen is not recommended for use for post-operative analgesia in animals that received halothane anesthesia ISONIAz ID!! : Possible increased risk of hepatotoxicity PHENOTHIAz INES!! : Possible increased risk for hypothermia WARFARIN!! : While acetaminophen is relatively safe to use, large doses may potentiate anticoagulant effects laboratory Considerations False positive results may occur for urinary T! 5­hydroxyindoleacetic acid Doses Note : For dosages of acetaminophen/codeine combination products refer to the codeine monograph. DOg S:T! As an analgesic: a) 15 mg/kg PO q8h (Dodman 1992); (Mc Laughlin 2000) b) 10 mg/kg PO q12h (Kelly 1995) c) In the treatment of degenerative myelopathy (in German Shepherds): 5 mg/kg PO (not to exceed 20 mg/kg per day) (Clemmons 1991) RAbb ITS/RODENTS/Sm All m Amm Al S:T! As an analgesic: a) Using Children's Tylenol ®: 1-2 mg/m L in drinking water. Effective for controlling low-grade nociception. (Huerkamp 1995) b) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 1-2 mg/m L in drinking wa ter (Adamcak and Otten 2000) monitoring When used at recommended doses for pain control in otherwise T! healthy patients, little monitoring should be necessary. Howev-er, with chronic therapy, occasional liver, renal and hematologic

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ACETAz Ol Am IDE 7 monitoring may be warranted, particularly when clinical signs occur. Client Information Follow directions carefully; do not exceed dosage or increase dos-T! ing fre quency. Do not administer to cats or ferrets for any reason. Keep out of reach of children. Chemistry/Synonyms A synthetic non-opiate analgesic, acetaminophen (also known as paracetamol) oc curs as a crystalline, white powder with a slightly bitter taste. It is soluble in boiling water and freely soluble in alco-hol. Acetaminophen is known in the U. K. as paracetamol. Acetaminophen may also be known as: paracetamol, MAPAP or APAP; many trade names are available. Storage/Stability Acetaminophen products should be stored at temperatures less than 40°C. Do not freeze oral solution or suspension. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: There are many different trade names and products of acetamino-phen available. The most com monly known trade name is Tylenol®. Acetaminophen is commonly available in, 325 mg, 500 mg, 650 mg tablets; 80 mg chewable tablets; 650 mg extended release tablets; 160mg, 500 mg, & 650 mg caplets; 500 mg gelcaps; 325 mg, & 500 mg capsules, 80 mg and 160 mg sprin kle capsules; 80 mg/0. 8 m L drops; 80 mg/2. 5 m L, 80 mg/5 m L, 120 mg/5 m L, & 160 mg/5 m L elixirs; 160 mg/5 m L, 500 mg/15 m L, and 100 mg/m L liquids and solutions; 80 mg, 120 mg, 125 mg 300 mg, 325 mg and 650 mg sup-positories. Combinations with other analgesics (aspirin, codeine phosphate, oxycodone or propoxyphene) are also available. Acet Azol Amide Acet Azol Amide sodium (ah-seet-a-zole-a-mide) Diamox®, Dazamide® carb Onic anhydrase inhibit Or diuretic; antiglauc Oma agent Prescriber Highlights Used primarily for metabolic alkalosis or glaucoma in T T small animals; HYPP in horses Contraindicated in patients with significant hepatic, T T renal, pulmonary or adrenocortical in sufficiency, hypona-tremia, hypokalemia, hyperchloremic acidosis or electro-lyte imbal ance Give oral doses with food if GI upset occurs T T Electrolytes & acid/base status should be monitored with T T chronic or high dose therapy Monitor with tonometry if using for glaucoma T TUses/Indications Acetazolamide has been used principally in veterinary medicine for its effects on aque ous humor production in the treatment of glaucoma, metabolic alkalosis, and for its diuretic action. It may be useful as an adjunctive treatment for syringomyelia in dogs. Acetazolamide's use in small animals is complicated by a relatively high occurrence of adverse effects. In horses, acetazolamide is used as an adjunctive treatment for hyperkalemic periodic paralysis (HYPP). In humans, the drug has been used as adjunctive therapy for epi-lepsy and for acute high-altitude sickness. Pharmacology/Actions The carbonic anhydrase inhibitors act by a noncompetitive, revers-ible inhibition of the enzyme carbonic anhydrase. This reduces the formation of hydrogen and bicarbonate ions from carbon dioxide thereby reducing the availability of these ions for active transport into body secretions. Pharmacologic effects of the carbonic anhydrase inhibitors in-clude: decreased formation of aqueous humor, thus reducing in-traocular pressure, increased renal tubular secretion of sodium and potas sium and, to a greater extent, bicarbonate, leading to increased urine alkalinity and volume. Acetazolamide has some anticon-vulsant activity, which is independent of its diuretic effects (mecha-nism is not fully understood, but may be due to carbonic anhydrase or a metabolic acidosis effect). Pharmacokinetics The pharmacokinetics of this agent have apparently not been stud-ied in domes tic animals. One report (Roberts 1985) states that after a dose of 22 mg/kg, the onset of action is 30 minutes; maximal ef-fects occur in 2-4 hours; duration of action is about 4-6 hours in small animals. In humans, the drug is well absorbed after oral administra-tion with peak levels occurring within 1-3 hours. It is distributed throughout the body with highest levels found in the kidneys, plas-ma and erythrocytes. Acetazolamide has been detected in the milk of lactating dogs and it crosses the pla centa (in unknown quanti-ties). Within 24 hours of administration, an average of 90% of the drug is ex creted unchanged into the urine by tubular secretion and passive reabsorption processes. Contraindications/Precautions/Warnings Carbonic anhydrase inhibitors are contraindicated in patients with significant hepatic disease (may precipitate hepatic coma), renal or adrenocortical insufficiency, hy ponatremia, hypokalemia, hyper-chloremic acidosis, or electrolyte imbalance. They should not be used in patients with severe pulmonary obstruction that are unable to increase alveolar ventilation or in those who are hypersensitive to them. Long-term use of carbonic anhydrase inhibitors is con-traindicated in patients with chronic, noncongestive, angle-closure glaucoma as angle closure may occur and the drug may mask the condition by lowering intraocular pressures. Acetazolamide should be used with caution in patients with se-vere respiratory acidosis or having preexisting hematologic abnor-malities. Cross sensitivity between acetazolamide and antibacterial sulfonamides may occur. Adverse Effects Potential adverse effects that may be encountered include: GI distur-bances, CNS effects (sedation, depression, weakness, excitement, etc. ), hematologic effects (bone marrow de pression), renal effects (crystalluria, dysuria, renal colic, polyuria), hypokalemia, hypergly-cemia, hyponatremia, hyperuricemia, hepatic insufficiency, derma-tologic effects (rash, etc. ), and hyper sensitivity reactions.

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8 ACETAz Ol Am IDE At the dosages used for HYPP in horses adverse effects are report-edly uncommon. Reproductive/Nursing Safety Acetazolamide has been implicated in fetal abnormalities in mice and rats when used at high (10X) dosages) and fetal toxicity has been noted when the drug has been used in pregnant humans. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In humans, the manufacturer states that either nursing or the drug must be discontinued if the mother is receiving acetazolamide. Veterinary significance is not clear. Overdosage/Acute Toxicity Information regarding overdosage of this drug was not locat-ed. Monitor serum electrolytes, blood gases, volume status, and CNS status during an acute overdose; treat symptomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acetazolamide and may be of significance in veterinary patients: Al KAl INE!! URINE : Drugs where acetazolamide-caused alkaline urine may affect their excretion rate: Decreased urinary excretion of quinidine, procainamide, tricyclic antidepressants; Increased urinary excretion of salicylates, phenobarbital ASPIRIN!! (or other salicylates ): Increased risk of acetazolamide ac-cumulation and toxicity; increased risk for metabolic acidosis DIg Ox IN!! : As acetazolamide may cause hypokalemia, increased risk for toxicity INSUl IN:T! Rarely, carbonic anhydrase inhibitors interfere with the hypoglycemic effects of insulin m ETHENAm INE COm POUNDS !! : Acetazolamide may negate methe-namine effects in the urine DRUg S AFFECTINg !! POTASSIUm (corticosteroids, amphotericin b, corti­ cotropin, or other diuretics ): Concomitant use may exacerbate po-tassium depletion PRIm IDONE!! : Decreased primidone concentrations laboratory Considerations By alkalinizing the urine, carbonic anhydrase inhibitors may T! cause false positive results in determining urine protein when us-ing bromphenol blue reagent (Albustix®, Albutest®, Labstix®), sul-fosalicylic acid (Bumintest®, Exton's Test Reagent), nitric acid ring test, or heat and acetic acid test methods Carbonic anhydrase inhibitors may T! decrease iodine uptake by the thyroid gland in hyperthyroid or euthyroid patients Doses Directions for reconstitution of injection: Reconstitute 500 mg vial with at least 5 m L of Sterile Water for Injection; use within 24 hours after reconstitution. DOg S:T! For adjunctive treatment of metabolic alkalosis: a) 10 mg/kg four times daily (may aggravate volume contraction and hypokalemia) (Hardy and Robin son 1986) For adjunctive therapy of glaucoma:a) 10-25 mg/kg divided 2-3 times daily (Brooks 2002a) b) 50-75 mg/kg PO 2-3 times a day (Bedford 2003) c) 50 mg/kg IV one time; 7 mg/kg, PO three times daily (Vestre 1985) For adjunctive therapy of hydrocephalus in pediatric patients: a) 0. 1 mg/kg PO q8h (Coates 2002) CATS:T! For adjunctive therapy of glaucoma: a) 50 mg/kg IV once; 7 mg/kg, PO three times daily (Vestre 1985) HORSES:T! (Note : ARCI UCGFS Class 4 Drug) For adjunctive therapy of hyperkalemic periodic paralysis (HYPP): a) 2. 2-4. 4 mg/kg PO twice daily (Schott II 2004) b) 0. 5-2. 2 mg/kg PO twice daily (Mayhew 2005a) c) 3 mg/kg PO (dosing interval not specified) (Harris and May-hew 1998) RUm INANTS:T! a) 6-8 mg/kg IV, IM, or SC (Howard 1986) SWINE:T! a) 6-8 mg/kg IV, IM, or SC (Howard 1986) monitoring Intraocular pressure tonometry (if used for glaucoma)T! Blood gases if used for alkalosis T! Serum electrolytes T! Baseline CBC with differential and periodic retests if using chron-T! ically Other adverse effects T! Client Information Give with food if using oral preparation and GI upset occurs T! Notify veterinar ian if abnormal bleeding or bruising occurs or if T! animal develops tremors or a rash Chemistry/Synonyms A carbonic anhydrase inhibitor, acetazolamide occurs as a white to faintly yellowish-white, odorless, crystalline powder with p K as of 7. 4 and 9. 1. It is very slightly soluble in water, sparingly soluble in hot water (90-100°C) and alcohol. Acetazolamide sodium occurs as a white lyophilized solid and is freely soluble in water. The injection has a p H of 9. 2 after reconstitution with Sterile Water for Injection. Acetazolamide may also known as: acetazolam, acetazolamidum, or sodium acetazolamide; many trade names are available. Storage/Stability/Compatibility Acetazolamide products should be stored at room temperature. T o prepare parenteral solution: reconstitute with at least 5 m L of Sterile Water for Injection. After reconstitution, the injection is stable for one week when refrigerated, but as it contains no preserva-tives, it should be used within 24 hours. Acetazolamide sodium for injection is reportedly physically com­ patible with all commonly used IV solutions and cimetidine HCl for injection. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Acetazolamide Tablets: 125 mg, 250 mg; generic; (Rx) Acetazolamide Sustained-Release Capsules: 500 mg; Diamox Se-quels® (Barr); (Rx)

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ACETIC ACID, ACETOHy DROx Am IC ACID 9 Acetazolamide Injection: 500 mg per vial; Diamox® (Wyeth-Ayerst); (Rx) Acetazolamide Powder for Injection (lyophilized): 500 mg for re-constitution; generic; (Rx) Acetic Acid (ah-see-tick ass-id) Vinegar gi acidifier Prescriber Highlights Used primarily for treatment of non-protein nitrogen-in-T T duced ammonia toxicosis (secondary to urea poisoning, etc. ) in ruminants or enterolith prevention in horses Contraindicated if potential lactic acidosis (grain over-T T load, rumen acidosis) is possible Given via stomach tube T T Uses/Indications Acetic acid is used via its acidifying qualities in ruminants to treat non-protein nitrogen-induced (e. g., urea poisoning) ammonia tox-icosis. It is also used as a potential treatment to prevent enterolith formation in horses by reducing colonic p H. Pharmacology/Actions Acetic acid in the rumen lowers p H due to shifting ammonia to ammonium ions and reducing absorption. It may also slow the hy-drolysis of urea. Pharmacokinetics No information was noted. Contraindications/Precautions/Warnings Should not be administered to ruminants until potential lactic aci-dosis (grain overload, rumen acidosis) is ruled out. Adverse Effects Because of the unpleasant taste and potential for causing mucous membrane irritation, acetic acid is generally recommended for ad-ministration via stomach tube. Overdosage/Acute Toxicity When used for appropriate indications there is little likelihood of se rious toxicity occurring after minor overdoses. Due to its poten-tial corrosiveness, the greatest concern would occur if a concentrat-ed form of acetic acid was mistakenly used. However, one human pa tient who had glacial acetic acid used instead of 5% acetic acid during colposcopy (cervix) demon strated no detectable harm. Drug Interactions There are no documented drug interactions with oral acetic acid, but because of its acidic qualities it could, potentially, affect the degradation of several drugs in the gut. Doses CATTl E/RUm INANTS:T! For cattle with putrefaction of rumen associated with a high ru-men p H: a) 4-10 liters of vinegar (Constable 1993)For treatment of urea poisoning: a) Using 5% acetic acid (vinegar) infuse 2-6 liters (for cattle) into rumen; may be repeated as necessary if clinical signs reoccur. Recovery ranges from 8-24 hours. A post-recovery pro-biotic rumen inoculation may enhance the gain and productivity of urea poisoned animals. (Hall 2006) HORSES:T! For enterolith prevention: a) Using vinegar: 250 m L/450 kg body weight PO once daily (Robinson 1992) Chemistry/Synonyms Glacial acetic acid is C 2H4O2. Acetic acid has a distinctive odor and a sharp acid taste. It is miscible with water, alcohol or glycerin. Much confusion can occur with the percentages of C 2H4O2 con-tained in various acetic acid solutions. Acetic Acid USP is defined as having a concen tration of 36-37% C 2H4O2. Diluted Acetic Acid NF contains 5. 7-6. 3% w/v of C 2H4O2. Solutions containing ap-proximately 3-5% w/v of C 2H4O2 are commonly known as vin-egar. Be certain of the concentration of the product you are using and your dilutions. Acetic acid may also be known as: E260, eisessig (glacial acetic acid), essigsaure, etanoico, or ethanoic acid. Storage/Stability Acetic acid solutions should be stored in airtight containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: None There are no systemic products commercially available. Acetic acid (in various concentrations) may be purchased from chemical sup-ply houses. Distilled white vinegar is available in gallon sizes from grocery stores. Acetohydrox Amic Acid (ah-seet-oh-hy-drox-am-ik) Lithostat®, AHA urease inhibit Or Prescriber Highlights Used occasionally in dogs for persistent struvite uroliths T T & persistent urease-producing bacteriuria Contraindicated in patients with renal impairment & dur-T T ing pregnancy; do not use in cats Adverse effects are common & can include GI effects T T (anorexia, vomiting, mouth/esophageal ulcers), hemolytic anemia, hyperbilirubinemia & bilirubinuria Monitor renal function (incl. urinalysis), CBC's, & bilirubin T T levels Uses/Indications Acetohydroxamic acid can be used in dogs as adjunctive therapy in some cases of recurrent urolithiasis or in the treatment of per-sistent urinary tract infections caused by the following bacteria: E. coli, Klebsiella, Morganella morganii, Staphylococci spp., and Pseudomonas aeruginosa. Adverse effects limit its usefulness. Pharmacology/Actions AHA inhibits urease thereby reducing production of urea and subsequent urinary concentrations of ammonia, bicarbonate and

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10 ACETyl Cy STEINE carbonate. While the drug does not directly reduce urine p H, by re-ducing ammonia and bicarbonate production by urease-producing bacteria, it prevents in creases in urine p H. The drug may act syner-gistically with several antimicrobial agents (e. g., car benicillin, gen-tamicin, clindamycin, trimethoprim-sulfa or chloramphenicol) in treating some urinary tract infections. The drug's effects on urinary p H and infection also indirectly inhibit the formation of urinary calculi (struvite, carbonate-apatite). Pharmacokinetics No canine specific data was located. In humans, the drug is rapidly absorbed after PO administration. Absolute bioavailability “in ani-mals” is reported to be 50-60%. AHA is well distributed throughout body fluids. It is partially metabolized to acetamide, which is active; 36-65% of a dose is excreted in the urine unchanged, and 9-14% excreted in the urine as acetamide. The re mainder is reportedly ex-creted as CO 2 via the respiratory tract. Contraindications/Precautions/Warnings AHA is contraindicated in patients with poor renal function (e. g., serum creatinine >2. 5 mg/dl) or when it is not specifically indicated (see Indications). Acetohydroxamic acid is reportedly very toxic in cats and should not be used in felines. Adverse Effects In dogs, GI effects (anorexia, vomiting, mouth/esophageal ulcers), hemolytic anemia, hyperbilirubinemia and bilirubinuria have been reported. Other potential adverse effects include: CNS disturbances (anxiety, depres sion, tremulousness), hematologic effects (reticulo-cytosis, bone marrow depression), phlebitis, and skin rashes/alope-cia. Effects on bilirubin metabolism have also been reported. Reproductive/Nursing Safety AHA use is considered contraindicated during pregnancy. In preg-nant beagles, doses of 25 mg/kg/day caused cardiac, coccygeal, and abdominal wall abnormalities in puppies. At high doses (>750 mg/kg) leg deformities have been noted in test animals. Higher doses (1500 mg/kg) caused significant encephalopathologies. In humans, the FDA categorizes this drug as category X for use during preg-nancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible benefit. ) Overdosage/Acute Toxicity In humans, mild overdoses have resulted in hemolysis after several weeks of treatment, particularly in patients with reduced renal func-tion. Acute overdoses are ex pected to cause clinical signs such as an-orexia, tremors, lethargy, vomiting and anxiety. Increased reticulo-cyte counts and a severe hemolytic reac tion are laboratory findings that would be expected. Treatment for an acute overdose may in-clude intensive hematologic monitoring with adjunctive supportive therapy, including possible transfusions. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acetohydroxamic acid (AHA) and may be of significance in veterinary patients: IRON!! : AHA may chelate iron salts in the gut if given concomitantly m ETHENAm INE!! : AHA may have a synergistic effect with meth-enamine in inhibiting the urine p H increases caused by urease-produc ing Proteus spp. ; AHA may also potentiate the antibacterial effect of methenamine against these bac teria Al COHOl!! : In humans, AHA with alcohol has resulted in rasheslaboratory Considerations Although AHA is a true urease inhibitor, it apparently does not T! inter fere with urea nitrogen determination using one of the fol-lowing: urease-Berthelot, urease-glutamate dehydroge nase or di-acetyl monoxime methods. Doses DOg S:T! For adjunctive therapy of persistent struvite uroliths and persis-tent urease-producing bacteria after treating with antibiotics and calculolytic diets: a) 12. 5 mg/kg twice daily PO (Osborne, Lulich et al. 1993); (Lu-lich, Osborne et al. 2000) monitoring CBCT! Renal/Hepatic (bilirubin) function T! Efficacy T! Client Information This medication can cause several adverse effects in dogs; contact T! veterinarian if dog develops persistent or severe vomiting, has a lack of appetite, a change in urine color, develops yellowing of the whites of the eyes, or has decreased energy/activity. Chemistry/Synonyms An inhibitor of urease, acetohydroxamic acid occurs as a white crys-tal having a p Ka of 9. 32-9. 4 and a p H of about 9. 4. 850 mg are soluble in one m L of water, and 400 mg are soluble in one m L of al cohol. Acetohydroxamic acid may also be known as: AHA, Acetic acid oxime, N-Acetylhydroxylamide, N-Hydroxyacetamide, Lithostat® or Uronefrex®. Storage/Stability Tablets should be stored in tight containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Acetohydroxamic Acid Tablets: 250 mg; Lithostat® (Mission); (Rx) Acetylcysteine (assah-teel-sis-tay-een) N-acetylcysteine, Mucomyst®, NAC antid Ote; muc Olytic Prescriber Highlights Used primarily as a treatment for acetaminophen or phe-T T nol toxicity & for its mucolytic effect; used anecdotally for treating degenerative myelopathy Also used as a topical ophthalmic (see the Topical Oph-T T thalmic section in the appendix)Has caused hypersensitivity & bronchospasm when used T T in pulmonary tree Administer via gastric-or duodenal tube for acetamino-T T phen poisoning in animals

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ACETyl Cy STEINE 11 Uses/Indications Acetylcysteine is used in veterinary medicine as both a mucolytic agent in the pulmonary tree and as a treatment for acetaminophen or phenol toxicity in small animals. It has been used anecdotally with aminocaproic acid to treat degenerative myelopathy in dogs. In horses with strangles, acetylcysteine instilled into the gutteral pouch has been used to help break up chondroids and avoid the need for surgical removal. Acetylcysteine enemas have been used in neonatal foals to break up meconium refractory to repeated en-emas. Pharmacology/Actions When administered into the pulmonary tree, acetylcysteine reduces the viscosity of both purulent and nonpurulent secretions and ex-pedites the removal of these secretions via coughing, suction, or postural drainage. The free sulfhydryl group on the drug is believed to reduce disulfide linkages in mucoproteins; this effect is most pro-nounced at a p H from 7-9. The drug has no effect on living tissue or fibrin. Acetylcysteine can reduce the extent of liver injury or methemo-globinemia after ingestion of acetaminophen or phenol, by provid-ing an alternate substrate for conjugation with the reactive metabo-lite of acetaminophen, thus maintaining or restoring glutathione levels. Pharmacokinetics When given orally, acetylcysteine is absorbed from the GI tract. When adminis tered via nebulization or intratracheally into the pulmonary tract, most of the drug is involved in the sulfhydryl-disulfide reaction and the remainder is absorbed. Absorbed drug is converted (deacetylated) into cysteine in the liver and then further metabolized. Contraindications/Precautions/Warnings Acetylcysteine is contraindicated (for pul monary indications) in animals hypersensitive to it. There are no contraindications for its use as an antidote. Because acetylcysteine may cause bronchospasm in some pa-tients when used in the pulmonary sys tem, animals with bron-chospastic diseases should be monitored carefully when using this agent. Adverse Effects When given orally for acetaminophen toxicity, acetylcysteine can cause GI effects (nausea, vomiting) and rarely, urticaria. Because the taste of the solution is very bad, use of taste masking agents (e. g., colas, juices) have been used. Since oral dosing of these drugs may be very difficult in animals, gastric or duodenal tubes may be necessary. Rare adverse effects reported when acetylcysteine is administered into the pulmonary tract, include: hypersensitivity, chest tightness, bronchoconstriction, and bronchial or tracheal irritation. Reproductive/Nursing Safety Reproduction studies in rabbits and rats have not demonstrated any evidence of teratogenic or em bryotoxic effects when used in doses up to 17 times normal. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is unknown if acetylcysteine enters milk. Use caution when administering to a nursing dam. Overdosage/Acute Toxicity The LD50 of acetylcysteine in dogs is 1 g/kg (PO) and 700 mg/kg (IV). It is believed that acetylcysteine is quite safe (with the excep-tion of the adverse effects listed above) in most overdose situations. Drug Interactions ACTIVATED CHARCOAl:T! The use of activated charcoal as a gut adsor-bent of acetaminophen is controversial, as charcoal may also ad-sorb acetylcysteine. Be cause cats can develop methemoglobin-emia very rapidly after ingestion of acetaminophen, do not delay acetylcysteine treatment and preferably give the first dose intra-venously. If using the solution (not labeled for injectable use), it is preferable to use a 0. 2 micron in-line filter. Doses DOg S:T! For acetaminophen toxicity:a) A 2-3 hour wait between activated charcoal and PO admin-istration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin®, ascorbic acid and SAMe. (Wismer 2006a) b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 ad-ditional doses (Bailey 1986a) c) Loading dose of 140 mg/kg PO, then 70 mg/kg PO every 6 hours for 7 treatments (Grauer and Hjelle 1988a) For phenol toxicity: a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascor-bic acid or methylene blue. (Dorman and Dye 2005) For respiratory use: a) 50 m L/hr for 30-60 minutes every 12 hours by nebulization (Kirk 1986) For degenerative myelopathy:a) 25 mg/kg PO q8h for 2 weeks, then q8h every other day. The 20% solution should be diluted to 5% with chicken broth or suitable diluent. Used in conjunction with aminocaproic acid (500 mg per dog PO q8h indefinitely). Other treatments may include prednisone (0. 25-0. 5 mg/kg PO daily for 10 days then every other day), Vitamin C (1000 mg PO q12h) and Vitamin E (1000 Int. Units PO q12h). Note : No treatment has been shown to be effective in published trials. (Shell 2003a) CATS:T! For acetaminophen toxicity:a) A 2-3 hour wait between activated charcoal and PO admin-istration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin®, ascorbic acid and SAMe. (Wismer 2006a)

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12 ACITRETIN b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 ad-ditional doses (Bailey 1986a) For phenol toxicity: a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascor-bic acid or methylene blue. (Dorman and Dye 2005) For respiratory use: a) 50 m L/hr for 30-60 minutes every 12 hours by nebulization (Kirk 1986) For adjunctive treatment of hepatic lipidosis (see also Carnitine): a) Identify underlying cause of anorexia and provide a protein replete feline diet, give acetylcysteine (NAC) at 140 mg/kg IV over 20 minutes, then 70 mg/kg IV q12h; dilute 10% NAC with saline 1:4 and administer IV using a 0. 25 micron filter; correct hypokalemia and hypophosphatemia, beware of elec-trolyte changes with re-feeding phenomenon (Center 2006c) HORSES:T! T o help break up chondroids in the gutteral pouch: a) Instill 20% solution (Foreman 1999) In neonatal foals to break up meconium refractory to repeated enemas: a) 8 grams in 20 g sodium bicarbonate in 200 m L water (p H of 7. 6), give as enema as needed to effect (Freeman 1999) b) With foal in lateral recumbency, insert a 30 french foley cath-eter with a 30 cc bulb for a retention enema. Using gravity flow, infuse slowly 100-200 m L of 4% acetylcysteine solution and retain for 30-45 minutes. IV fluids and pain medication should be considered. Monitor for possible bladder disten-tion. (Pusterla, Magdesian et al. 2003) monitoring When used for acetaminophen poisoning: Hepatic enzymes (particularly in dogs) T! Acetaminophen level, if available (particularly in dogs) T! Hemogram, with methemoglobin value (particularly in cats) T! Serum electrolytes, hydration status T! Client Information This agent should be used in a clinically supervised setting only T! Chemistry/Synonyms The N-acetyl derivative of L-cysteine, acetylcysteine occurs as a white, crystalline powder with a slight acetic odor. It is freely soluble in water or alcohol. Acetylcysteine may also be known as: N-acetylcysteine or N-acetyl-L-cysteine, NAC, 5052 acetylcysteinum, NSC-111180, Acetadote®, Mucomyst® or ACC ®. Storage/Stability/Compatibility When unopened, vials of sodium acetylcysteine should be stored at room temperature (15-30°C). After opening, vials should be kept refrigerated and used within 96 hours. The product labeled for IV use states to use within 24 hours. Acetylcysteine is incompatible with oxidizing agents; solutions can become discolored and lib erate hydrogen sulfide when exposed to rubber, copper, iron, and during autoclaving. It does not re act to aluminum, stainless steel, glass or plastic. If the solution becomes light purple in color, po tency is not appreciably affected, but it is best to use non-reactive materials when giving the drug via nebu-lization. Acetylcysteine solutions are incompatible with amphoteri-cin B, ampicillin sodium, erythromycin lactobionate, tetracycline, oxytetracycline, iodized oil, hydrogen peroxide and trypsin. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Acetylcysteine injection: 20% (200 mg/m L), (0. 5 mg/m L EDTA in 30 m L single-dose vials, preservative free; Acetadote® (Cumberland); (Rx) Acetylcysteine Solution: 10% & 20% (as sodium) in 4 m L, 10 m L, 30 m L & 100 m L (20% only) vials; Mucomyst® (Apothecon); (Rx) Note: If using this product for dilution and then intravenous dosing, it is preferable to use a 0. 2 micron in-line filter. Acetylsalicylic Acid — See Aspirin Acitretin (ase-a-tre-tin) Soriatane® retin Oid Note : Originally etretinate was used for certain dermatologic indications in small animals (primarily dogs). It has been withdrawn from the mar-ket and replaced with acitretin, an active metabolite of etretinate with the same indications, but a much shorter half-life. Much of the information below is extrapolated from etretinate data. Prescriber Highlights Retinoid that may be useful for certain dermatologic con-T T ditions in small animals Contraindications: Pregnancy; Caution: Cardiovascular T T disease, hypertriglyceridemia or sensitivity to retinoids Adverse Effects: Limited experience; appears to be fairly T T well tolerated in small animals Potentially: anorexia/ vomiting/diarrhea, cracking of foot pads, pruritus, ventral abdomi nal erythema, polydipsia, lassitude, joint pain/ stiffness, eyelid abnormalities & con junctivitis (KCS), swollen tongue, & behavioral changes Known teratogen; do not use in households with preg-T T nant women present (Plumb's rec ommendation) May be very expensive; may need to compound smaller T T capsules for small dogs or cats Drug-drug; drug-lab interactions T T Uses/Indications Acitretin may be useful in the treatment of canine lamellar ich-thyosis, solar-in duced precancerous lesions in Dalmatians or bull T erriers, actinic keratoses, squamous cell carci nomas, and intracuta-neous cornifying epitheliomas (multiple keratoacanthomas). While the drug has provided effective treatment of idiopathic seborrhea (particularly in cocker spaniels), it is not effective in treat-ing the ceruminous otitis that may also be present. Results have been disap pointing in treating idiopathic seborrheas seen in basset hounds and West Highland terriers. Acitretin's usage in cats is very limited, but etretinate has shown some usefulness in treating para neoplastic actinic keratosis, solar-induced squamous cell carcinoma and Bowen's Disease in this species. Pharmacology/Actions Acitretin is a synthetic retinoid agent potentially useful in the treat-ment of several disorders related to abnormal keratinization and/

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ACITRETIN 13 or sebaceous gland abnormalities in small animals. The drug has some antiinflammatory activity, but its exact mechanism of action is not known. Pharmacokinetics Acitretin absorption is enhanced by food in the gut. Acitretin is highly bound to plasma proteins. The drug is metabolized to conju-gate forms that are excreted in the bile and urine. T erminal half-life averages 50 hours in humans. Contraindications/Precautions/Warnings Acitretin use should not be considered when the following condi-tions exist: cardiovascular disease, hy pertriglyceridemia or known sensitivity to acitretin. Use with caution in patients with renal or hepatic failure. Adverse Effects Veterinary experience with this medication is lim ited, but the in-cidence of adverse effects appears to be less in companion animals than in people. Most ani mals treated (thus far) do not exhibit ad-verse effects. Potential adverse effects include: anorexia/vomiting/diarrhea, cracking of foot pads, pruritus, ventral abdominal erythe-ma, polydipsia, lassitude, joint pain/stiffness, eyelid abnormalities and conjunctivitis (KCS), swollen tongue, and be havioral changes. The most common adverse effect seen in cats is anorexia with resultant weight loss. If cats develop adverse effects, the time be-tween doses may be prolonged (e. g., Every other week give ev ery other day) to reduce the total dose given. Reproductive/Nursing Safety Acitretin is a known teratogen. Major anomalies have been reported in children of women receiving acitretin. It should not be handled by pregnant women nor used in a household where women are pregnant or planning to become pregnant. It should be considered absolutely contraindi cated in pregnant veterinary patients. In hu-mans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnor-malities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible benefit. ) Acitretin is excreted in rat milk. At this time, it cannot be recom-mended for use in nursing dams. Overdosage/Acute Toxicity Information on overdoses with this agent remains limited. One oral overdose (525 mg) in a human patient resulted only in vomiting. The oral LD50 in rats and mice is >4 grams/kg. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acitretin and may be of significance in veterinary patients: Al COHOl!! : Acitretin can form etretinate in the presence of alcohol; etretinate is a teratogen with an extremely long terminal half-life and (can persist in adipose tissue for years) HEPATOTOx IC DRUg S!! (especially methotrexate and potentially an­ abolic steroids, androgens, asparaginase, erythromycins, estrogens, fluconazole, halothane, keto conazole, sulfonamides or valproic acid ): May be increased potential for hepatotoxicity OTHER RETINOIDS !! (isotretinoin, tretinoin, or vitamin A): May cause additive toxic effects. TETRACy Cl INES!! : Acitretin with tetracyclines may increase the po-tential for the occurrence of pseudotumor cerebri (cerebral ede-ma and increased CSF pressure) laboratory Considerations In humans, acitretin may cause significant increases in T! plasma trig­ lycerides, serum cholesterol, serum Al T (Sg PT ), serum AST (Sg OT ), and serum l DH con centrations. Serum HDl (high density lipopro-tein) concentrations may be decreased. Veterinary significance of these effects is unclear. Doses DOg S:T! For dermatologic conditions where retinoids may be useful:a) 0. 5-1 mg/kg PO once daily (Kwochka 2003b) b) 0. 5-2 mg/kg PO once daily (Merchant 2000) c) For sebaceous adenitis: 0. 5-1 mg/kg once daily PO (Bloom 2006c) CATS:T! For actinic keratosis/solar-induced squamous cell carcinoma; or Bowen's Disease: a) 10 mg per cat once daily PO. (Power and Ihrke 1995) Note : this dose is for etretinate, but as the smallest cap sule is 10 mg, this dose may need to suffice as well for cats. b) For Bowen's Disease: 3 mg/kg/day (Hnilica 2003d) monitoring Efficacy T! Liver function tests (baseline and if clinical signs appear) T! Schirmer tear tests (monthly—especially in older dogs)T! Client Information Acitretin should not be handled by pregnant women in the house-T! hold; veterinarians must take responsibility to educate clients of the potential risk of in gestion by pregnant females Food will increase the absorption of acitretin. T o reduce variabil-T! ity of absorption, either have clients consistently give with meals or when fasted Long-term therapy can be quite expensive T! Chemistry/Synonyms Acitretin, a synthetic retinoid occurs as a yellow to greenish-yellow powder. Acitretin may also be known as: acitretinum, etretin, Ro-10-1670, Ro-10-1670/000, Soriatane®, Acetrizoic Acid®, or Iodophil Viscous®. Storage/Stability Store at room temperature and protected from light. After bottle is opened, protect from high temperature and humidity. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Acitretin Capsules: 10 mg & 25 mg; Soriatane® (Connetics); (Rx) ACTH — See Corticotropin Activated Charcoal — See Charcoal, Activated

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14 ACy Cl OVIR Acyclovir (ay-sye-kloe-vir) Zovirax® antiviral (herpes) Prescriber Highlights Used primarily in birds for Pacheco's disease; may be use-T T ful in cats for Herpes infection If given rapidly IV, may be nephrotoxic T T Oral use may cause GI distress T T Reduce dosage with renal insufficiency T T May be fetotoxic at high dosages T T Uses/Indications Acyclovir may be useful in treating herpes infections in a variety of avian species and in cats with corneal or conjunctival herpes infec-tions. Its use in veterinary medicine is not well established, however, and it should be used with caution. Acyclovir has relatively mild ac-tivity against Feline Herpesvirus-1 when compared to some of the newer antiviral agents (e. g., ganciclovir, cidofovir, or penciclovir). Acyclovir is being investigated as a treatment for equine herpes virus type-1 myeloencephalopathy in horses, but clinical efficacy has not yet been proven and the drug's poor oral bioavailability is problematic. There continues to be interest in finding a dosing regi-men that can achieve therapeutic levels and be economically viable, particularly since the drug's use during a recent outbreak appeared to have some efficacy in reducing morbidity and mortality (not sta-tistically proven). Also, intravenous acyclovir may be economically feasible to treat some neonatal foals. Pharmacology/Actions Acyclovir has antiviral activity against a variety of viruses includ-ing herpes sim plex (types I and II), cytomegalovirus, Epstein-Barr, and varicella-Zoster. It is preferentially taken up by these viruses, and converted into the active triphosphate form where it inhibits viral DNA replica tion. Pharmacokinetics In dogs, acyclovir bioavailability varies with the dose. At doses of 20 mg/kg and below, bioavailability is about 80%, but declines to about 50% at 50 mg/kg. Bioavailability in horses after oral administration is very low (<4%) and oral doses of up to 20 mg/kg may not yield sufficient levels to treat equine herpes virus. Elimination half-lives in dogs, cats and horses are approximately 3 hours, 2. 6 hours, and 10 hours, respectively. In humans, acyclovir is poorly absorbed after oral administration (approx. 20%) and ab sorption is not significantly affected by the presence of food. It is widely distributed throughout body tissues and fluids including the brain, semen, and CSF. It has low protein binding and crosses the placenta. Acyclovir is primarily hepatically metabolized and has a half-life of about 3 hours in hu mans. Renal disease does not significantly alter half-life unless anuria is present. Contraindications/Precautions/Warnings Acyclovir is potentially contraindicated (assess risk vs. benefit) during dehydrated states, pre-existing renal function impairment, hypersensitiv ity to it or other related antivirals, neurologic deficits, or previous neurologic reactions to other cyto toxic drugs. Adverse Effects With parenteral therapy potential adverse effects include throm-bophlebitis, acute renal failure, and ecephalopathologic changes (rare). GI disturbances may occur with either oral or parenteral therapy. Preliminary effects noted in cats, include leukopenia and anemias, which are apparently reversible with discontinuation of therapy. Reproductive/Nursing Safety Acyclovir crosses the placenta, but rodent studies have not demon-strated any teratogenic effects thus far. Acyclovir crosses into ma-ternal milk but associated adverse effects have not been noted. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Acyclovir concentrations in milk of women following oral admin-istration have ranged from 0. 6 to 4. 1 times those found in plasma. These concentrations would potentially expose the breastfeeding in-fant to a dose of acyclovir up to 0. 3 mg/kg/day. Data for animals was not located. Use caution when administering to a nursing patient. Overdosage/Acute Toxicity Oral overdose is unlikely to cause significant toxicity. In a review of 105 dogs ingesting acyclovir (Richardson 2000), 10 animals were considered cases of acyclovir toxicosis. Adverse effects included vom-iting, anorexia, diarrhea and lethargy. One dog developed polyuria/polydipsia and another dog developed a mildly elevated BUN and serum creatinine 24 hours after ingesting 2068 mg/kg of acyclovir. Per the APCC database, acute renal injury was reported in one dog at a dose of 250 mg/kg. Treatment consists of standard decontami-nation procedures and supportive therapy. Contact an animal poi-son control center for further information, if necessary. There were 92 exposures to acyclovir reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 90 were dogs with 7 showing clinical signs; the remaining 2 cases were cats that showed no clinical signs. Common findings recorded in decreasing frequency included vom-iting, diarrhea, lethargy, anorexia, and crystalluria. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acyclovir and may be of significance in veterinary patients: NEPHROTOx IC m EDICATIONS !! : Concomitant administration of IV acyclovir with nephrotoxic medications may increase the poten-tial for nephrotoxicity occurring. Amphotericin B may potentiate the antiviral effects of acyclovir but it also increases chances for development of nephrotoxicity. z IDOVUDINE!! : Concomitant use with zidovudine may cause addi-tional CNS depression. Doses b IRDS:T! For treatment of Pacheco's Disease:a) 80 mg/kg PO q8h or 40 mg/kg q8h IM (do not use parenter-ally for more than 72 hours as it can cause tissue necrosis at site of injection) (Oglesbee and Bishop 1994) b) 80 mg/kg in oral suspension once daily PO; mix suspension with peanut butter or add to drinking water 50 mg in 4 oz of water for 7-14 days (Jenkins 1993) c) When birds are being individually treated: 80 mg/kg PO or IM twice daily (Speer 1999)

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Agl EPRISTONE 15 d) For prophylaxis: Exposed birds are given 25 mg/kg IM once (give IM with caution as it is very irritating), and then acy-clovir is added to drinking water at 1 mg/m L and to the food at 400 mg/quart of seed for a minimum of 7 days. Quaker parrots have been treated with a gavage of acyclovir at 80 mg/kg q8h for 7 days. (Johnson-Delaney 2005b) CATS:T! For Herpesvirus-1 infections: a) 10-25 mg/kg PO twice daily. Never begin therapy until diag-nostic evaluation is completed. May be toxic in cats; monitor CBC every 2-3 weeks. (Lappin 2003b) HORSES:T! a) Although efficacy is undetermined, anecdotal use of acyclovir orally at 10 mg/kg PO 5 times daily or 20 mg/kg PO q8h may have had some efficacy in preventing or treating horses dur-ing EHV-1 outbreaks. Additional studies may further clarify the usefulness of such dosing regimens—Plumb 2007; based upon (Wilkins 2004a) & (Henninger, Reed et al. 2007) monitoring Renal function tests (BUN, Serum Cr) with prolonged or IV T! therapy Cats: CBCT! Chemistry/Synonyms An antiviral agent, acyclovir (also known as ACV or acycloguanos-ine), occurs as a white, crystalline powder. 1. 3 mg are soluble in one m L of water. Acyclovir sodium has a solubility of greater than 100 mg/m L in water. However, at a p H of 7. 4 at 37°C it is practically all unionized and has a solubility of only 2. 5 mg/m L in water. There is 4. 2 m Eq of sodium in each gram of acy clovir sodium. Acyclovir may be known as: aciclovirum, acycloguanosine, acy-clovir, BW-248U, Zovirax®, Acic®, Aciclobene®, Aciclotyrol®, Acivir ®, Acyrax®, Cicloviral®, Geavir®, Geavir®, Herpotern ®, Isavir®, Nycovir ®, Supraviran®, Viclovir®, Virherpes®, Viroxy ®, Xorox®, or Zovirax®. Storage/Stability/Compatibility Acyclovir capsules and tablets should be stored in tight, light re-sistant containers at room temperature. Acyclovir suspension and sodium sterile powder should be stored at room temperature. When reconstituting acyclovir sodium do not use bacteriostatic water with parabens as precipitation may occur. The manufacturer does not recommend using bacteriostatic water for injection with ben zyl alcohol because of the potential toxicity in neonates. After reconstitution with 50-100 m L of a standard electrolyte or dex-trose solution, the resulting solution is stable at 25°C for 24 hours. Acy clovir is reportedly incompatible with biologic or colloidial prod-ucts (e. g., blood products or protein containing solutions). It is also incompatible with dopamine HCl, dobutamine, fludarabine phos-phate, foscarnet sodium, meperidine and morphine sulfate. Many other drugs have been shown to be compatible in specific situations. Compatibility is dependent upon factors such as p H, concentra-tion, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific in formation. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Acyclovir Tablets: 400 mg & 800 mg; Zovirax® (Glaxo Wellcome); generic; (Rx) Acyclovir Capsules: 200 mg; Zovirax® (Glaxo Wellcome); generic; (Rx)Acyclovir Suspension: 200 mg/5 m L in 473 m L; Zovirax® (Glaxo W-ellcome); generic; (Rx)Acyclovir Sodium Injection (for IV infusion only): 50 mg/m L (as sodium): generic; (Rx) Acyclovir Powder for Injection: 500 mg/vial (as sodium) in 10 m L vials; 1000 mg/vial (as sodium) in 20 m L vials; 500 mg/vial Lyo-philized in 10 m L vials; Zovirax® (Glaxo Wellcome); generic; (Rx) Acyclovir Ointment: 5% (50 mg/g) in 15 g; Zovirax® (Biovail); (Rx) Acyclovir Cream: 5% (50 mg/g) in 2g tubes; Zovirax® (Biovail); (Rx) Aglepristone (a-gle-pris-tone) Alizin®, Alizine® injectable pr Ogester One bl Ocker Prescriber Highlights Injectable progesterone blocker indicated for pregnancy T T termination in bitches; may also be of benefit in inducing parturition or in treating pyometra complex in dogs & progesterone-dependent mammary hyperplasia in cats Not currently available in USA; marketed for use in dogs T T in Europe, South America, etc. Localized injection site reactions are most commonly T T noted adverse effect; other adverse effects reported in >5% of patients include: anorexia (25%), excitation (23%), depression (21%), & diarrhea (13%) Uses/Indications Aglepristone is labeled (in the U. K. and elsewhere) for pregnancy termination in bitches up to 45 days after mating. In dogs, aglepristone may prove useful in inducing parturition or treating pyometra complex (often in combination with a prosta-glandin F analog such as cloprostenol). In cats, it may be of benefit for pregnancy termination (one study documented 87% efficacy when administered at the recom-mended dog dose at day 25) or in treating mammary hyperplasias or pyometras. Pharmacology/Actions Aglepristone is a synthetic steroid that binds to the progesterone (P4) receptors thereby preventing biological effects from progesterone. It has an affinity for uterine progesterone receptors approximately three times that of progesterone. As progesterone is necessary for maintaining pregnancy, pregnancy can be terminated or parturition induced. Abortion occurs within 7 days of administration. Benign feline mammary hyperplasias (fibroadenomatous hy-perplasia; FAHs) are usually under the influence of progesterone and aglepristone can be used to medically treat this condition. When used for treating pyometra in dogs, aglepristone can cause opening of the cervix and resumption of miometral contractility. Within 24 hours of administration, aglepristone does not ap-preciably affect circulating plasma levels of progesterone, cortisol, prostaglandins or oxytocin. Plasma levels of prolactin are increased within 12 hours when used in dogs during mid-pregnancy which is probably the cause of mammary gland congestion often seen in these dogs.

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16 Agl EPRISTONE Aglepristone also binds to glucocorticoid receptors but has no glucocorticoid activity; it can prevent endogenous or exogenously administered glucocorticoids from binding and acting at these sites. Pharmacokinetics In dogs, after injecting two doses of 10mg/kg 24 hours apart, peak serum levels occur about 2. 5 days later and mean residence time is about 6 days. The majority (90%) of the drug is excreted via the feces. Contraindications/Precautions/Warnings Aglepristone is contraindicated in patients who have documented hypersensitivity to it and during pregnancy, unless used for preg-nancy termination or inducing parturition. Because of its antagonistic effects on glucocorticoid receptors, the drug should not be used in patients with hypoadrenocorticism or in dogs with a genetic predisposition to hypoadrenocorticism. The manufacturer does not recommend using the product in patients in poor health, with diabetes, or with impaired hepatic or renal function as there is no data documenting its safety with these conditions. Adverse Effects As the product is in an oil-alcohol base, localized pain and inflam-matory reactions (edema, skin thickening, ulceration, and local-ized lymph node enlargement) can be noted at the injection site. Resolution of pain generally occurs shortly after injection; other in-jection site reactions usually resolve within 2-4 weeks. The manu-facturer recommends light massage of the injection site after admin-istration. Larger dogs should not receive more than 5 m L at any one subcutaneous injection site. One source states that severe injection reactions can be avoided if the drug is administered into the scruff of the neck. Systemic adverse effects reported from field trials include: an-orexia (25%), excitation (23%), depression (21%), vomiting (2%), diarrhea (13%) and uterine infections (3. 4%). Transient changes in hematologic (RBC, WBC indices) or biochemical (BUN, creatinine, chloride, potassium, sodium, liver enzymes) laboratory parameters were seen in <5% of dogs treated. When used for pregnancy termination, a brown mucoid vaginal discharge can be seen approximately 24 hours before fetal expul-sion. This discharge can persist for an additional 3-5 days. If used in bitches after the 20 th day of gestation, abortion may be accompanied with other signs associated with parturition (e. g., inappetance, rest-lessness, mammary congestion). Bitches may return to estrus in as little as 45 days after pregnancy termination. Reproductive/Nursing Safety Unless used for pregnancy termination or at term to induce parturi-tion, aglepristone is contraindicated during pregnancy. One study (Baan, Taverne et al. 2005) using aglepristone to in-duce parturition (day 58) demonstrated no significant differences in weight gain between those puppies in the treatment group versus the control group suggesting that aglepristone did not have effect on milk production of treated bitches. Overdosage/Acute Toxicity When administered at 3X (30mg/kg) recommended doses, bitches demonstrated no untoward systemic effects. Localized reactions were noted at the injection site, presumably due to the larger vol-umes injected. Drug Interactions No documented drug interactions were noted. Theoretically, the fol-lowing interactions may occur with aglepristone: PROg ESTINS!! (natural or synthetic ): Could reduce the efficacy of aglepristone gl UCOCORTICOIDS!! : Aglepristone could reduce the efficacy of gluco-corticoid treatment KETOCONAz Ol E, ITRACONAz Ol E, ER y THROmy CIN !! : The manufacturer states that although there is no data, these drugs may interact with aglepristone laboratory Considerations None were noted Doses WARNINg: As accidental injection of this product can induce abor-tion; it should not be administered or handled by pregnant women. Accidental injection can also cause severe pain, intense swelling and ischemic necrosis that can lead to serious sequelae, including loss of a digit. In cases of accidental injection, prompt medical attention must be sought. DOg S:T! T o terminate pregnancy (up to day 45): a) 10 mg/kg (0. 33 m L/kg) subcutaneous injection only. Repeat one time, 24 hours after the first injection. A maximum of 5 m L should be injected at any one site. Light massage of the injection site is recommended after administration. (Label information; Alizin®—Virbac U. K. ) T o induce parturition: a) After day 58 of pregnancy: 15 mg/kg subcutaneously one time. 24 hours after aglepristone injection, give oxytocin 0. 15 Units/kg every 2 hours until the end of parturition. (Fieni, Bruyas et al. 2001) b) On or after day 58 of pregnancy: 15 mg/kg subcutaneously; repeat in 9 hours. In treated group, expulsion of first pup oc-curred between 32 and 56 hours after treatment. Use standard protocols to assist with birth (including oxytocin to assist in pup expulsion if necessary) or to intervene if parturition does not proceed. (Baan, Taverne et al. 2005) As an adjunct to treating pyometra/metritis: a) For closed cervix: 6 mg/kg twice daily on the first day followed by the same dose once daily on days 2, 3, and 4. Some pre-fer using larger doses (10mg/kg) once daily on days 1, 3,and 8, then follow up also on days 15 and 28 depending on the bitch's condition. (Romagnoli 2003a) b) For metritis: 10 mg/kg subcutaneously once daily on days 1, 2 and 8. For open or closed pyometra: aglepristone 10 mg/kg subcuta-neously once daily on days 1, 2 and 8 and cloprostenol 1 mcg/kg subcutaneously on days 3 to 7. Bitches with closed pyo-metra or with elevated temperature or dehydration should also receive intravenous fluids and antibiotics (e. g., amoxicil-lin/clavulanate at 24 mg/kg/day on days 1-5). If pyometra has not resolved, additional aglepristone doses should be given on days 14 and 28. (Fieni 2006) CATS:T! For treating mammary fibroadenomatous hyperplasia:a) 20 mg/kg aglepristone subcutaneously once weekly until reso-lution of signs. Cats who present with heart rates greater than 200 BPM should receive atenolol at 6. 25 mg (total dose) until heart rate is less than 200 BPM with regression in size of the mammary glands. (Gorlinger, Kooistra et al. 2002)

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Alb ENDAz Ol E 17 monitoring Clinical efficacy T! For pregnancy termination: ultrasound 10 days after treatment T! and at least 30 days after mating Adverse effects (see above)T! Client Information Only veterinary professionals should handle and administer this T! product When used for pregnancy termination in the bitch, clients should T! understand that aglepristone might only be 95% effective in ter-minating pregnancy when used between days 26-45 A brown mucoid vaginal discharge can be seen approximately 24 T! hours before fetal expulsion Bitch may exhibit the following after treatment: lack of appetite, T! excitement, restlessness or depression, vomiting, or diarrhea Clients should be instructed to contact veterinarian if bitch ex-T! hibits a purulent or hemorrhagic discharge after treatment or if vaginal discharge persists 3 weeks after treatment Chemistry/Synonyms Aglepristone is a synthetic steroid. The manufactured injectable dosage form is in a clear, yellow, oily, non-aqueous vehicle that con-tains arachis oil and ethanol. No additional antimicrobial agent is added to the injection. Aglepristone may also be known as RU-534, Alizine®, or Alizin®. Storage/Stability/Compatibility Aglepristone injection should be stored below 25°C and protected from light. The manufacturer recommends using the product with-in 28 days of withdrawing the first dose. Although no incompatibilities have been reported, due to the product's oil/alcohol vehicle formulation it should not be mixed with any other medication. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Note : Not presently available or approved for use in the USA. In several countries: Aglepristone 30 mg/m L in 5 m L and 10 m L vials; Alizine® or Al-izin® (Virbac); (Rx)The FDA may allow legal importation of this medication for com-passionate use in animals; for more information, see the Instruc-tions for Legally Importing Drugs for Compassionate Use in the USA found in the appendix. HUm AN­l Ab El ED PRODUCTS: None Albend Azole (al-ben-da-zole) Albenza®, Valbazen® antiparasitic Prescriber Highlights Broad spectrum against a variety of nematodes, cestodes T T & protozoa; labeled for cattle & sheep (suspension only) Contraindicated with hepatic failure, pregnancy, lactating T T dairy cattle May cause GI effects (including hepatic dysfunction) & T T rarely blood dyscrasias (aplastic anemia)Do not use in pigeons, doves or crias T T Uses/Indications Albendazole is labeled for the following endoparasites of cattle (not lactating): Ostertagia ostertagi, Haemonchus spp., Trichostrongylus spp., Nematodius spp., Cooperia spp., Bunostomum phlebotomum, Oesphagostomum spp., Dictacaulus vivaparus (adult and 4th stage larva), Fasciola hepatica (adults), and Moniezia spp. In sheep, albendazole is approved for treating the following endoparasites: Ostertagia circumcincta, Marshallagia marshalli, Haemonchus contortus, Trichostrongylus spp., Nematodius spp., Cooperia spp., Oesphagostomum spp., Chibertia ovina, Dictacaulus filaria, Fasciola hepatica, Fascioides magna, Moniezia expansa, and Thysanosoma actinoides. Albendazole is also used (extra-label) in small mammals, goats and swine for endoparasite control. In cats, albendazole has been used to treat Paragonimus kelli-cotti infections. In dogs and cats, al bendazole has been used to treat capillariasis. In dogs, albendazole has been used to treat Filaroides infections. It has been used for treating giardia infections in small animals, but concerns about bone marrow toxicity have diminished enthusiasm for the drug's use. Pharmacology/Actions Benzimidazole antiparasitic agents have a broad spectrum of activ-ity against a variety of pathogenic internal parasites. In susceptible parasites, their mechanism of action is believed due to disrupting intracellular microtubular transport systems by binding selectively and damaging tubulin, preventing tubulin polymerization, and in-hibiting microtubule formation. Benzimidazoles also act at higher concentrations to disrupt metabolic pathways within the helminth, and inhibit metabolic enzymes, including malate dehydrogenase and fumarate reductase. Pharmacokinetics Pharmacokinetic data for albendazole in cattle, dogs and cats was not located. The drug is thought better absorbed orally than other benzimidazoles. Approximately 47% of an oral dose was recovered (as metabolites) in the urine over a 9-day period. After oral dosing in sheep, the parent compound was either not detectable or only transiently de tectable in plasma due to a very rapid first-pass effect. The active metabolites, albendazole sulphox-ide and albendazole sulfone, reached peak plasma concentrations 20 hours after dosing.

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18 Alb ENDAz Ol E Contraindications/Precautions/Warnings The drug is not approved for use in lactating dairy cattle. The manu-facturer recommends not administering to female cattle during the first 45 days of pregnancy or for 45 days after removal of bulls. In sheep, it should not be administered to ewes during the first 30 days of pregnancy or for 30 days after removal of rams. Pigeons and doves may be susceptible to albendazole and fen-bendazole toxicity (intestinal crypt epithelial necrosis and bone marrow hypoplasia). Nine alpaca crias receiving albendazole at dosages from 33-100 mg/kg/day once daily for 4 consecutive days developed neutropenia and severe watery diarrhea. All required treatment and 7 of 9 ani-mals treated died or were euthanized secondary to sepsis or multiple organ failure. (Gruntman and Nolen-Walston 2006) In humans, caution is recommended for use in patients with liver or hemato logic diseases. Albendazole was implicated as being an oncogen in 1984, but subsequent studies were unable to demonstrate any oncogenic or carcinogenic activity of the drug. Adverse Effects Albendazole is tolerated without significant adverse effects when dosed in cattle or sheep at recommended dosages. Dogs treated at 50 mg/kg twice daily may develop anorexia. Cats may exhibit clinical signs of mild lethargy, depression, anorexia, and resistance to receiving the medication when albendazole is used to treat Paragonimus. Albendazole has been implicated in causing aplastic anemia in dogs, cats, and humans. Reproductive/Nursing Safety Albendazole has been associated with teratogenic and embry otoxic effects in rats, rabbits and sheep when given early in pregnancy. The manufacturer recommends not administering to female cattle dur-ing the first 45 days of pregnancy or for 45 days after removal of bulls. In sheep, it should not be administered to ewes during the first 30 days of pregnancy or for 30 days after removal of rams. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Safety during nursing has not been established. Overdosage/Toxicity Doses of 300 mg/kg (30X recommended) and 200 mg/kg (20X) have caused death in cattle and sheep, respectively. Doses of 45 mg/kg (4. 5X those recommended) did not cause any adverse effects in cattle tested. Cats receiving 100 mg/kg/day for 14-21 days showed signs of weight loss, neutropenia and mental dullness. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving albendazole and may be of significance in veterinary patients: CIm ETIDINE!! : Increased albendazole levels in bile and cystic fluid DEx Am ETHASONE!! : May increase albendazole serum levels PRAz IQUANTEl!! : May increase albendazole serum levels Doses DOg S:T! For Filaroides hirthi infections: a) 50 mg/kg q12h PO for 5 days; repeat in 21 days. Clinical signs may suddenly worsen during therapy, presumably due to a reaction to worm death. (Hawkins, Ettinger, and Suter 1989)b) 25 mg/kg PO q12h for 5 days; may repeat in 2 weeks (also for Oslerus osleri) (Reinemeyer 1995) For Filaroides osleri (also known as Oslerus osleri) infections: a) 9. 5 mg/kg for 55 days or 25 mg/kg PO twice daily for 5 days. Repeat therapy in 2 weeks. (T odd, Paul, and Di Pietro 1985) For Capillaria plica: a) 50 mg/kg q12h for 10-14 days. May cause anorexia. (Brown and Barsanti 1989) For Paragonimus kellicotti: a) 50 mg/kg PO per day for 21 days (Roberson 1988b) b) 30 mg/kg once daily for 12 days (T odd, Paul, and Di Pietro 1985) c) 25 mg/kg PO q12h for 14 days (Reinemeyer 1995) For Giardia:a) 25 mg/kg PO q12h for 4 doses (Barr, Bowman et al. ) b) 25 mg/kg PO twice daily for 5 days (Barr and Bowman 1994) c) 25 mg/kg PO twice daily for 2-5 days (Lappin 2000) For Leishmaniasis: a) 10 mg/kg PO once daily for 30 days or 5 mg/kg PO q6h for 60 days (Greene and Watson 1998) CATS:T! For Paragonimus kellicotti: a) 50 mg/kg PO per day for 21 days (Roberson 1988b) b) 25 mg/kg PO q12h for 10-21 days (Hawkins, Ettinger, and Suter 1989) c) 30 mg/kg once a day for 6 days (T odd, Paul, and Di Pietro 1985) ] d) 25 mg/kg PO q12h for 14 days (Reinemeyer 1995) For Giardia:a) 25 mg/kg PO twice daily for 5 days (Barr and Bowman 1994) b) 25 mg/kg PO q12h for 3-5 days; may cause bone marrow suppression in dogs and cats. (Vasilopulos 2006) For treatment of liver flukes (Platynosum or Opisthorchiidae families): a) 50 mg/kg PO once daily until ova are gone (Taboada 1999) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: For Encephalitozoon phacoclastic uveitis: 30 mg/kg PO once daily for 30 days, then 15 mg/kg PO once daily for 30 days (Ivey and Morrisey 2000) b) Chinchillas: For Giardia: 50-100 mg/kg PO once a day for 3 days (Hayes 2000) CATTl E:T! For susceptible parasites:a) 10 mg/kg PO (Labeled directions; Valbazen® —Pfizer) b) 7. 5 mg/kg PO; 15 mg/kg PO for adult liver flukes (Roberson 1988b) c) For adult liver flukes: 10 mg/kg PO; best used in fall when the majority are adults (little or no efficacy against immature forms). A second treatment in winter may be beneficial. (Herd 1986b) d) For gastrointestinal cestodes: 10 mg/kg PO (Herd 1986a) SWINE:T! For susceptible parasites: a) 5-10 mg/kg PO (Roberson 1988b) SHEEP & g OATS:T! For susceptible parasites:a) 7. 5 mg/kg PO (0. 75 m L of the suspension per 25 lb. body weight). (Labeled directions; Valbazen® Suspension—Pfizer) b) 7. 5 mg/kg PO; 15 mg/kg PO for adult liver flukes (Roberson 1988b)

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Alb UTEROl SUl FATE 19 c) For adult liver flukes in sheep: 7. 6 mg/kg (Paul 1986) d) For treatment of nematodes in sheep: 3 m L of suspension per 100 lbs of body weight PO (Bulgin 2003) b IRDS:T! a) Ratites: Using the suspension: 1 m L/22 kg of body weight twice daily for 3 days; repeat in 2 weeks. Has efficacy against flagellate parasites and tapeworms. (Jenson 1998) monitoring Efficacy T! Adverse effects if used in non-approved species or at dosages T! higher than recommended Consider monitoring CBC's and liver enzymes (q4-6 weeks) if T! treating long-term (>1 month) Client Information Shake well before administering T! Contact veterinarian if adverse effects occur (T! e. g., vomiting, diar-rhea, yellowish sclera/mucous membranes or skin) Chemistry/Synonyms A benzimidazole anthelmintic structurally related to mebendazole, albendazole has a molecular weight of 265. It is insoluble in water and soluble in alcohol. Albendazole may also be known as. Albendazole may also be known by these synonyms: albendazolum, SKF-62979, Valbazen® or Albenza®; many other trade names are available. Storage/Stability Albendazole suspension should be stored at room tempera-ture (15-30°C); protect from freezing. Shake well before using. Albendazole paste should be stored at controlled room temperature (15-30°C); protect from freezing. Dosage Forms/ Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Albendazole Suspension: 113. 6 mg/m L (11. 36%) in 500 m L, 1 liter, 5 liters; Valbazen® Suspension (Pfizer); (OTC). Approved for use in cattle (not female cattle during first 45 days of pregnancy or for 45 days after removal of bulls, or of breeding age) and sheep (do not administer to ewes during the first 30 days of pregnancy or for 30 days after removal of rams). Slaughter withdrawal for cattle = 27 days at la beled doses. Slaughter withdrawal for sheep = 7 days at labeled dose. Since milk withdrawal time has not been established, do not use in female dairy cattle of breeding age. ) Albendazole Paste: 30% in 205 g (7. 2 oz); Valbazen® (Pfizer); (OTC). Approved for use in cattle (not female cattle during first 45 days of pregnancy or for 45 days after removal of bulls or of breed-ing age). Slaughter withdrawal = 27 days at labeled doses. Since withdrawal time in milk has not been established, do not use in female dairy cattle of breeding age. HUm AN­l Ab El ED PRODUCTS: Albendazole Tablets: 200 mg; Albenza® (Smith Kline Beecham); (Rx) Albuterol sulf Ate (al-byoo-ter-ole) Salbutamol, Proventil®, Ventolin® beta-adrenergic ag Onist Prescriber Highlights Used primarily as a bronchodilator after PO or inhaled T T dosing Use with caution in patients with cardiac dysrhythmias T T or dysfunction, seizure disorders, hyper tension or hyperthyroidism May be teratogenic (high doses) or delay labor T T Uses/Indications Albuterol is used principally in dogs and cats for its effects on bron-chial smooth muscle to alleviate bronchospasm or cough. It is also used in horses as a bron chodilator. Pharmacology/Actions Like other beta-agonists, albuterol is believed to act by stimulat-ing production of cyclic AMP through activation of adenyl cyclase. Albuterol is considered to be predominantly a beta 2 agonist (relax-ation of bronchial, uterine, and vascular smooth muscles). At usual doses, al buterol possesses minimal beta 1 agonist (heart) activity. Beta-adrenergics can promote a shift of potassium away from the serum and into the cell, perhaps via stimulation of Na +-K+-ATPase. T em porary decreases in either normal or high serum potassium levels are possible. Pharmacokinetics The specific pharmacokinetics of this agent have apparently not been thor oughly studied in domestic animals. In general, albuterol is absorbed rapidly and well after oral ad ministration. Effects oc-cur within 5 minutes after oral inhalation; 30 minutes after oral adminis tration (e. g., tablets). It does not cross the blood-brain bar-rier but does cross the placenta. Duration of effect generally per-sists for 3-6 hours after inhalation and up to 12 hours (depending on dosage form) after oral administration. The drug is extensively metabolized in the liver principally to the inactive metabolite, al-buterol 4'-O-sulfate. After oral administration the serum half-life in humans has been reported as 2. 7-5 hours. Contraindications/Precautions/Warnings Albuterol is contraindicated in patients hy persensitive to it. It should be used with caution in patients with diabetes, hyperthy-roidism, hypertension, seizure disorders, or cardiac disease (espe-cially with concurrent arrhythmias). Use during the late stages of pregnancy may inhibit uterine contractions. Adverse Effects Most adverse effects are dose-related and those that would be ex-pected with sympathomimetic agents including increased heart rate, tremors, CNS excitement (nervousness) and dizziness. These effects are generally transient and mild and usually do not re quire discontinuation of therapy. Decreased serum potassium values may be noted; rarely is potas sium supplementation required. Some cats don't like the “hiss” occurring during actuation of the metered-dose inhaler or the taste of the drug/vehicle.

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20 Alb UTEROl SUl FATE Reproductive/Nursing Safety In very large doses, albuterol is teratogenic in rodents. It should be used (particularly the oral dosage forms) during pregnancy only when the potential benefits outweigh the risks. Like some other beta agonists, it may delay pre-term labor after oral administration. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Clinical signs of significant overdose after systemic administration (including when dogs bite an aerosol canister) may include: arrhyth-mias (bradycardia, tachycardia, heart block, extrasystoles), hyperten-sion, fever, vomiting, mydriasis, and CNS stimulation. Hypokalemia may also be noted. If recently orally ingested, and if the animal does not have significant cardiac or CNS effects, it should be handled like other overdoses (empty gut, give activated charcoal and a cathartic). If cardiac arrhythmias require treatment, a beta-blocking agent (e. g., atenolol, metoprolol) can be used. The oral LD 50 of albuterol in rats is reported to be greater than 2 g/kg. Contact an animal poison control center for further information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving albuterol (primarily when albuterol is given orally and not via inhalation) and may be of significance in veterinary patients: b ETA­ADRENERg IC bl OCKINg Ag ENTS !! (e. g., propranolol ): May antago-nize the actions of albuterol DIg Ox IN!! : Albuterol may increase the risk of cardiac arrhythmias INHAl ATION ANESTHETICS !! (e. g., halothane, isoflurane, methoxyflurane ): Albuterol may predispose the patient to ventricular arrhythmias, particularly in patients with preexisting cardiac disease—use cau-tiously OTHER Sym PATHOm Im ETIC Am INES !! : Used with albuterol may increase the risk of developing adverse cardiovascular effects TRICy Cl IC ANTIDEPRESSANTS OR m ONOAm INE Ox IDASE INHIb ITORS !! : May potentiate the vascular effects of albuterol Doses DOg S:T! WARNINg: There are several older references that state that the oral dose is 50 mg/kg q8h. This is an obvious overdose and should not be followed. A more reasonable dose orally in dogs is: 0. 05 mg/kg (50 micrograms/kg) PO q8-12h. a) 0. 05 mg/kg (50 micrograms/kg) PO q8h (Johnson 2000) b) 0. 02 mg/kg PO q12h for 5 days; if no improvement and no adverse effects may increase to 0. 05 mg/kg PO q8-12h. If patient responds, reduce to lowest effective dose. (Church 2003) c) For inhalation, based on a 60 lb dog: 0. 5 m L of the 0. 5% so-lution for nebulization in 4 m L of saline nebulized every 6 hours (Mc Connell and Hughey 1992) CATS:T! a) For bronchodilation in feline asthma using the 90 mcg/puff aerosol albuterol inhaler and an appropriate spacer and mask: For mild symptoms give one puff albuterol as needed with one puff of 110 mcg fluticasone twice daily. Moderate symptoms may be treated with albuterol one puff as needed with a 5 day course of prednisone at 1 mg/kg PO daily, and 220 mcg of fluticasone twice daily. Severely affected cats should be treated on an emergency basis with oxygen, an intravenous dose of a glucocorticoid, 90 mcg (one puff) albuterol every 30 minutes as needed. Chronic therapy should include fluticasone 220 mcg twice daily, 90 mcg albuterol as needed and 1 mg/kg prednisone ev-ery other day. (Dowling 2003b) b) For intermittent (not daily) signs (e. g., wheeze, increased cough or respiratory rate and effort at rest) of feline asthma: two puffs into an appropriate spacer (e. g., Aerokat) twice dai-ly; cat should breathe through the mask and spacer for 7-10 seconds. Positive clinical effect should be seen within 5-10 minutes. Can be used every H hour for 2-4 hours in crisis. (Padrid 2006) HORSES:T! (Note : ARCI UCGFS Class 3 Drug) a) 8 micrograms/kg PO q12h (Enos 1993) b) 2-3 mcg/kg via inhalation using a specially designed mask and spacer (Aeromask® and Aerovent ®) (Foreman 1999) c) For heaves: 0. 8-2 mcg/kg in a metered dose inhaler (Lavoie 2003) d) For short-acting bronchodilation: 450-900 mcg (5-10 puffs) as needed, not to exceed 4 times per week unless in conjunc-tion with a corticosteroid (Mazan 2003) e) For heaves: 360 mcg (4 puffs) inhaled as needed. T olerance develops rapidly if used as a sole therapy. (Rush 2006a) monitoring Clinical symptom improvement; auscultation, blood gases (if T! indi cated) Cardiac rate, rhythm (if warranted) T! Serum potassium, early in therapy if animal is sus ceptible to hy-T! pokalemia Client Information Contact veterinarian if animal's condition deteriorates or it be-T! comes acutely ill. If using the aerosol, shake well before using. Be certain how to ap-T! propriately administer the product to maximize effectiveness. Do not puncture or use near an open flame; do not allow exposure to temperatures greater than 120°F. Keep out of reach of children and pets. Chemistry/Synonyms A synthetic sympathomimetic amine, albuterol sulfate occurs as a white, almost taste less crystalline powder. It is soluble in water and slightly soluble in alcohol. One mg of albuterol is equivalent to 1. 2 mg of albuterol sulfate. Albuterol sulfate may also be known as: salbutamol hemisul-phate, salbutamol sulphate, or salbutamoli sulfas; many trade names are available. Storage/Stability Oral albuterol sulfate products should be stored at 2-30°C. The in-haled aerosol should be stored at room temperature; do not allow exposure to temperatures above 120°F or the canister may burst. The 0. 5% nebs should be stored at room temperature; the 0. 083% nebs should be stored in the refrigerator. Discard solutions if they become colored. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: T! None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

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Al ENDRONATE SODIUm 21 HUm AN­l Ab El ED PRODUCTS: Albuterol Tablets: 2 mg & 4 mg; Proventil ® (Schering); generic; (Rx) Albuterol Extended Release Tablets: 4 mg & 8 mg; Vo Spire® ER (Od-yssey); (Rx) Albuterol Syrup: 2 mg (as sulfate) per 5 m L in 473 m L & 480 m L; Proventil ® (Schering); generic; (Rx) Albuterol Aerosol: Each actualization delivers 90 mcg albuterol in 6. 7g, 6. 8g, 8. 5g, 17g and 18g; Proven til® (Schering); Albuterol HFA ® & Pro Air HFA® (Ivax); Proventil HFA® (Key); Ventolin HFA® (Glaxo Smith Kline); generic; (Rx). Note : At the time or writing (2007), manufacturers of albuterol aerosols are transitioning their products from CFC propellants to ozone-friendly HFA propellants. While these new dosage forms have been shown to be effective, they are not considered generically equivalent to the CFC-containing products. Dosage adjustments may be required. Albuterol Solution for Inhalation (“Nebs”): 0. 021% preservative-free (0. 63 mg (as sulfate)/3m L), 0. 042% preservative-free (1. 25 mg (as sulfate)/3 m L), 0. 083% (2. 5 mg (as sulfate)/3 m L) and 0. 5% (5 mg (as sulfate)/m L) in 0. 5 m L vials, 3 m L UD vials or 20 m L; Proventil ® (Schering); Accu Neb® (Dey); generic; (Rx) Also available: 14. 7 g aerosol metered dose inhaler containing 18 mcg ipratropium bromide (an inhaled anticholinergic) and 103 mcg albuterol sulfate per puff; Combivent® (B-I); (Rx) and 3 m L unit dose solution for inhalation (neb) containing 0. 5 mg ipratro-pium bromide and 3 mg albuterol, Duo Neb® (Dey); (Rx) Alendron A te sodium (a-len-droe-nate) Fosamax® Oral bisph Osph Onate b One res Orpti On inhibit Or Prescriber Highlights Orally dosed bisphosphonate that reduces osteoclastic T T bone resorption Potentially useful for refractory hypercalcemia, FORLs, T T osteosarcoma Very limited clinical experience with use of this drug in T T animals; adverse effect profile, dosages, etc. may signifi-cantly change with more experience & clinical research Potentially can cause esophageal erosions; risks are not T T clear for dogs or cats Accurate dosing may be difficult & bioavailability is ad-T T versely affected by food, etc. Cost may be an issue T T Uses/Indications Alendronate use in small animals has been limited, but it may prove useful for treating refractory hypercalcemia in dogs or cats, feline odontoclastic resorptive lesions (FORLs), and as an osteosarcoma treatment adjuvant. Pharmacology/Actions Alendronate, like other bisphosphonates, inhibits osteoclastic bone resorption by inhibiting osteoclast function after binding to bone hydroxyapatite. Secondary actions that may contribute to therapeu-tic usefulness in osteogenic neoplasms include promoting apopto-sis and inhibiting osteoclastogenesis, angiogenesis and cancer cell proliferation. Pharmacokinetics Specific pharmacokinetic values are limited for dogs and appar-ently unavailable for cats. Oral bioavailability in all species studied is less than 2%. In humans, alendronate sodium has very low oral bioavailability (<1%) and the presence of food can reduce bioavail-ability further to negligible amounts. In women, taking the medi-cation with coffee or orange juice reduced bioavailability by 60% when compared to plain water. Absorbed drug is rapidly distributed to bone or excreted into the urine. The drug is reportedly not highly plasma protein bound in dogs, but it is in rats. Alendronate apparently accumulates on sub-gingival tooth surfaces and bordering alveolar bone. Plasma con-centrations are virtually undetectable after therapeutic dosing. Alendronate is not metabolized and drug taken up by bone is very slowly eliminated. It is estimated that the terminal elimination half-life in dogs is approximately 1000 days and, in humans, ap-proximately 10 years, however once incorporated into bone, alen-dronate is no longer active. Contraindications/Precautions/Warnings Alendronate is contraindicated in human patients with esopha-geal abnormalities (e. g., strictures, achalasia) that cause delayed esophageal emptying and those who cannot stand or sit upright for 30 minutes after administration. At present, it is not believed that small animal patients need to remain upright after administration. Because of a lack of experience, the drug is not recommended for use in human patients with severe renal dysfunction (Cr Cl <35 m L/min). Alendronate should not be used in patients who have demon-strated hypersensitivity reactions to it. Alendronate use in small animals should be considered inves-tigational at this point. Limited research and experience, dosing questions, risks of esophageal irritation or ulcers, and medication expense all are potential hindrances to its therapeutic usefulness. Adverse Effects Little information on the specific adverse effect profile for dogs or cats is published. In humans, alendronate can cause upper GI ir-ritation and erosions. Anecdotal reports of GI upset, vomiting and inappetance have been reported in dogs receiving the drug. It has been suggested that after administration, walking or playing with the dog for 30 minutes may reduce the incidence of esophageal problems. In cats, buttering the lips after administration to induce salivation and reduce esophageal transit time has been suggested. Other potential adverse effects of concern include jaw osteone-crosis and musculoskeletal pain. Reproductive/Nursing Safety Alendronate at dosages of 2 mg/kg in rats caused decreased post-implantation survival rates and at 1 mg/kg caused decreased weight gain in healthy pups. Higher dosages (10 mg/kg) caused incomplete fetal ossification of several bone types. In humans, the FDA catego-rizes alendronate as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) While it is unknown if alendronate enters maternal milk, it would be unexpected that measurable quantities would be found in milk or enough would be absorbed in clinically significant amounts in nursing offspring.

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22 Al FENTANIl HCl Overdosage/Acute Toxicity No lethality was observed in dogs receiving doses of up to 200 mg/ kg. Lethality in mice and rats was seen at dosages starting at 966 mg/kg and 552 mg/kg, respectively. Observed adverse effects associated with overdoses included hypocalcemia, hypophosphatemia, and up-per GI reactions. A recently ingested overdose should be treated with orally ad-ministered antacids or milk to bind the drug and reduce absorption. Do not induce vomiting. Monitor serum calcium and phosphorus and treat supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving alendronate and may be of significance in veterinary patients: ASPIRIN!! : Increased risk of upper GI adverse effects CAl CIUm­CONTAININg ORAl PRODUCTS !! or FOOD : Likely to significantly decrease oral bioavailability of alendronate RANITIDINE !! (IV): increased oral alendronate bioavailability two-fold in a human study NSAIDS!! : Humans taking NSAIDs with alendronate had no higher rates of GI adverse reactions than when NSAIDs were used with placebo laboratory Considerations No specific laboratory concerns or interactions have been noted. Doses DOg S:T! a) For refractory hypercalcemia: 0. 5-1 mg/kg PO once daily (Davies 2005) CATS:T! a) For feline odontoclastic resorptive lesions (FORLs): 3 mg/kg PO q12h (Gores 2004) Note : Use for this indication in cats is at present very controversial. (Plumb 2006) b) For idiopathic hypercalcemia (after dietary change has been attempted): Initially 2 mg/kg PO once weekly. Most cats re-spond to 10 mg (total dose). Administer at least 6 m L of water after administration and butter the lips to increase salivation and increase transit. If efficacious, effects usually seen in 3-4 weeks. Monitor via serum ionized calcium. (Chew and Green 2006) monitoring Serum calcium (ionized)T! GI adverse effects. T! Note : Depending on diagnosis (e. g., hypercalce-mia, adjunctive treatment of osteogenic sarcomas, or FORLs) oth-er monitoring of serum electrolytes (total calcium, phosphorus, potassium sodium) or disease-associated signs may be required Client Information Inform clients of the “investigational” nature with using this drug T! in small animals Potentially can cause esophageal erosions; risks are not clear for T! dogs or cats. Be sure adequate liquid is consumed after dosage and, ideally, do not feed for at least 30 minutes after dosing. See Adverse Effects for suggestions to minimize risks in dogs and cats. Chemistry/Synonyms Alendronate sodium is a synthetic analog of pyrophosphonate with the chemical name: (4-amino-1-hydroxy-1-phosphono-butyl) phosphonic acid. One mg is soluble in one liter of water. Alendronate may also be known as: Alendronic acid, Acide Alendronique, Acido Alendronico, Acidum Alendronicum, Adronat®, Alendros®, Arendal®, Onclast® or Fosamax®. Storage/Stability Alendronate tablets should be stored in well-closed containers at room temperature. The oral solution should be stored at room tem-perature; do not freeze. Dosage Forms/Regulatory Status VETERINAR y PRODUCTS: None HUm AN PRODUCTS: Alendronate Sodium Tablets: 5 mg, 10 mg, 35 mg, 40 mg, & 70 mg (as base): Fosamax® (Merck); (Rx) Alendronate Oral Solution: 70 mg (as base) in 75 m L; raspberry fla-vor; Fosamax® (Merck); (Rx) Alfent Anil hcl (al-fen-ta-nil) Alfenta® Opiate anesthetic adjunct Prescriber Highlights Injectable, potent opiate that may be useful for adjunc-T T tive anesthesia, particularly in cats Marginal veterinary experience & little published data T T available to draw conclusions on appropriate usage in veterinary species Dose-related respiratory & CNS depression are the most T T likely adverse effects seen Dose may need adjustment in geriatric patients & those T T with liver disease Class-II controlled substance; relatively expensive T T Uses/Indications An opioid analgesic, alfentanil may be useful for anesthesia, analge-sia, or sedation similar to fentanyl; fentanyl is generally preferred be-cause of the additional experience with its use in veterinary patients and cost. Alfentanil may be particularly useful in cats as adjunctive therapy during anesthesia to reduce other anesthetic (i. e., propofol or isoflurane) concentrations. Pharmacology/Actions Alfentanil is a potent mu opioid with the expected sedative, analge-sic, and anesthetic properties. When comparing analgesic potencies after IM injection, 0. 4-0. 8 mg of alfentanil is equivalent to 0. 1-0. 2 mg of fentanyl and approximately 10 mg of morphine. Pharmacokinetics The pharmacokinetics of alfentanil have been studied in the dog. The drug's steady state volume of distribution is about 0. 56 L/kg, clearance is approximately 30 m L/kg/minute, and the terminal half-life is approximately 20 minutes. In humans, onset of anesthetic action occurs within 2 minutes after intravenous dosing, and within 5 minutes of intramuscular in-jection. Peak effects occur approximately 15 minutes after IM injec-tion. The drug has a volume of distribution of 0. 4-1 L/kg. About 90% of the drug is bound to plasma proteins. Alfentanil is primarily metabolized in the liver to inactive metabolites that are excreted by

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Al FENTANIl HCl 23 the kidneys into the urine; only about 1% of the drug is excreted unchanged into the urine. T otal body clearance in humans ranges from 1. 6-17. 6 m L/minute/kg. Clearance is decreased by about 50% in patients with alcoholic cirrhosis or in those that are obese. Clearance is reduced by approximately 30% in geriatric patients. Elimination half-life in humans is about 100 minutes. Contraindications/Precautions/Warnings Alfentanil is contraindicated in patients hypersensitive to opioids. Because of the drug's potency and potential for significant adverse effects, it should only be used in situations where patient vital signs can be continuously monitored. Initial dosage reduction may be required in geriatric or debilitated patients, particularly those with diminished cardiopulmonary function. Adverse Effects Adverse effects are generally dose related and consistent with other opiate agonists. Respiratory depression, and CNS depression are most likely to be encountered. In humans, bradycardia that is usu-ally responsive to anticholinergic agents can occur. Dose-related skeletal muscle rigidity is not uncommon and neuromuscular blockers are routinely used. Alfentanil has rarely been associated with asystole, hypercarbia and hypersensitivity reactions. Respiratory or CNS depression may be exacerbated if alfentanil is given with other drugs that can cause those effects. Reproductive/Nursing Safety In humans, the FDA categorizes alfentanil as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). If alfentanil is administered systemically to the mother close to giv-ing birth, offspring may show behavioral alterations (hypotonia, depression) associated with opioids. Although high dosages given for 10-30 days to laboratory animals have been associated with embryotoxicity, it is unclear if this is a result of direct effects of the drug or as a result of maternal toxicity secondary to reduced food and water intake. The effects of alfentanil on lactation or its safety for nursing off-spring is not well defined, but it is unlikely to cause significant ef-fects when used during anesthetic procedures in the mother. Overdosage/Acute Toxicity Intravenous, severe overdosages may cause circulatory collapse, pulmonary edema, seizures, cardiac arrest and death. Less severe overdoses may cause CNS and respiratory depression, coma, hy-potension, muscle flaccidity and miosis. Treatment is a combina-tion of supportive therapy, as necessary, and the administration of an opiate antagonist such as naloxone. Although alfentanil has a relatively rapid half-life, multiple doses of naloxone may be neces-sary. Because of the drug's potency, the use of a tuberculin syringe to measure dosages less than 1 m L with a dosage calculation and measurement double-check system, are recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving alfentanil and may be of significance in veterinary patients: DRUg S THAT INHIb IT HEPATIC ISOENzym E Cy P3A4 !!, such as erythromy­ cin, cimetidine, ketoconazole, itraconazole, fluconazole or diltiazem : May increase the half-life and decrease the clearance of alfentanil leading to prolonged effect and an increased risk of respiratory depression D!!RUg S THAT DEPRESS CARDIAC FUNCTION OR REDUCE VAg Al TONE, such as beta­blockers or other anesthetic agents : May produce bra-dycardia or hypotension if used concurrently with alfentanil laboratory Considerations Patients receiving opiates may T! have increased plasma levels of amy­ lase or lipase secondary to increased biliary tract pressure. Values may be unreliable for 24 hours after administration of alfentanil. Doses (Note : in very obese patients, figure dosages based upon lean body weight. ) DOg S:T! As a premed: a) 5 mcg/kg alfentanil with 0. 3-0. 6 mg of atropine IV 30 sec-onds before injecting propofol can reduce the dose of propo-fol needed to induce anesthesia to 2 mg/kg, but apnea may still occur. (Hall, Clarke et al. 2001b) As an analgesic supplement to anesthesia: a) 2-5 mcg/kg IV q20 minutes. (Hall, Clarke et al. 2001b), (Hall, Clarke et al. 2001a) b) For intra-operative analgesia in patients with intracranial disease: 0. 2 mcg/kg/minute (Raisis 2005) monitoring Anesthetic and/or analgesic efficacy T! Cardiac and respiratory rate T! Pulse oximetry or other methods to measure blood oxygenation T! when used for anesthesia Client Information Alfentanil is a potent opiate that should only be used by pro-T! fessionals in a setting where adequate patient monitoring is available Chemistry/Synonyms A phenylpiperidine opioid anesthetic-analgesic related to fenta-nyl, alfentanil HCl occurs as a white to almost white powder. It is freely soluble in alcohol, water, chloroform or methanol. The com-mercially available injection has a p H of 4-6 and contains sodium chloride for isotonicity. Alfentanil is more lipid soluble than mor-phine, but less so than fentanyl. Alfentanil may also be known as: alfentanyl, Alfenta®, Fanaxal®, Fentalim®, Limifen®, or Rapifen®. Storage/Stability/Compatibility Alfentanil injection should be stored protected from light at room temperature. In concentrations of up to 80 mcg/m L, alfentanil in-jection has been shown to be compatible with Normal Saline, D5 in Normal Saline, D5W, and Lactated Ringers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 1 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Alfentanil HCl for injection: 500 mcg/m L in 2 m L, 5 m L, 10 m L, and 20 m L amps; preservative free; Alfenta® (Akorn); Alfentanil HCl (Abbott); (Rx, C-II).

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24 All OPURINOl Allopurinol (al-oh-pyoor-i-nol) Zyloprim® Xanthine O Xidase inhibit Or; purine anal Og Prescriber Highlights Used as a uric acid reducer in dogs, cats, reptiles & birds T T & as an alternative treatment Leishmaniasis & Trypano-somiasis in dogs Use with caution (dosage adjustment may be required) in T T patients with renal or hepatic dysfunc tion Contraindicated in red-tailed hawks & should be used T T with caution, if at all, in other raptors Diet may need to be adjusted to lower purine T T GI effects are most likely adverse effects, but hypersensi-T T tivity, hepatic & renal effects can occur Many potential drug interactions T T Uses/Indications The principle veterinary uses for allopurinol are for the prophylactic treatment of recurrent uric acid uroliths and hyperuricosuric cal-cium oxalate uroliths in small animals. It has also been used in an attempt to treat gout in pet birds and reptiles. Allopurinol has been recommended as an alternative treatment for canine Leishmaniasis. Al though it appears to have clinical efficacy, it does not apparently clear the parasite in most dogs at usual dosag-es. Allopurinol may also be useful for American Trypanosomiasis. Pharmacology/Actions Allopurinol and its metabolite, oxypurinol, inhibit the enzyme xan-thine oxidase. Xanthine oxidase is responsible for the conversion of oxypurines (e. g., hypoxanthine, xanthine) to uric acid. Hepatic microsomal enzymes may also be inhibited by allopurinol. It does not increase the renal excretion of uric acid nor does it possess any antiinflammatory or analgesic activity. Allopurinol is metabolized by Leishmania into an inactive form of inosine that is incorporated into the organism's RNA leading to faulty protein and RNA synthesis. Allopurinol, by inhibiting xanthine oxidase, can inhibit the for-mation of superoxide anion radi cals, thereby providing protection against hemorrhagic shock and myocardial ischemia in laboratory conditions. The clinical use of the drug for these indications requires further study. Pharmacokinetics In Dalmatians, absorption rates were variable between subjects. Peak levels occur within 1-3 hours after oral dosing. Elimination half-life is about 2. 7 hours. In dogs (not necessarily Dalmatians), the serum half-life of allopurinol is approximately 2 hours and for oxipurinol, 4 hours. Food does not appear to alter the absorption of allopurinol in dogs. In horses, oral bioavailability of allopurinol is low (approximate-ly 15%). Allopurinol is rapidly converted to oxypurinol in the horse as the elimination half-life of allopurinol is approximately 5-6 min-utes. Oxypurinol has an elimination half-life of about 1. 1 hours in the horse. In humans, allopurinol is approximately 90% absorbed from the GI tract after oral dosing. Peak levels after oral allopurinol adminis-tration occur 1. 5 and 4. 5 hours later, for allopurinol and oxypurinol, respectively. Allopurinol is distributed in total body tissue water but levels in the CNS are only about 50% of those found elsewhere. Neither al-lopurinol nor oxypurinol are bound to plasma proteins, but both drugs are excreted into milk. Xanthine oxidase metabolizes allopurinol to oxypurinol. In humans, the serum half-life for allopurinol is 1-3 hours and for oxypurinol, 18-30 hours. Half-lives are in creased in patients with diminished renal function. Both allopurinol and oxypurinol are dia-lyzable. Contraindications/Precautions/Warnings Allopurinol is contraindicated in patients who are hypersensitive to it or have previously developed a severe reaction to it. It should be used cautiously and with intensified monitoring in patients with impaired hepatic or renal function. When used in patients with re-nal in sufficiency, dosage reductions and increased monitoring are usually warranted. Red-tailed hawks appear to be sensitive to the effects of al-lopurinol. Doses at 50 mg/kg PO once daily caused clinical signs of vomiting and hyperuricemia with renal dysfunction. Doses of 25 mg/kg PO once daily were safe but not effective in reducing plasma uric acid. Adverse Effects Adverse effects in dogs are apparently uncommon with allopurinol when fed low purine diets. There has been one report of a dog de-veloping hemolytic anemia and trigeminal neuropathy while receiv-ing allopurinol. Xanthine coatings have formed around ammonium urate uroliths in dogs that have been fed diets containing purine. If the drug is required for chronic therapy, reduction of purine precur-sors in the diet with dosage reduction should be considered. Several adverse effects have been reported in humans including GI dis tress, bone marrow suppression, skin rashes, hepatitis, and vasculitis. Human patients with renal dys function are at risk for fur-ther decreases in renal function and other severe adverse effects un-less dosages are reduced. Until further studies are performed in dogs with decreased renal function, the drug should be used with caution and at reduced dosages. Reproductive/Nursing Safety While the safe use of allopurinol during pregnancy has not been established, dosages of up to 20 times normal in rodents have not demonstrated decreases in fertility. Infertility in males (humans) has been reported with the drug, but a causal effect has not been firmly established. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Allopurinol and oxypurinol may be excreted into milk; use cau-tion when allopurinol is administered to a nursing dam. Overdosage/Acute Toxicity Vomiting is common in dogs at doses >100 mg/kg per the APCC database. A human ingesting 22. 5 grams did not develop serious toxicity. The oral LD50 in mice is 78 mg/kg. There were 27 exposures to allopurinol reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 25 were dogs with 2 showing clini-cal signs; the remaining 2 reported cases were cats that showed no clinical signs. Common findings recorded in decreasing frequency included vomiting and tachycardia.

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All OPURINOl 25 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving allopurinol and may be of significance in veterinary patients: Am INOPHyll INE !! or THEOPHyll INE : Large doses of allopurinol may decrease metabolism thereby increasing their serum levels Am Ox ICIll IN !! or Am PICIll IN : In humans, concomitant use with al-lopurinol has been im plicated in increased occurrences of skin rashes; the veterinary significance of this interaction is un known Az ATHIOPRINE !! or m ERCAPTOPURINE : Allopurinol may inhibit me-tabolism and increase toxicity; if concurrent use is necessary, dosages of the antineoplastic/immunosuppressive agent should be reduced initially to 25-33% of their usual dose and then ad-justed, dependent upon patient's response CHl ORPROPAm IDE!! : Allopurinol may increase risks for hypoglyce-mia and hepato-renal reactions Cy Cl OPHOSPHAm IDE!! : Increased bone marrow depression may oc-cur in patients receiving both allop urinol and cyclophosphamide Cy Cl OSPORINE!! : Allopurinol may increase cyclosporine levels DIURETICS!! (Furosemide, Thiazides, Diazoxide, and Alcohol ): Can in-crease uric acid levels ORAl ANTICOAg Ul ANTS!! (e. g., Warfarin ): Allopurinol may reduce the metabolism of warfarin thereby increasing effect TRIm ETHOPRIm/SUl FAm ETHOx Az Ol E!! : In a few human patients, thrombocytopenia has occurred when used with allopurinol URICOSURIC Ag ENTS!! (e. g., Probenecid, Sulfinpyrazone ): May increase the renal excretion of oxypuri nol and thereby reduce xanthine oxidase inhibition; in treating hyperuricemia the additive effects on blood uric acid may, in fact, be beneficial to the patient URINAR y ACIDIFIERS!! (e. g., methionine, Ammonium Chloride ) May re-duce the solubility of uric acid in the urine and induce urolithiasis Doses DOg S:T! For urate uroliths:a) 7-10 mg/kg PO three times daily for both dissolution and prevention. Goal is to reduce urine urate:creatinine ratio by 50%. (Senior 1989) b) For dissolution: 15 mg/kg PO q12h; only in conjunction with low purine foods. For prevention: 10-20 mg/kg/day; because prolonged high doses of allopurinol may result in xanthine uroliths, it may be preferable to minimize recurrence with dietary therapy, with the option of treating infrequent episodes of urate uro-lith formation with dissolution protocols. (Osborne, Lulich et al. 2003a) c) Alkalinize urine to a p H of 6. 5-7 (see sodium bicarbonate monograph), give low purine diet and eliminate any UTI. Al-lopurinol at 10 mg/kg three times daily for the first month, then 10 mg/kg once daily thereafter. Reduce dose in patients with renal failure. (Polzin and Os borne 1985), (Lage, Polzin, and Zenoble 1988) For Leishmaniasis: a) 15 mg/kg PO twice daily for months (Lappin 2000) b) If possible use with meglumine antimoniate, if not, use al-lopurinol alone at 10 mg/kg PO twice daily. If animal has re-nal insufficiency, use at 5 mg/kg PO twice daily. (Font 1999) c) Meglumine antimoniate (100 mg/kg/day SQ) until resolu-tion, with allopurinol at 20 mg/kg PO q12h for 9 months. An alternate protocol using allopurinol alone: allopurinol 10 mg/kg PO q8h or 10-20 mg/kg PO q12h for 1-4 months. (Brosey 2005) CATS:T! For urate uroliths: a) 9 mg/kg PO per day (Schultz 1986) b IRDS:T! For gout:a) In budgies and cockatiels: Crush one 100 mg tablet into 10 m L of water. Add 20 drops of this solution to one ounce of drinking water. (Mc Donald 1989) b) For parakeets: Crush one 100 mg tablet into 10 m L of water. Add 20 drops of this solution to one ounce of drinking water or give 1 drop 4 times daily. (Clubb 1986) REPTIl ES:T! a) For elevated uric acid levels in renal disease in lizards: 20 mg/kg PO once daily (de la Navarre 2003a) b) For gout: 20 mg/kg PO once daily. Suggested dosage based upon human data as dose is not established for reptiles. (Johnson-Delaney 2005d) monitoring Urine uric acid (for urolithiasis) T! Adverse effects T! Periodic CBC, liver and renal function tests (T! e. g., BUN, Creati-nine, liver enzymes); espe cially early in therapy Client Information Unless otherwise directed, administer after meals (usually 1 hour T! or so). No tify veterinarian if animal develops a rash, becomes le-thargic or ill. Chemistry/Synonyms A xanthine oxidase inhibitor, allopurinol occurs as a tasteless, fluffy white to off-white powder with a slight odor. It melts above 300° with decomposition and has an apparent p K a of 9. 4. Oxypurinol (aka oxipurinol, alloxanthine), its active metabolite, has a p K a of 7. 7. Allopuri nol is only very slightly soluble in both water and alcohol. Allopurinol may also be known as: allopurinolum, BW-56-158, HPP, or NSC-1390; many trade names are available. Storage/Stability/Compatibility Allopurinol tablets should be stored at room temperature in well-closed containers. The drug is stated to be stable in both light and air. The powder for injection should be stored at 25°C; may be ex-posed to 15-30°C. Once diluted to a concentration ≤ 6 mg/m L, store at room temperature and use within 10 hours; do not refriger-ate. Compatible IV solutions include D5W and normal saline. An extemporaneously prepared suspension containing 20 mg/ m L allopurinol for oral use can be prepared from the commercially available tablets. Tablets are crushed and mixed with an amount of Cologel® suspending agent equal to N the final volume. A mixture of simple syrup and wild cherry syrup at a ratio of 2:1 is added to produce the final volume. This preparation has been reported to be stable for at least 14 days when stored in an amber bottle at either room temperature or when refrigerated. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Allopurinol Tablets: 100 mg & 300 mg; Zyloprim® (Glaxo Well-come); generic; (Rx) Allopurinol Powder for Injection: 500 mg preservative-free in 30 m L vials; Aloprim® (Nabi); Allopurinol Sodium (Bedford Labs); (Rx)

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26 Al PRAz Ol Am Alpr Azol Am (al-prah-zoe-lam) Xanax® benz Odiazepine sedative/tranquilizer Prescriber Highlights Oral benzodiazepine that may be useful for unwanted T T behaviors in dogs or cats Contraindications: Aggressive animals (controversial), T T benzodiazepine hypersensitivity Caution: Hepatic or renal disease T T Adverse Effects: Sedation, behavior changes, & contradic-T T tory responses; physical depen dence is a possibility; may impede training C-IV controlled substance T T Uses/Indications Alprazolam may be useful for adjunctive therapy in anxious, aggres-sive dogs or in those demonstrating panic reactions. ( Note : Some cli-nicians believe that benzodiazepines are contraindicated in aggres-sive dogs as anxiety may actually restrain the animal from aggressive tendencies). It may be useful in cats to treat anxiety disorders. Alprazolam may have less effect on motor function at low doses than does diazepam. Pharmacology/Actions Subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNS are depressed by alprazolam and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action is un known, but postulated mechanisms include: antagonism of se-rotonin, increased release of and/or fa cilitation of gamma-amin-obutyric acid (GABA) activity, and diminished release or turnover of acetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalian brain, kidney, liver, lung, and heart. In all species studied, receptors are lacking in the white matter. Pharmacokinetics The pharmacokinetics of alprazolam have not been described for either dogs or cats. In humans, alprazolam is well absorbed and is characterized as having an inter mediate onset of action. Peak plasma levels occur in 1-2 hours. Alprazolam is highly lipid soluble and widely distributed throughout the body. It readily crosses the blood-brain barrier and is somewhat bound to plasma proteins (80%). Alprazolam is metabolized in the liver to at least two metabolites, including alpha-hydroxy-alprazo lam which is pharmacologically active. Elimination half-lives range from 6-27 hours in people. Contraindications/Precautions/Warnings Some clinicians believe that benzodi azepines are contraindicated in aggressive dogs as anxiety may actually restrain the animal from ag-gressive tendencies. This remains controversial. Alprazolam is con-traindicated in patients with known hy persensitivity to the drug. Use cautiously in patients with hepatic or renal disease, narrow an-gle glaucoma and debilitated or geriatric patients. Benzodiazepines may impair the abilities of working animals. Adverse Effects Benzodiazepines can cause sedation, increased appetite, and tran-sient ataxia. Cats may exhibit changes in be havior (irritability, in-creased affection, depression, aberrant demeanor) after receiving benzodi azepines. Dogs may rarely exhibit a contradictory response (CNS excite-ment) following administration of benzodiazepines. Chronic usage of benzodiazepines may induce physical depen-dence. Animals appear to be less likely than humans to develop physical dependence. Benzodiazepines may impede the ability of the animal to learn and may retard training. Reproductive/Nursing Safety Diazepam and other benzodiazepines have been implicated in caus-ing congenital abnormalities in humans if administered during the first trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepines shortly before delivery have been reported to suffer from apnea, im paired metabolic response to cold stress, dif-ficulty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms have occurred in infants whose mothers chronically took benzodiazepines during pregnancy. The veterinary significance of these effects is unclear, but the use of these agents during the first trimester of pregnancy should only occur when the benefits clearly outweigh the risks associated with their use. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Overdosage/Acute Toxicity When administered alone, alprazolam overdoses are generally lim-ited to significant CNS depression (confusion, coma, decreased re-flexes, etc. ). Hypotension, respiratory depression, and cardiac arrest have been reported in human patients but apparently, are quite rare. The reported LD50 in rats for alprazolam is >330 mg/kg, but cardiac arrest occurred at doses as low as 195 mg/kg. There were 935 exposures to alprazolam reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 863 were dogs with 208 showing clinical signs, 63 were cats with 20 showing clinical signs, 3 were rodents with 1 reported as having clinical signs, and 2 cases were rabbits with 1 reported as having clinical signs. Common findings in dogs recorded in decreasing frequency included ataxia, lethargy, hyperac-tivity, disorientation, depression. Common findings in cats recorded in decreasing frequency included ataxia disorientation, sedation, hy-peractivity and restlessness. Common findings in rodents recorded in decreasing frequency included ataxia, somnolence and vomiting. Common findings in lagomorphs recorded in decreasing frequency included ataxia and lethargy. Treatment of acute toxicity consists of standard protocols for re-moving and/or binding the drug in the gut if taken orally and sup-portive systemic measures. Flumazenil (see separate monograph) may be employed to reverse the sedative effects of alprazolam, but only if the patient has significant CNS or respiratory depression. Seizures may be precipitated in patients physically dependent. The use of analeptic agents (CNS stimulants such as caffeine) is generally not recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving alprazolam and may be of significance in veterinary patients:

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Al TRENOg EST 27 ANTACIDS!! : May slow the rate, but not the extent of oral absorption of alprazolam; administer 2 hours apart to avoid this potential interaction CNS DEPRESSANT Ag ENTS !! (barbiturates, narcotics, anesthetics, etc. ): Additive effects may occur DIg Ox IN!! : Serum levels may be increased; monitor serum digoxin levels or clinical signs of toxicity Fl UOx ETINE, Fl UVOx Am INE!! : Increased alprazolam levels HEPATICAlly m ETAb Ol Iz ED DRUg S !! (e. g., cimetidine, erythromycin, iso­ niazid, ketoconazole, itracona zole): Metabolism of alprazolam may be decreased and excessive sedation may occur RIFAm PIN:!! May induce hepatic microsomal enzymes and decrease the pharmacologic effects of ben zodiazepines TRICy Cl IC ANTIDEPRESSANTS!! (e. g., amitriptyline, clomipramine, imip­ ramine ): Alprazolam may increase levels of these drugs; clinical significance is not known and some state that clomipramine and alprazolam together may improve efficacy for phobias (e. g., thunderstorm phobia) Doses DOg S:T! a) For treatment of canine anxiety disorders: 0. 01-0. 1 mg/kg PO as needed for panic, not to exceed 4 mg/dog/day. Start with 1-2 mg (total dose) for a medium-sized dog. (Overall 1997) b) For separation anxiety: 0. 25 mg-2 mg (total dose) once daily to three times daily PO. (Hunthausen 2006) c) For storm phobias: 0. 02-0. 4 mg/kg PO q4h as needed; helps to minimize impact of experiencing a severe storm (Crowell-Davis 2003c); 0. 02 mg/kg PO as needed one hour before anticipated storm and every 4 hours as needed; used as an adjunct after behav-ior modification and prior clomipramine treatment (see clo-mipramine monograph for further information) (Crowell-Davis 2003d) d) For phobias, night waking: 0. 01-0. 1 mg/kg or 0. 25-2 mg (total dose) per dog PO q6-12h PO (Siebert 2003c) CATS:T! a) For treatment of feline anxiety disorders: 0. 125-0. 25 mg/kg PO q12h (Start at 0. 125 mg/kg PO) (Overall 1997) b) For refractory house soiling: 0. 1 mg/kg or 0. 125-0. 25 mg (total dose) per cat PO q8-12h (Siebert 2003c) c) For urine marking: 0. 05-0. 2 mg/kg PO q12-24h (Virga 2002) d) For fears/phobias/anxieties: 0. 125-0. 25 mg (total dose) PO once to three times a day. (Landsberg 2005a) monitoring Efficacy T! Adverse Effects T! Consider monitoring hepatic enzymes particularly when treating T! cats chronically Client Information Try to dose approximately one hour in advance of storms or oth-T! er anticipated stimuli that evokes negative responses If difficulty with pilling the medication occurs, consider using the T! orally-disintegrating tablets; hands must be dry before handling If excessive sedation or yellowing of the whites of eyes (especially T! in cats) occurs, contact veterinarian Chemistry/Synonyms A benzodiazepine, alprazolam occurs as a white to off-white, crys-talline powder. It is soluble in alcohol and insoluble in water. Alprazolam may also be known as D65 MT, U 31889, or alprazo-lamum; many trade names available internationally. Storage/Stability Alprazolam tablets should be stored at room temperature in tight, light-resistant containers. The orally disintegrating tablets should be stored at room temperature and protected from moisture. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Alprazolam Tablets: 0. 25 mg, 0. 5 mg, 1 mg & 2 mg; Xanax® (Pfizer); generic; (Rx; C-IV) Alprazolam Extended-release Tablets: 0. 5 mg, 1 mg, 2 mg, & 3 mg; Xanax XR® (Pfizer); generic; (Rx; C-IV) Alprazolam Orally Disintegrating Tablets: 0. 25 mg, 0. 5 mg, 1 mg, & 2 mg; Niravam® (Pfizer); (Rx; C-IV) Alprazolam Oral Solution: 1 mg/m L in 30 m L; Alprazolam Inten-sol® (Roxane); (Rx; C-IV) Altrenogest (al-tre-noe-jest) Regu-Mate®, Matrix® Oral pr Ogestin Prescriber Highlights Progestational drug used in horses to suppress estrus T T or maintain pregnancy when progestin deficient; used in swine to synchronize estrus May be used in dogs for luteal deficiency or as a treat-T T ment to prevent premature delivery Many “handling” warnings for humans (see below) T T Very sensitive to light T T Uses/Indications Altrenogest (Regu-Mate®) is indicated (labeled) to suppress estrus in mares to allow a more predictable occurrence of estrus following withdrawal of the drug. It is used clinically to assist mares to es-tablish normal cycles during the transitional period from anestrus to the normal breeding season often in conjunction with an artifi-cial photoperiod. It is more effective in assisting in pregnancy at-tainment later in the transition period. Some authors (Squires et al. 1983) suggest selecting mares with considerable follicular activ-ity (mares with one or more follicles 20 mm or greater in size) for treatment during the transitional phase. Mares that have been in estrus for 10 days or more and have active ovaries are also consid-ered excellent candidates for progestin treatment. Altrenogest is effective in normally cycling mares for minimizing the necessity for estrus detection, for the synchronization of estrus, and permitting scheduled breeding. Estrus will ensue 2-5 days af-ter treatment is completed and most mares ovulate between 8-15 days after withdrawal. Altrenogest is also effective in suppressing

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28 Al TRENOg EST estrus expression in show mares or mares to be raced. Although the drug is labeled as contraindicated during pregnancy, it has been demonstrated to maintain pregnancy in oophorectomized mares and may be of benefit in mares that abort due to sub-therapeutic pro gestin levels. The product Matrix® is labeled for synchronization of estrus in sexually mature gilts that have had at least one estrous cycle. Treatment with altrenogest results in estrus (standing heat) 4-9 days after completion of the 14-day treatment period. Altrenogest has been used in dogs for luteal insufficiency and as a treatment to prevent premature delivery. Pharmacology/Actions Progestins are primarily produced endogenously by the corpus lu-teum. They trans form proliferative endometrium to secretory en-dometrium, enhance myometrium hypertrophy and inhibit spon-taneous uterine contraction. Progestins have a dose-dependent inhibitory effect on the secretion of pituitary gonadotropins and have some degree of estrogenic, anabolic and andro genic activity. Pharmacokinetics In horses, the pharmacokinetics of altrenogest have been studied (Machnik, Hegger et al. 2007). After oral dosing of 44 mg/kg PO, peak levels usually occur within 15-30 minutes post-dose; 24 hours post-dose, levels were below the level of quantification. Elimination half-lives are approximately 2. 5-4 hours. Altrenogest appears to be primarily eliminated in the urine. Peak urine levels occur 3-6 hours after oral dosing. Urine levels were detectable up to 12 days post-administration. Contraindications/Precautions/Warnings The manufacturer (Regu-Mate®—Intervet) lists pregnancy as a con-traindication to the use of altrenogest, however it has been used clin-ically to maintain pregnancy in certain mares (see Dosages below). Altrenogest should also not be used in horses intended for food pur-poses. Adverse Effects Adverse effects of altrenogest appear to be minimal when used at la beled dosages. One study (Shideler et al. 1983) found negligible changes in hematologic and most “standard” laboratory tests after administering altrenogest to 4 groups of horses (3 dosages, 1 con-trol) over 86 days. Occasionally, slight changes in Ca ++, K+, alkaline phosphatase and AST were noted in the treatment group, but values were only slightly elevated and only noted sporadically. No pattern or definite changes could be attributed to altrenogest. No outward adverse effects were noted in the treatment group during the trial. Use of progestational agents in mares with chronic uterine infec-tions should be avoided as the in fection process may be enhanced. Overdosage/Acute Toxicity The LD 50 of altrenogest is 175-177 mg/kg in rats. No information was located re garding the effects of an accidental acute overdose in horses or other species. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving altrenogest and may be of significance in veterinary patients: RIFAm PIN!! : May decrease progestin activity if administered con-comitantly. This is presumably due to microsomal enzyme induc-tion with resultant increase in progestin metabolism. The clinical significance of this potential interaction is unknown. laboratory Considerations Unlike exogenously administered progesterone, altrenogest does T! not interfere or cross-react with progesterone assays Doses DOg S:T! For luteal insufficiency: a) Document luteal insufficiency and rule out infectious causes of pregnancy loss. Best to avoid during first trimester. Give equine product (Regumate®) at 2 m L per 100 lbs of body weight PO once daily. Monitor pregnancy with ultrasound. Re member that exogenous progesterone is the experimental model for pyometra in the bitch, so monitor carefully. (Pur-swell 1999) b) For luteal insufficiency, pre-term labor: 0. 1 m L per 10 lb body weight PO once daily. (Barber 2006) c) T o maintain pregnancy if tocolytics (e. g., terbutaline) do not control myometrial contractility: 0. 088 mg/kg once dai-ly (q24h). Must be withdrawn 2-3 days prior to predicted whelp date. (Davidson 2006) HORSES:T! T o suppress estrus for synchronization:a) Administer 1 m L per 110 pounds body weight (0. 044 mg/kg) PO once daily for 15 con secutive days. May administer directly on tongue using a dose syringe or on the usual grain ration. (Package insert; Regu-Mate®—Intervet) b) 0. 044 mg/kg PO for 8-12 days (Bristol 1987) T o maintain pregnancy in mares with deficient progesterone levels: a) 22-44 mg daily PO (Squires et al. 1983) b) 0. 044 mg/kg PO once daily. Three options for treatment: 1) treatment until day 60 of pregnancy or greater AND measure-ment of endogenous progesterone level of >4 ng/m L; 2) treat-ment until day 120 of pregnancy; or 3) treatment until end of pregnancy. (Mc Cue 2003b) T o maintain pregnancy in mares with placentitis: a) 10-20 m L (22-44 mg) daily PO (Vaala 2003a) T o suppress estrus (long-term): a) 0. 044 mg/kg PO daily (Squires et al. 1983) SWINE:T! For synchronization of estrous in sexually mature gilts that have had at least one estrous cycle: a) Follow label directions for safe use. Administer 6. 8 m L (15 mg) per gilt for 14 consecutive days. Apply as a top-dressing on a portion of gilt's daily feed allowance. Estrous should oc-cur 4-9 days after completing treatment. (Package insert; Matrix®—Intervet) Client Information The manufacturer (T! Regu-Mate®, Matrix®—Intervet) lists the fol-lowing people as those who should not handle the product: 1. Women who are or suspect that they are pregnant 2. Anyone with thrombophlebitis or thromboembolic disorders or with a history of these events 3. Anyone having cerebrovascular or coronary artery disease 4. Women with known or suspected carcinoma of the breast 5. People with known or suspected estrogen-dependent neoplasias 6. Women with undiagnosed vaginal bleeding 7. People with benign or malignant tumor that developed dur-ing the use of oral contracep tives or other estrogen contain-ing products

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Al Um INUm Hy DROx IDE 29 Altrenogest can be absorbed after skin contact and absorption T! can be enhanced if the drug is covered by occlusive materials (e. g., under latex gloves, etc. ). If exposed to the skin, wash off im-mediately with soap and water. If the eyes are exposed, flush with water for 15 minutes and get medical atten tion. If the product is swallowed, do not induce vomiting and contact a physician or poison control center. This medication is prohibited from use in an extra-label manner T! to enhance food and/or fiber production in animals Chemistry/Synonyms An orally administered synthetic progestational agent, altrenogest has a chemical name of 17 alpha-Allyl-17beta-hydroxyestra-4,9,11-trien-3-one. Altrenogest may also be known as: allyl tren bolone, A-35957, A-41300, RH-2267, or RU-2267, Regu-Mate®, or Matrix®. Storage/Stability Altrenogest oral solution should be stored at room temperature. Altrenogest is extremely sensitive to light; dispense in light-resistant containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Altrenogest 0. 22% (2. 2 mg/m L) in oil solution in 150 m L and 1000 m L bottles; Regu-Mate® (Intervet); (Rx). Approved for use in horses not intended for food. This medication is banned in racing animals in some countries. Altrenogest 0. 22% (2. 2 mg/m L) in 1000 m L bottles; Matrix® (In-tervet); (OTC, but extra-label use prohibited). Approved for use in sexually mature gilts that have had at least one estrous cycle. Gilts must not be slaughtered for human consumption for 21 days af-ter the last treatment. The FDA prohibits the extra-label use of this medication to enhance food and/or fiber production in animals. HUm AN­l Ab El ED PRODUCTS: None Aluminum hydroxide (ah-loo-min-um hye-droks-ide) Amphogel® Oral antacid/ph Osphate binder Prescriber Highlights Used to treat hyperphosphatemia in small animal pa-T T tients & sometimes as a gastric antacid for ulcers Chronic use may lead to electrolyte abnormalities; pos-T T sible aluminum toxicity Many potential drug interactions T T Availability has been an issue T T Uses/Indications Orally administered aluminum hydroxide is used to reduce hyper-phosphatemia in patients with renal failure. Pharmacology/Actions Aluminum salts reduce the amount of phosphorus absorbed from the intestine by physically binding to dietary phosphorus. Contraindications/Precautions/Warnings Aluminum-containing antacids may inhibit gastric emptying; use cautiously in patients with gastric outlet ob struction. Adverse Effects In small animals, the most likely side effect of aluminum hydrox-ide is constipation. If the patient is receiving a low phosphate diet and the patient chronically receives aluminum antacids, hypophos-phatemia can develop. Potentially, aluminum toxicity could occur with prolonged use but is thought unlikely to occur in small animal patients. Reproductive/Nursing Safety In a system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), these drugs are categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse ef-fects in laboratory animals or women. ) Overdosage/Acute Toxicity Acute toxicity is unlikely with an oral overdose. If necessary, GI and electrolyte imbalances that occur with chronic or acute overdose should be treated symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving oral aluminum salts and may be of significance in veterinary patients: Aluminum salts can decrease the amount absorbed or the pharma-cologic effect of: All OPURINOl!! CHl OROQUINE!! CORTICOSTEROIDS!! DIg Ox IN!! ETHAmb UTOl!! Fl UOROQUINOl ONES!! H­2 ANTAg ONISTS !! (RANITIDINE, FAm OTIDINE, etc. ) IRON SAl TS !! ISONIAz ID!! PENICIll Am INE!! PHENOTHIAz INES!! TETRACy Cl INES!! THy ROID HORm ONES!! Separate oral doses of aluminum hydroxide and these drugs by two hours to help reduce this interaction. Doses DOg S:T! For hyperphosphatemia:a) Aluminum hydroxide: Initially at 30-90 mg/kg per day. Dos-age must be individualized. Capsules or suspension are pre-ferred as they are more easily mixed with food and dispersed throughout ingesta. Evaluate serum phosphate levels at 10-14 day intervals to determine optimum dosage. (Polzin and Osborne 1985) b) Aluminum hydroxide: 30-90 mg/kg PO once a day to three times a day with meals (Morgan 1988) c) 15-45 mg/kg PO q12h (Bartges 2002c) For adjunctive therapy for gastric ulcers:a) Aluminum hydroxide suspension or aluminum hydroxide/magnesium hydroxide suspen sion: 2-10 m L PO q2-4h (Hall and Twedt 1988) b) Aluminum hydroxide tablets: 0. 5-1 tablet PO q6h (Matz 1995)

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30 Am ANTADINE HCl CATS:T! For hyperphosphatemia: a) Aluminum hydroxide: Initially at 30-90 mg/kg per day. Dosage must be individualized. Capsules or suspension are preferred as they are more easily mixed with food and dis-persed throughout ingesta. Evaluate serum phosphate levels at 10-14 day intervals to determine optimum dosage. (Polzin and Osborne 1985) b) 15-45 mg/kg PO q12h (Bartges 2002c) As an antacid: a) Aluminum hydroxide tablets: 0. 25 tablets PO q6h (Matz 1995) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Chinchillas: Aluminum hydroxide gel: 1 m L PO as needed Guinea pigs: 0. 5-1 m L PO as needed (Adamcak and Otten 2000) CATTl E:T! As an antacid: a) Aluminum hydroxide: 30 grams (Jenkins 1988) HORSES:T! For adjunctive gastroduodenal ulcer therapy in foals: a) Aluminum/magnesium hydroxide suspension: 15 m L 4 times a day (Clark and Becht 1987) monitoring Initially at 10-14 day intervals; once “stable” at 4-6 week intervals: Serum phosphorus (after a 12-hour fast) T! Client Information Oral aluminum hydroxide products are available without pre-T! scription (OTC), but should be used under the supervision of the veterinarian. Tablets or capsules (may be compounded) are easier to administer T! than human liquids or suspensions Give either just before feeding or mixed in food T! Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Aluminum Hydroxide Gel: Capsules: 500 mg, Dialume® (RPR): (OTC)Tablets: 500 mg Alu-Tab® (3M Pharm); 600 mg Amphojel® (Wyeth-Ayerst); (OTC)Suspension/Liquid: 320 mg/5 m L in 360 and 480 m L, UD 15 and 30 m L; generic; (OTC) 450mg/5 m L in 500 m L and UD 30 m L; Aluminum Hydroxide Gel (Roxane); (OTC) 675 mg/5 m L in 180 and 500 m L, UD 20 and 30 m L; Concentrated Aluminum Hydroxide Gel (Roxane); (OTC) Liquid: 600 mg/5 m L in 30, 150, 180, 360 and 480 m L; Alterna Gel® (J and J-Merck); generic; (OTC) Note : There are also many products available that have aluminum hydroxide and a magnesium or calcium salt (e. g., Maalox®, etc. ) that are used as antacids. All oral aluminum and magnesium hydroxide preparations are OTC. Am Ant Adine hcl (a-man-ta-deen) Symmetrel® antiviral (influenza a); nmda antag Onist Prescriber Highlights Antiviral drug with NMDA antagonist properties; may T T be useful in adjunctive therapy of chronic pain in small animals & treatment of equine influenza in horses Very limited clinical experience; dogs may exhibit agita-T T tion & GI effects, especially early in therapy Large interpatient variations of pharmacokinetics in T T horses limit its therapeutic usefulness Overdoses are potentially very serious; fairly nar-T T row therapeutic index in dogs & cats; may need to be compounded Extra-label use prohibited (by FDA) in chickens, turkeys & T T ducks Uses/Indications While amantadine may have efficacy and clinical usefulness against some veterinary viral diseases, presently the greatest interest for its use in small animals is as a NMDA antagonist in the adjunctive treatment of chronic pain, particularly those tolerant to opioids. Amantadine has also been investigated for treatment of equine-2 influenza virus in the horse. However, because of expense, interpa-tient variability in oral absorption and other pharmacokinetic pa-rameters, and the potential for causing seizures after intravenous dosing, it is not commonly used for treatment. In humans, amantadine is used for treatment and prophylaxis of influenza A, parkinsonian syndrome, and drug-induced extrapy-ramidal effects. As in veterinary medicine, amantadine's effect on NMDA receptors in humans are of active interest, particularly its use as a co-analgesic with opiates and in the reduction of opiate toler-ance development. Pharmacology/Actions Like ketamine, dextromethorphan and memantine, amantadine an-tagonizes the N-methyl-D-aspartate (NMDA) receptor. Within the central nervous system, chronic pain can be maintained or exacer-bated when glutamate or aspartate bind to this receptor. It is believed that this receptor is particularly important in allodynia (sensation of pain resulting from a normally non-noxious stimulus). Amantadine alone is not a particularly good analgesic, but in combination with other analgesics (e. g., opiates, NSAIDs), it is thought that it may help alleviate chronic pain. Amantadine's antiviral activity is primarily limited to strains of influenza A. While its complete mechanism of action is unknown, it does inhibit viral replication by interfering with influenza A virus M2 protein. Amantadine's antiparkinsonian activity is not well understood. The drug does appear to have potentiating effects on dopaminergic neurotransmission in the CNS and anticholinergic activity. Pharmacokinetics The pharmacokinetics of this drug have apparently not been de-scribed in dogs or cats. In horses, amantadine has a very wide in-terpatient variability of absorption after oral dosing; bioavailability ranges from 40-60%. The elimination half-life in horses is about 3. 5 hours and the steady state volume of distribution is approxi-mately 5 L/kg.

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Am ANTADINE HCl 31 In humans, the drug is well absorbed after oral administration with peak plasma concentrations occurring about 3 hours after dos-ing. Volume of distribution is 3-8 L/kg. Amantadine is primarily eliminated via renal mechanisms. Oral clearance is approximately 0. 28 L/hr/kg; half-life is around 17 hours. Contraindications/Precautions/Warnings In humans, amantadine is contraindicated in patients with known hypersensitivity to it or rimantadine, and in patients with un-treated angle-closure glaucoma. It should be used with caution in patients with liver disease, renal disease (dosage adjustment may be required), congestive heart failure, active psychoses, eczematoid dermatitis or seizure disorders. In veterinary patients with similar conditions, it is advised to use the drug with caution until more information on its safety becomes available. In 2006, the FDA banned the use of amantadine and other influ-enza antivirals in chickens, turkeys and ducks. Adverse Effects There is very limited experience in domestic animals with amanta-dine and its adverse effect profile is not well described. It has been reported that dogs given amantadine occasionally develop agita-tion, loose stools, flatulence or diarrhea, particularly early in thera-py. Experience in cats is limited; an adverse effect profile has yet to be fully elucidated, but the safety margin appears to be narrow. Reproductive/Nursing Safety In humans, the FDA categorizes amantadine as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). High dosages in rats demonstrated some teratogenic effects. Amantadine does enter maternal milk. The manufacturer does not recommend its use in women who are nursing. Veterinary sig-nificance is unclear. Overdosage/Acute Toxicity T oxic dose reported for cats is 30 mg/kg and behavioral effects may be noted at 15 mg/kg in dogs and cats. In humans, overdoses as low as 2 grams have been associated with fatalities. Cardiac dysfunction (arrhythmias, hypertension, tachycardia), pulmonary edema, CNS toxicity (tremors, seizures, psychosis, agitation, coma), hyperthermia, renal dysfunction and respiratory distress syndrome have all been documented. There is no known specific antidote for amantadine overdose. Treatment should consist of gut emptying, if possible, intensive monitoring and supportive therapy. Forced urine acidifying diuresis may in-crease renal excretion of amantadine. Physostigmine has been sug-gested for cautious use in treating CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amantadine and may be of significance in veterinary patients: ANTICHOl INERg IC DRUg S !! : May enhance the anticholinergic effects of amantadine CNS STIm Ul ANTS!! (including selegiline ): Concomitant use with amantadine may increase the drug's CNS stimulatory effects TRIm ETHOPRIm/SUl FA, QUINIDINE, QUININE, THIAz IDE DIURETICS !! or TRIAm TERENE : May decrease the excretion of amantadine, yield-ing higher blood levels URINAR y ACIDIFIERS !! (e. g., methionine, ammonium chloride, ascorbic acid): May increase the excretion of amantadine laboratory Considerations No laboratory interactions identified Doses DOg S:T! As adjunctive therapy for chronic pain: a) 1. 25-4 mg/kg PO q12-24h. Usually use 3 mg/kg PO once daily as an adjunct with a NSAID. May require 5-7 days to have a positive effect. (Hardie, Lascelles et al. 2003) b) Approximate dose is 3-5 mg/kg PO once daily. (Gaynor 2002) c) T o decrease wind-up: 3-5 mg/kg PO once daily for one week. (Perkowski 2006a) CATS:T! As adjunctive therapy for chronic pain: a) 3 mg/kg PO once daily. May be useful addition to NSAIDs; not been evaluated for toxicity. May need to be compounded. (Lascelles, Robertson et al. 2003) b) Approximate dose is 3-5 mg/kg PO once daily. (Gaynor 2002) c) 3 mg/kg PO once daily. (Hardie 2006) HORSES:T! For acute treatment of equine-2 influenza: a) 5 mg/kg IV q4h (Rees, Harkins et al. 1997) monitoring Adverse effects (GI, agitation) T! Efficacy T! Client Information When used in small animals, the drug must be given as prescribed T! to be effective and may take a week or so to show effect. Gastrointestinal effects (loose stools, gas, diarrhea) or some agi-T! tation may occur, particularly early in treatment. Contact the vet-erinarian if these become serious or persist. Overdoses with this medication can be serious; keep well out of T! reach of children and pets. Chemistry/Synonyms An adamantane-class antiviral agent with NMDA antagonist prop-erties, amantadine HCl occurs as a white to practically white, bitter tasting, crystalline powder with a p Ka of 9. Approximately 400 mg are soluble in 1 m L of water; 200 mg are soluble in 1 m L of alcohol. Amantadine HCl may also be known as: adamantana-mine HCl, Adekin®, Amanta®, Amantagamma®, Amantan®, Amantrel®, Amixx®, Antadine®, Antiflu-DES®, Atarin®, Atenegine®, Cerebramed®, Endantadine®, Infectoflu®, Influ-A®, Lysovir ®, Mantadine®, Mantadix®, Mantidan®, Padiken®, Symadine®, Symmetrel®, Viroifral® and Virucid®. Storage/Stability Tablets, capsules and the oral solution should be stored in tight con-tainers at room temperature. Limited exposures to temperatures as low as 15°C and as high as 30°C are permitted. Avoid freezing the liquid. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Amantadine HCl Tablets & Capsules: 100 mg; Symmetrel® (Endo); generic; (Rx) Amantadine HCl Syrup: 10 mg/m L in 480 m L; Symmetrel® (Endo); generic; (Rx)In 2006, the FDA banned the extra-label use of amantadine and other influenza antivirals in chickens, turkeys and ducks.

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32 Am IKACIN SUl FATE Amik Acin sulf Ate (am-i-kay-sin) Amikin®, Amiglyde-V® amin O glyc Oside antibi O tic Prescriber Highlights Parenteral aminoglycoside antibiotic that has good ac-T T tivity against a variety of bacte ria, predominantly gram-negative aerobic bacilli Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-T T lar blockade Cats may be more sensitive to toxic effects T T Risk factors for toxicity: Preexisting renal disease, age T T (both neonatal & geriatric), fever, sepsis & dehydration Now usually dosed once daily when used systemically T T Uses/Indications While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resis tant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a docu-mented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported. Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis. Pharmacology/Actions Amikacin, like the other aminoglycoside antibiotics, act on suscep-tible bacteria presumably by irreversibly binding to the 30S ribo-somal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic. Amikacin's spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, in-cluding most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin. Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment. The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria. Pharmacokinetics Amikacin, like the other aminoglycosides is not appreciably ab-sorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiv-ing oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM admin-istration to dogs and cats, peak levels occur from H -1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bioavail ability from extravascular injection (IM or SC) is greater than 90%. After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericar-dial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are mini-mally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the in-ner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0. 15-0. 3 L/kg in adult cats and dogs, and 0. 26-0. 58 L/kg in horses. Volumes of distribution may be signifi cantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum. Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomeru lar filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1. 14-2. 3 hours in adult horses, 2. 2-2. 7 hours in calves, 1-3 hours in cows, 1. 5 hours in sheep, and 0. 5-2 hours in dogs and cats. Patients with decreased renal func tion can have significantly prolonged half-lives. In humans with normal renal function, elimi-nation rates can be highly variable with the aminoglycoside antibi-otics. Contraindications/Precautions/Warnings Aminoglycosides are contraindicated in pa tients who are hyper-sensitive to them. Because these drugs are often the only effective agents in se vere gram-negative infections, there are no other abso-lute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration. Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e. g., “seeing-eye,” herding, dogs for the hearing impaired, etc. ). Aminoglycosides should be used with caution in patients with neuromuscular disorders (e. g., myas thenia gravis) due to their neu-romuscular blocking activity. Because aminoglycosides are eliminated primarily through re-nal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals. Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals. Adverse Effects The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely under stood, but are probably related to in-terference with phospholipid metabolism in the lysosomes of proxi-mal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increas-es in BUN, creatinine, nonprotein nitrogen in the serum, and de-creases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring. Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with

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Am IKACIN SUl FATE 33 streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but ei-ther form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides. The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neu-ropathy and hypersensitivity reactions. Rarely, GI clinical signs, hemato logic and hepatic effects have been reported. Reproductive/Nursing Safety Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of ther-apy may exceed the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the benefit of therapy clearly outweighs the risks. ) Aminoglycosides are excreted in milk. While potentially, ami-kacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period). Overdosage/Acute Toxicity Should an inadvertent overdosage be administered, three treat-ments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12 -20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this ef fect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amikacin and may be of significance in veterinary patients: b ETA­l ACTAm ANTIb IOTICS!! (penicillins, cephalosporins ): May have synergistic effects against some bacteria; some potential for inac-tivation of aminoglycosides in vitro (do not mix together) and in vivo (patients in renal failure) CEPHAl OSPORINS!! : The concurrent use of aminoglycosides with cephalosporins is somewhat controversial. Potentially, cepha-losporins could cause additive nephrotoxicity when used with aminoglycosides, but this interac tion has only been well docu-mented with cephaloridine and cephalothin (both no longer marketed). DIURETICS, l OOP !! (e. g., furosemide, torsemide ) or OSm OTIC (e. g., man­ nitol): Concurrent use with loop or osmotic diuretics may increase the nephrotoxic or ototoxic potential of the aminoglycosides NEPHROTOx IC DRUg S, OTHER !! (e. g., cisplatin, amphotericin b, polymyxin b, or vancomycin ): Potential for increased risk for nephrotoxicity NEUROm USCUl AR bl OCKINg Ag ENTS & ANESTHETICS, g ENERAl !! : Con-comitant use with general anesthetics or neuromuscular block-ing agents could potenti ate neuromuscular blockadelaboratory Considerations Amikacin serum concentrations may be falsely decreased if the T! patient is also receiving beta­lactam antibiotics and the serum is stored prior to analysis. It is recom mended that if assay is de-layed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. Doses Note : Most infectious disease clinicians now agree that aminoglyco-sides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bac-terial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacte-ria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the tox icity of amino-glycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly sug-gested for these patients. DOg S:T! For susceptible infections:a) Sepsis: 20 mg/kg once daily IV (Hardie 2000) b) 15 mg/kg (route not specified) once daily (q24h). Neutro-penic or immunocompromised patients may still need to be dosed q8h (dose divided). (Trepanier 1999) c) 15-30 mg/kg IV, IM or SC once daily (q24h) (Papich 2002b) CATS:T! For susceptible infections:a) Sepsis: 20 mg/kg once daily IV (Hardie 2000) b) 15 mg/kg (route not specified) once daily (q24h). Neutro-penic or immunocompromised patients may still need to be dosed q8h (dose divided). (Trepanier 1999) c) 10-15 mg/kg IV, IM or SC once daily (q24h) (Papich 2002b) FERRETS:T! For susceptible infections: a) 8-16 mg/kg IM or IV once daily (Williams 2000) b) 8-16 mg/kg/day SC, IM, IV divided q8-24h (Morrisey and Carpenter 2004) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV. Increased ef ficacy and decreased toxicity if giv-en once daily. If given IV, dilute into 4 m L/kg of saline and give over 20 minutes. (Ivey and Morrisey 2000) b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h (Morrisey and Carpenter 2004) c) Chinchillas: 2-5 mg/kg SC, IM q8-12h (Hayes 2000) CATTl E :T! For susceptible infections:a) 10 mg/kg IM q8h or 25 mg/kg q12h (Beech 1987b) b) 22 mg/kg/day IM divided three times daily (Upson 1988)

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34 Am IKACIN SUl FATE HORSES:T! For susceptible infections: a) 21 mg/kg IV or IM once daily (q24h) (Moore 1999); (Fore-man 1999) b) In neonatal foals: 21 mg/kg IV once daily (Magdesian, Wilson et al. 2004) c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. (Bucki, Giguere et al. 2004) d) Adults: 10 mg/kg IM or IV once daily (q24h) Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h). (Geor and Papich 2003) For uterine infusion: a) 2 grams mixed with 200 m L sterile normal saline (0. 9% sodi-um chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V®— Fort Dodge) b) 1-2 grams IU (Perkins 1999) For intra-articular injection as adjunctive treatment of septic ar-thritis in foals: a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxic-ity may result (particularly if systemic therapy is also given). (Moore 1999) For regional intravenous limb perfusion (RILP) administration in standing horses: a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. (Parra-Sanchez, Lugo et al. 2006) b IRDS:T! For susceptible infections:a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush si-nuses with saline mixed with appropriate antibiotic (10-30 m L per nostril). May require 2 weeks of treatment. (Karpinski and Clubb 1986) b) 15 mg/kg IM or SC q12h (Hoeffer 1995) c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0. 015 mg/g) IM once a day or twice a day (Clubb 1986) d) Ratites: 7. 6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water p H of 6 (Jenson 1998) REPTIl ES:T! For susceptible infections:a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2. 5 mg/kg q72h for 7-9 treat ments. Commonly used in respira-tory infections. Use a lower dose for Python curtus. (Gauvin 1993) b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2. 5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. (Mader, Conzelman, and Baggot 1985) c) For bacterial shell diseases in turtles: 10 mg/kg daily in wa-ter turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 m L/kg fluid injec-tion. Maintain hydration and monitor uric acid levels when possible. (Rosskopf 1986)d) For Crocodilians: 2. 25 mg/kg IM q 72-96h (Jacobson 2000) e) For gram-negative respiratory disease: 3. 5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. (Klaphake 2005b) FISH:T! For susceptible infections: a) 5 mg/kg IM loading dose, then 2. 5 mg/kg every 72 hours for 5 treatments. (Lewbart 2006) monitoring Efficacy (cultures, clinical signs, WBC's and clinical signs associ-T! ated with infection). Therapeu tic drug monitoring is highly rec-ommended when using this drug systemically. Attempt to draw samples at 1, 2, and 4 hours post dose. Peak level should be at least 40 mcg/m L and the 4-hour sample less than 10 mcg/m L. Adverse effect monitoring is essential. Pre-therapy renal func-T! tion tests and urinalysis (re peated during therapy) are recom-mended. Casts in the urine are often the initial sign of impend ing nephrotoxicity. Gross monitoring of vestibular or auditory toxicity is T! recommended. Client Information With appropriate training, owners may give subcutaneous injec-T! tions at home, but routine monitoring of therapy for efficacy and toxicity must still be done Clients should also un derstand that the potential exists for severe T! toxicity (nephrotoxicity, ototoxicity) developing from this medi-cation Use in food producing animals is controversial as drug residues T! may persist for long periods Chemistry/Synonyms A semi-synthetic aminoglycoside derived from kanamycin, amika-cin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufac turing process. 1. 3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50. 9 mg of base. The commercial in jection is a clear to straw-colored solution and the p H is adjusted to 3. 5-5. 5 with sulfuric acid. Amikacin sulfate may also be known as: amikacin sulphate, ami-kacini sulfas, or BB-K8; many trade names are available. Storage/Stability/Compatibility Amikacin sulfate for injection should be stored at room tempera ture (15-30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency. Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pres-sure at 120°C for 60 minutes did not result in any loss of potency. Note : When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and adminis-tered over at least 30 minutes. Amikacin sulfate is reportedly compatible and stable in all com-monly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, cal cium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhy dramine HCl, epinephrine HCl, ergonovine maleate, hy-aluronidase, hydrocortisone sodium phos phate/succinate, lincomy-cin HCl, metaraminol bitartrate, metronidazole (with or without

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Am INOCAPROIC ACID 35 sodium bi carbonate), norepinephrine bitartrate, pentobarbital so-dium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCl, secobarbital so-dium, sodium bicarbonate, succinylcholine chloride, vancomycin HCl and verapamil HCl. The following drugs or solutions are reportedly incompatible or only compatible in specific situa tions with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, ce-fazolin sodium, cephalothin sodium, cephapirin sodium, chloro-thiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCl, penicillin G potas-sium, phenytoin sodium, potassium chloride (in dextran 6% in so-dium chloride 0. 9%; stable with potassium chloride in “standard” solu tions), tetracycline HCl, thiopental sodium, vitamin B-complex with C and warfarin sodium. Com patibility is dependent upon fac-tors such as p H, concentration, temperature and diluent used; con-sult specialized references or a hospital pharmacist for more spe-cific in formation. In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less suscep-tible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless admin-istration occurs promptly. See also the information in the Drug Interaction and Drug/Lab Interaction sections. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Amikacin Sulfate Injection: 50 mg (of amikacin base) per m L in 50 m L vials; Amiglyde-V® (Fort Dodge), Amiject D® (Butler), Amikacin K-9® (RXV), Amikacin C® (Phoenix), Amtech Amimax C® (IVX), Caniglide® (Vedco); generic (Vet T ek); (Rx); Approved for use in dogs. Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per m L in 48 m L vials; Amifuse E® (Butler), Amiglyde-V® (Fort Dodge), Amikacin E® (Phoenix), Amikacin E® (RXV), Amtech Ami-max E® (IVX), Equi-phar Equiglide® (Vedco); (Rx); Approved for use in horses not intended for food. WARNINg: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Drug residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information). HUm AN­l Ab El ED PRODUCTS: Amikacin Injection: 50 mg/m L and 250 mg/m L in 2 m L and 4 m L vials and 2 m L syringes; Amikin® (Apothecon); generic; (Rx) Aminoc Aproic Acid (a-mee-noe-ka-proe-ik) Amicar® fibrin Olysis inhibit Or/antipr Otease Prescriber Highlights May be useful for treating degenerative myelopathies in T T dogs; efficacy not well documented Treatment may be very expensive, especially with large T T dogs Contraindicated in DIC T T Infrequently causes GI distress T TUses/Indications Aminocaproic acid has been used as a treatment to degenerative myelopathy (seen primarily in German shepherds), but no con-trolled studies documenting its efficacy were located. There is in-terest in evaluating aminocaproic acid for adjunctive treatment of thrombocytopenia in dogs, but efficacy and safety for this purpose remains to be investigated. In humans, it is primarily used for treat-ing hyperfibrinolysis-induced hemorrhage. Pharmacology/Actions Aminocaproic acid inhibits fibrinolysis via its inhibitory effects on plasminogen activator substances and via some antiplasmin action. Aminocaproic acid is thought to affect degenerative myelopathy by its antiprotease activity thereby reducing the activation of in-flammatory enzymes that damage myelin. Pharmacokinetics No pharmacokinetic data was located for dogs. In a study where 70 mg/kg doses were given IV to horses over 20 minutes, the drug was distributed rapidly and plasma levels re-mained above the proposed therapeutic level of 130 mcg/m L for one hour after the end of the infusion. Elimination half-life was 2. 3 hours. The authors proposed that a constant rate infusion of 15 mg/kg/hr after the original infusion would maintain more prolonged therapeutic levels (Ross, Dallop et al. 2006). In humans, the drug is rapidly and completely absorbed after oral administra tion. The drug is well distributed in both intravas-cular and extravascular compartments and pene trates cells (includ-ing red blood cells). It is unknown if the drug enters maternal milk. It does not bind to plasma proteins. T erminal half-life is about 2 hours in humans and the drug is primarily renally excreted as un-changed drug. Contraindications/Precautions/Warnings Aminocaproic acid is contraindicated in patients with active in-travascular clotting. It should only be used when the benefits out-weigh the risks in patients with preexisting cardiac, renal or hepatic disease. Adverse Effects In dogs treated, about 1% exhibit clinical signs of GI irritation. It potentially can cause hyperkalemia particularly in renal impaired patients. Reproductive/Nursing Safety Some, but not all, animal studies have demonstrated teratogenic-ity; use when risk to benefit ratio merits. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity There is very limited information on overdoses with aminocaproic acid. The IV lethal dose in dogs is reportedly 2. 3 g/kg. At lower IV overdosages, tonic-clonic seizures were noted in some dogs. There is no known antidote, but the drug is dialyzable. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aminocaproic acid and may be of significance in veterinary patients: ESTROg ENS!! : Hypercoagulation states may occur in patients re-ceiving aminocaproic acid and estrogens

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36 Am INOPENTAm IDE Hy DROg EN SUl FATE laboratory Considerations Serum T! potassium may be elevated by aminocaproic acid, especially in patients with preexisting renal failure Doses DOg S:T! For adjunctive treatment of degenerative myelopathy (seen pri-marily in German shepherds): a) In combination with exercise, vitamin support (vitamin B-complex, vitamin E), and anal gesia (if required; using acet-aminophen): Aminocaproic acid: 500 mg (regardless of size of animal, approximate dose is 15 mg/kg) PO q8h. Mix 192 m L of the 250 mg/m L injec tion with 96 m L of hematinic compound (e. g., Lixotinic®) producing a 288 m L final vol-ume. Give 3 m L per dose (500 mg). Store solution in refriger-ator. Clinical improvement seen within 8 weeks. (Clemmons 1991) b) Aminocaproic acid 500 mg/dog PO q8h indefinitely. Used in conjunction with acetylcysteine at 25 mg/kg PO q8h for 2 weeks, then q8h every other day. The 20% solution should be diluted to 5% with chicken broth or suitable diluent. Other treatments may include prednisone (0. 25-0. 5 mg/kg PO daily for 10 days then every other day), Vitamin C (1000 mg PO q12h) and Vitamin E (1000 Int. Units PO q12). Note : No treatment has been shown to be effective in published trials. (Shell 2003a) As an antifibrinolytic: a) No published doses for dogs, but has been used anecdotally at 50-100 mg/kg IV or PO q6h. (Hopper 2006b) Client Information Drug costs to treat a German shepherd-sized dog can be T! substantial As no well controlled studies have documented that this drug is T! effective for treating degenerative myelopathy, its use should be considered investigational Chemistry/Synonyms An inhibitor of fibrinolysis, aminocaproic acid is a synthetic monamino carboxylic acid occurring as a fine, white crystalline powder. It is slightly soluble in alcohol and freely soluble in water and has p Ka's of 4. 43 and 10. 75. The injectable product has its p H adjusted to approximately 6. 8. Aminocaproic acid may also be known as: acidum aminocap-roicum, CL-10304 CY-116, EACA, epsilon aminocaproic acid, JD-177, NSC-26154, Amicar®, Capracid®, Capramol®, Caproamin®, Caprolisin®, Epsicaprom®, Hemocaprol®, Hemocid®, Hexalense®, or Ipsilon®. Storage/Stability/Compatibility Products should be stored at room temperature. Avoid freezing liq-uid preparations. Discoloration will occur if aldehydes or aldehydic sugars are present. When given as an intravenous infusion, normal saline, D 5W and Ringer's Injection have been recom mended for use as the infusion diluent. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Aminocaproic Acid Tablets: 500 mg & 1000 mg; Amicar® (Xano-dyne); Aminocaproic Acid (Versa Pharm); (Rx)Aminocaproic Oral Solution: 250 mg/m L in 237 m L & 473 m L; Aminocaproic Acid (Versa Pharm); (Rx) Aminocaproic Syrup: 250 mg/m L in 473 m L; Amicar® (Xanodyne); (Rx)Aminocaproic Acid Injection for Intravenous Infusion: 250 mg/m L in 20 m L vials; generic; (Rx) Aminopent Amide hydrogen sulf Ate (a-mee-noe-pent-a-mide) Centrine® antich Olinergic/antispasm Odic Prescriber Highlights Anticholinergic/antispasmodic for GI indications in small T T animals Typical adverse effect profile (“dry, hot, red”); potentially T T could cause tachycardia Contraindicated in glaucoma; relatively contraindicated T T in tachycardias, heart disease, GI obstruction, etc. Uses/Indications The manufacturer states that the drug is indicated “in the treatment of acute ab dominal visceral spasm, pylorospasm or hypertrophic gastritis and associated nausea, vomiting and/or diarrhea” for use in dogs and cats. Pharmacology/Actions Aminopentamide is an anticholinergic agent that when com pared to atropine has been described as having a greater effect on reduc-ing colonic contractions and less mydriatic and salivary effects. It reportedly may also reduce gastric acid secretion. Pharmacokinetics No information was located. Contraindications/Precautions/Warnings The manufacturer lists glaucoma as an absolute contraindication to therapy and to use the drug cautiously, if at all, in patients with pylo-ric obstruction. Additionally, aminopentamide should not be used if the patient has a history of hypersensitivity to anticholinergic drugs, tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, un stable cardiac status during acute hemor-rhage, GI obstructive disease, paralytic ileus, severe ulcera tive colitis, obstructive uropathy or myasthenia gravis (unless used to reverse adverse muscarinic ef fects secondary to therapy). Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections, or with autonomic neuropathy. Atropine or other antimuscarinic agents can decrease GI motility and prolong retention of the causative agent(s) or toxin(s) resulting in prolonged clinical signs. Antimuscarinic agents should be used with caution in patients with hepatic disease, renal disease, hyperthyroidism, hypertension, CHF, tachyarrhythmias, prostatic hypertrophy, esophageal reflux, and in geriatric or pediatric patients.

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Am INOPHyll INE; THEOPHyll INE 37 Adverse Effects Adverse effects resulting from aminopentamide therapy may in-clude dry mouth, dry eyes, blurred vision, and urinary hesitancy. Urinary retention is a symptom of too high a dose and the drug should be withdrawn until resolved. Overdosage/Acute Toxicity No specific information was located regarding acute overdosage clinical signs or treat ment for this agent. The following discussion is from the Atropine monograph that could be used as a guideline for treating overdoses: If a recent oral ingestion, emptying of gut contents and admin-istration of activated charcoal and saline cathartics may be war-ranted. Treat clinical signs supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholin-ergic effects. Fluid therapy and standard treatments for shock may be instituted. The use of physostigmine is controversial and should probably be reserved for cases where the pa tient exhibits either extreme agi-tation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are se-vere or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult), if no response, may re peat every 20 minutes until reversal of toxic antimuscarinic ef-fects or cholinergic effects takes place. The human pediatric dose is 0. 02 mg/kg slow IV (repeat q10 minutes as above) and may be a rea sonable choice for treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine. Drug Interactions No specific interactions were noted for this product. The follow-ing drug interactions have either been reported or are theoretical in humans or animals receiving atropine, a similar drug and may be of significance in veterinary patients: ANTIHISTAm INES, PROCAINAm IDE, QUINIDINE, m EPERIDINE, b ENz ODI­ !! Az EPINES, PHENOTHIAz INES : May enhance the activity of atropine and its derivatives PRIm IDONE, DISOPy RAm IDE, NITRATES!! : May potentiate the adverse effects of atropine and its derivatives CORTICOSTEROIDS!! (long­term use ): May increase intraocular pressure NITROFURANTOIN, THIAz IDE DIURETICS, Sym PATHOm Im ETICS !! : Atro-pine and its derivatives may enhance actions m ETOCl OPRAm IDE!! : Atropine and its derivatives may antagonize metoclopramide actions Doses DOg S:T! a) May be administered every 8-12 hours via IM, SC or oral routes. If the desired effect is not attained, the dosage may be gradually increased up to 5 times those listed below: Animals weighing: 10 lbs or less: 0. 1 mg; 11-20 lbs: 0. 2 mg; 21-50 lbs: 0. 3 mg; 51-100 lbs: 0. 4 mg; over 100 lbs: 0. 5 mg (Package Insert; Centrine® —Fort Dodge) b) T o decrease tenesmus in malabsorption/maldigestion syn-dromes: 0. 1-0. 4 mg SC, or IM twice daily-three times daily (Chiapella 1988) c) As an antiemetic: 0. 1-0. 4 mg SC, or IM two to three times daily (Johnson 1984)CATS:T! a) As in “a” above in dogs b) As an antiemetic: 0. 1-0. 4 mg SC, or IM two to three times daily (Johnson 1984) c) As second-line adjunctive therapy for refractory IBD: 0. 1-0. 4 mg/kg SC two to three times daily (Washabau 2000) monitoring Clinical efficacy T! Adverse effects (see above)T! Client Information Contact veterinarian if animal has difficulty urinating or if ani-T! mal is bothered by dry eyes or mouth Chemistry/Synonyms An antispasmodic, anticholinergic agent, aminopentamide hydro-gen sulfate has a chem ical name of 4-(dimethylamino)-2,2-diphe-nylvaleramide. Aminopentamide hydrogen sulfate may also be known as dime-vamid or Centrine®. Storage/Stability Store aminopentamide tablets and injection at controlled room temperature (15-30°C; 59-86°F). Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Aminopentamide Hydrogen Sulfate Tablets: 0. 2 mg; Centrine® (Fort Dodge); (Rx). Approved for use in dogs and cats only. Aminopentamide Hydrogen Sulfate Injection: 0. 5 mg/m L in 10 m L vials; Centrine® (Fort Dodge); (Rx). Approved for use in dogs and cats only. HUm AN­l Ab El ED PRODUCTS: None Aminophylline theophylline (am-in-off-i-lin); (thee-off-i-lin) ph Osph Odiesterase inhibit Or br Onch Odilat Or Prescriber Highlights Bronchodilator drug with diuretic activity; used for bron-T T chospasm & cardiogenic pul monary edema Narrow therapeutic index in humans, but dogs appear to be T T less susceptible to toxic effects at higher plasma levels Therapeutic drug monitoring recommended T T Many drug interactions T T Uses/Indications The theophyllines are used primarily for their bronchodilatory ef-fects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity. Pharmacology/Actions The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of c AMP may also

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38 Am INOPHyll INE; THEOPHyll INE inhibit the release of histamine and slow reacting substance of ana-phylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess may be a result of translocating intracellular ionized calcium. The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chrono-tropic and inotropic action, stimulate the CNS and can cause respi-ratory stimulation (centrally-mediated). Pharmacokinetics The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sus-tained release products are used. One study in dogs that compared various sustained-release products (Koritz, Neff-Davis, and Munsiff 1986), found bioavailabilities ranging from approximately 30-76% depending on the product used. Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the pla centa and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distri-bution of theophylline for dogs has been reported to be 0. 82 L/kg. The volume of distribution in cats is reported to be 0. 46 L/kg, and in horses, 0. 85-1. 02 L/kg. Because of the low volumes of distribu-tion and theophylline's low lipid solubility, obese patients should be dosed on a lean body weight basis. Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weak bronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clear-ance of theophylline. The reported elimination half-lives (mean val-ues) in various species are: dogs ≈ 5. 7 hours; cats ≈ 7. 8 hours, pigs ≈ 11 hours; and horses ≈ 11. 9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be ex pected that similar variability exists in veteri-nary patients, particularly those with concurrent ill nesses. Contraindications/Precautions/Warnings The theophyllines are contraindicated in patients who are hyper-sensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline. The theophyllines should be administered with caution in pa-tients with severe cardiac disease, seizure disorders, gas tric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Be cause it may cause or worsen preexisting arrhyth-mias, patients with cardiac arrhythmias should re ceive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline. Adverse Effects The theophyllines can produce CNS stimulation and gastrointesti-nal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in con junction with monitoring and dosage adjustments. Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid se cretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose re lated and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Clinical signs of toxicity (see above) are usually associated with lev-els greater than 20 mcg/m L in humans and become more severe as the serum level exceeds that value. Tachy cardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/m L. Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic ad-ministered using the standardized methods and cautions associ ated with these practices. Patients suffering from seizures should have an adequate airway main tained and treated with IV diazepam. The pa-tient should be constantly monitored for cardiac ar rhythmias and tachycardia. Fluid and electrolytes should be monitored and cor-rected as necessary. Hyperthermia may be treated with phenothiaz-ines and tachycardia treated with propranolol if either condition is considered life threatening. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aminophylline or theo-phylline and may be of significance in veterinary patients: The following drugs can decrease theophylline levels: b ARb ITURATEST! (phenobarbital ) CARb Am Az EPINET! (may increase or decrease levels) CHARCOAl T! Hy DANTOINST! (phenytoin ) ISONIAz IDT! (may increase or decrease levels) KETOCONAz Ol ET! l OOP DIURETICST! (furosemide ); (may increase or decrease levels) RIFAm PINT! Sym PATHOm Im ETICST! (beta­agonists ) The following drugs can increase theophylline levels: All OPURINOl T! b ETA­bl OCKERST! (non­selective such as propranolol ) CAl CIUm CHANNEl bl OCKERS T! (e. g., diltiazem, verapamil ) CIm ETIDINET! CORTICOSTEROIDST! Fl UOROQUINOl ONEST! (enrofloxacin, ciprofloxacin ): If adding either, consider reducing the dose of theophylline by 30%. Monitor for toxic ity/efficacy. Marbofloxacin reduces clearance of theophylline in dogs, but not with clinical significance. In animals with renal impairment, marbofloxacin may interfere with theophylline me-tabolism in a clinically relevant manner. m ACROl IDEST! (e. g., erythromycin; clindamycin, lincomycin ) THIAb ENDAz Ol ET! THy ROID HORm ONEST! (in hypothyroid patients) THEOPHyll INE T! may decrease the effects of following drugs: b ENz ODIAz EPINEST!

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Am INOPHyll INE; THEOPHyll INE 39 l ITHIUm T! PANCURONIUm T! PROPOFOl T! EPHEDRINE, ISOPROTERENOl T! : T oxic synergism (arrhythmias) can occur if theophylline is used concurrently with sympathomimet-ics (especially ephedrine) or possibly isoproterenol HAl OTHANET! : Theophylline with halothane may cause in creased in-cidence of cardiac dysrhythmias KETAm INET! : Theophylline with ketamine can cause an increased incidence of seizures laboratory Considerations Theophylline can cause falsely elevated values of serum T! uric acid if measured by the Bittner or colorimetric methods. Values are not affected if using the uricase method. Theophylline serum levels can be falsely elevated by T! furosemide, phenylbutazone, probenecid, theobromine, caffeine, sulfathiazole, chocolate, or acetaminophen if using a spectrophotometric meth-od of assay. Doses Note : Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline's pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route. DOg S:T! a) Using Theochron® Extended-Release Tablets or Theo-Cap® Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the de-sired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. (Bach, Ku Kanich et al. 2004) b) For adjunctive medical therapy for mild clinical signs associ-ated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. (Fossom 2005) c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. (Ware 2003) d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily (Anderson-Westberg 2005) e) As a bronchodilator tor collapsing trachea: 11 mg/kg PO or IV q6-12h (Ettinger and Kantrowitz 2005) CATS:T! a) Using Theo-Dur®: 20 mg/kg PO once daily in the PM; using Slo-Bid®: 25 mg/kg PO once daily in the PM (Johnson 2000) [ Note : The products Theo-Dur® and Slo-Bid® mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al—Plumb] b) Using aminophylline tablets: 6. 6. mg/kg PO twice daily; us-ing sustained release tablets (Theo-Dur®): 25-50 mg (total dose) per cat PO in the evening (Noone 1999) c) For adjunctive medical therapy for mild clinical signs associ-ated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. (Fossom 2005)d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. (Ware 2003) e) For cough: Aminophylline: 5 mg/kg PO twice daily (Ander-son-Westberg 2005) FERRETS:T! a) 4. 25 mg/kg PO 2-3 times a day (Williams 2000) HORSES:T! (Note : ARCI UCGFS Class 3 Drug) NOTE : Intravenous aminophylline should be diluted in at least 100 m L of D 5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema: a) Aminophylline 2-7 mg/kg IV q6-12h; Theophylline 5-15 mg/kg PO q12h (Mogg 1999) b) 11 mg/kg PO or IV q8-12h. T o “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitor-ing serum levels. (Foreman 1999) For adjunctive treatment for heaves (RAO): a) Aminophylline: 5-10 mg/kg PO or IV twice daily. (Lavoie 2003) b) Aminophylline: 4-6 mg/kg PO three times a day. (Ainsworth and Hackett 2004) monitoring Therapeutic efficacy and clinical signs of toxicity T! Serum levels at steady state. The therapeutic serum levels of T! theophylline in humans are generally described to be between 10-20 micrograms/m L. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/m L ( Note : Some recom-mend not exceeding 15 micrograms/m L in horses). Client Information Give dosage as prescribed by veterinarian to maximize the drug's T! benefit Chemistry/Synonyms Xanthine derivatives, aminophylline and theophylline are consid-ered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theo-phylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydra-tion. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous);100 mg of aminophylline (an-hydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous). Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a p K a of 5. Aminophylline is soluble in water and insoluble in alcohol. Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point be tween 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a p H of 7, but solubility increases with increasing p H. Aminophylline may also be known as: aminofilina, aminophyl-linum, euphyllinum, metaphyllin, theophyllaminum, theophyl-line and ethylenediamine, theophylline ethylenediamine com-pound, or theophyllinum ethylenediaminum; many trade names are available.

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40 Am IODARONE HCl Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available. Storage/Stability/Compatibility Unless otherwise specified by the manufacturer, store aminophyl-line and theophylline oral products in tight, light-resistant contain-ers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible. Aminophylline for injection should be stored in single-use con-tainers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freez-ing and light. Upon exposure to air (carbon dioxide), aminophyl-line will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals. Aminophylline for injection is reportedly compatible when mixed with all commonly used IV so lutions, but may be incompatible with 10% fructose or invert sugar solutions. Aminophylline is reportedly compatible when mixed with the fol-lowing drugs: amobarbital sodium, bretylium tosylate, calcium glu-conate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCl, erythromycin lactobionate, heparin so-dium, hydrocortisone sodium succinate, lidocaine HCl, mephenter-mine sulfate, methicillin sodium, methyldopate HCl, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital so-dium, potassium chloride, secobarbital sodium, sodium bicarbon-ate, sodium iodide, terbutaline sulfate, thiopental sodium, and vera-pamil HCl. Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleo-mycin sulfate, cephalothin sodium, cephapirin sodium, clin damycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCl, doxoru bicin HCl, epinephrine HCl, erythromycin gluceptate, hydralazine HCl, hydroxyzine HCl, insulin (regular), iso-proterenol HCl, levorphanol bitartrate, meperidine HCl, methadone HCl, methylpred nisolone sodium succinate, morphine sulfate, naf-cillin sodium, norepinephrine bitartrate, oxytetra cycline, penicillin G potassium, pentazocine lactate, procaine HCl, prochlorperazine edisylate or me sylate, promazine HCl, promethazine HCl, sulfisox-azole diolamine, tetracycline HCl, vancomycin HCl, and vitamin B complex with C. Compatibility is dependent upon factors such as p H, concentra tion, temperature, and diluent used and it is suggested to consult specialized references for more specific information. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: The listing below is a sampling of products and sizes available; con-sult specialized references for a more complete listing. Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx) Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) m L in 10 m L & 20 m L vials, amps and syringes; generic; (Rx) Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. ( Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24® (UCB Pharma); Theophylline SR (various); Theochron® (Forest, various); Theophylline (Able); Theo-cron® (Inwood); Uniphyl® (Purdue Frederick); generic; (Rx) Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl® (Winthrop); Elixophyllin® (Forest); generic; (Rx) Theophylline Elixir: 80 mg/15 m L (26. 7 mg/5 m L) in pt, gal, UD 15 and 30 m L, Asmalix® (Century); Elixophyllin® (Forest); Lanophyllin® (Lannett); generic; (Rx) Theophylline & Dextrose Injection: 200 mg/container in 50 m L (4 mg/m L) & 100 m L (2 mg/m L); 400 mg/container in 100 m L (4 mg/m L), 250 m L (1. 6 mg/m L), 500 m L (0. 8 mg/m L) & 1000 m L (0. 4 mg/m L); 800 mg/container in 250 m L (3. 2 mg/m L), 500 m L (1. 6 mg/m L) & 1000 m L (0. 8 mg/m L); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx) Amiod Arone hcl (a-mee-oh-da-rone) Cordarone®, Pacerone® class iii antiarrhythmic Prescriber Highlights Antidysrhythmic agent that can be used in dogs for ar-T T rhythmias associated with left ventricular dysfunction or to convert atrial fib into sinus rhythm; very limited experi-ence warrants cautious use May be useful in horses to convert atrial fib or V tach into T T sinus rhythm Contraindicated in 2nd, 3rd degree heart block, T T bradyarrhythmias In T TDOGS: GI disturbances (vomiting, anorexia) most likely adverse effect, but neutropenia, thrombocytopenia, bra-dycardia, hepatotoxicity, positive Coombs' test reported In T THORSES: Limited use, accurate adverse effect profile to be determined; Hind limb weakness, increased biliru-bin reported when used IV to convert atrial fib Many drug interactions T T Uses/Indications Because of its potential toxicity and lack of experience with use in canine and equine patients, amiodarone is usually used when other less toxic or commonly used drugs are ineffective. It may be useful in dogs and horses to convert atrial fib into sinus rhythm and in dogs for arrhythmias associated with left ventricular dysfunction. In horses, one horse with Ventricular tachycardia was converted into sinus rhythm using amiodarone. As the risk of sudden death is high in Doberman pinschers exhib-iting rapid, wide-complex ventricular tachycardia or syncope with recurrent VPC's, amiodarone may be useful when other drug thera-pies are ineffec tive. Pharmacology/Actions Amiodarone's mechanism of action is not fully understood; it ap-parently is a potassium channel blocker that possesses unique phar-macology from other antiarrhythmic agents. It can be best classi-

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Am IODARONE HCl 41 fied a Class III antiarrhythmic agent that also blocks sodium and calcium channels, and beta-adrenergic receptors. Major properties include prolongation of myocardial cell action-potential duration and refractory period. Pharmacokinetics Amiodarone may be administered parenterally or orally. Amiodarone is widely distributed throughout the body and can ac-cumulate in adipose tissue. Amiodarone is metabolized by the liver into the active metabolite desethylamiodarone. After oral adminis-tration of a single dose in normal dogs, amiodarone's plasma half-life averaged 7. 5 hours, but repeated dosing increased its half-life from 11 hours to 3. 2 days. In horses, amiodarone has a low oral bioavailability (range from 6-34%) and peak levels of amiodarone and desethylamiodarone occur about 7-8 hours after an oral dose. After IV administration amiodarone is rapidly distributed with a high apparent volume of distribution of 31 L/kg. In horses, amiodarone is relatively high-ly bound to plasma proteins (96%). Clearance was 0. 35 L/kg/hr and median elimination half-lives for amiodarone and desethyla-miodarone were approximately 51 and 75 hours, respectively (De Clercq, Baert et al. 2006). In humans, oral absorption is slow and variable, with bioavail-abilities ranging from 22-86%. Elimination half-lives for amio-darone and desethylamiodarone range from 2. 5-10 days after a single dose, but with chronic dosing, average 53 days and 60 days, respectively. Contraindications/Precautions/Warnings Amiodarone is considered contraindicated in patients (humans) hypersensitive to it, having severe sinus-node dysfunction with se-vere sinus brady cardia, 2nd or 3rd degree heart block, or bradycar-dial syncope. Clinical experience in veterinary patients is limited. Consider use only when other less toxic and more com monly used drugs are ineffective. Adverse Effects Gastrointestinal effects (e. g., anorexia, vomiting) are apparently the most likely adverse effects seen in the limited number of canine patients treated. Hepatopathy (bilirubinemia, increased hepatic enzymes) has been reported in dogs on amiodarone. Because he-patic effects can occur before clinical signs are noted, routine serial evaluation of liver enzymes and bilirubin is recommended. Other adverse effects reported in dogs include bradycardia, neutropenia, thrombocytopenia, or positive Coombs' test. During IV infusion, pain at injection site, and facial pruritus and hyperemia have been noted. Corneal deposits may be seen in dogs treated with amio-darone, but this affect apparently occurs less frequently in dogs than in humans. In human patients, adverse effects are very common while on amiodarone therapy. Those that most commonly cause discontinu-ation of the drug include: pulmonary infiltrates or pulmonary fi-brosis (sometimes fatal), liver enzyme elevations, congestive heart failure, paroxysmal ventricular tachy cardia, and thyroid dysfunc-tion (hypo-or hyperthyroidism). An odd effect seen in some indi-viduals is a bluish cast to their skin. Reversible corneal deposits are seen in a majority of humans treated with amiodarone. Clinical experience in dogs is limited; the adverse effect profile of this drug in people warrants its use in veterinary patients only when other less toxic agents are ineffective and treatment is deemed necessary. Reproductive/Nursing Safety In laboratory animals, amiodarone has been embryotoxic at high doses and congenital thyroid ab normalities have been detected in offspring. Use during pregnancy only when the potential benefits outweigh the risks of the drug. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Overdosage/Acute Toxicity Clinical overdosage experience is limited; most likely adverse effects seen are hy potension, bradycardia, cardiogenic shock, A V block, and hepatotoxicity. Treatment is supportive. Bradycardia may be managed with a pacemaker or beta-1 agonists (e. g., isoproterenol); hypotension managed with positive inotropic agents or vasopres-sors. Neither amiodarone nor its active metabolite are dialyzable. Drug Interactions Several potentially significant interactions may occur with amio-darone. The following is a partial list of interactions that have either been reported or are theoretical in humans or animals receiving amiodarone and may be of significance in veterinary patients: Amiodarone may significantly increase the serum levels and/or pharmacologic or toxic effects of: ANTI COAg Ul ANTS!! (warfarin ) DIg Ox IN!! Cy Cl OSPORINE!! l IDOCAINE!! m ETHOTREx ATE!! (with prolonged amiodarone administration ) PHENy TOIN!! PROCAINAm IDE!! QUINIDINE!! Amiodarone may have additive effects on QTc interval ; possible seri-ous arrhythmias may result: Az Ol E ANTIFUNg Al S!! (ketoconazole, itraconazole, etc. ) CISAPRIDE!! DISOPy RAm IDE!! DOl ASETRON!! Fl UOROQUINOl ONE ANTIb IOTICS !! (some, such as moxifloxacin, not en­ rofloxacin, marbofloxacin, etc. ) m ACROl IDE ANTIb IOTICS!! (e. g., erythromycin ) Other amiodarone drug interactions: ANESTHETICS, g ENERAl !! : Increased risks for hypotension or arrhythmias b ETA­ADRENERg IC bl OCKERS !! : Possible potentiation of bradycardia, A V block or sinus arrest CAl CIUm­CHANNEl bl OCKERS !! (e. g., diltiazem, verapamil ): Possible potentiation of bradycardia, A V block or sinus arrest CIm ETIDINE!! : Increased amiodarone levels Cy Cl OSPORINE!! : Increased cyclosporine levels; may increase creatinine FENTANyl!! : Possible hypotension, bradycardia RIFAm PIN!! : Decreased amiodarone levels laboratory Considerations While most human patients remain euthyroid while receiving T! amiodarone, it may cause an increase in serum T4 and serum re-verse T 3 levels, and a reduction in serum T 3 lev els The human therapeutic serum concentrations of 1-2. 5 mcg/m L T! are believed to apply to dogs as well Amiodarone may cause a T! positive Coombs' test result

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42 Am ITRIPTyl INE HCl Doses Note : Some human references state that because of the potential for drug interactions with previous drug therapies, the life-threatening nature of the arrhythmias being treated, and the unpredictability of response from amiodarone, the drug should be initially given (loaded) over several days in an inpatient setting where adequate monitoring can occur. DOg S:T! For conversion of atrial fibrillation: a) At the time of writing (2007) one case report (Oyama and Prosek 2006) and one retrospective evaluation (Saunders, Miller et al. 2006) have been published using amiodarone to convert atrial fibrillation in dogs. Dosage recommendations are yet to be fully defined; monitor the current literature for further recommendations. For recurrent ventricular tachycardia not controlled with other less toxic drugs:a) 10-25 mg/kg PO twice daily for 7 days, followed by 5-7. 5 mg/kg PO twice daily for 14 days, followed by 7. 5 mg/kg PO once daily (Calvert 1995) b) For ventricular arrhythmias secondary to occult cardiomyo-pathy in Doberman pinschers: 10 mg/kg PO twice daily for one week and then 8 mg/kg PO once daily. For severe V-Tach, mex iletine is added at 5-8 mg/kg three times daily for one week. Once efficacy confirmed, patient weaned off mexiletine. (Calvert and Mieurs 2000) c) Amiodarone as above in “b”, but after 6 months may be re-duced to 5 mg/kg once daily. (Meurs 2005) d) 10-20 mg/kg PO q12h (Fox 2003a) HORSES: T! For conversion of atrial fibrillation or ventricular tachycardia: a) 5 mg/kg/hr for one hour, followed by 0. 83 mg/kg/hr for 23 hours and then 1. 9 mg/kg/hour for the following 30 hours. In the study (A fib), infusion was discontinued when con-version occurred or when any side effects were noted. 4 of 6 horses converted from A fib; one horse from V tach. In order to increase success rate and decrease adverse effects, regimen should be further adapted based upon PK/PD studies in hors-es. (De Clercq, van Loon et al. 2006a), (De Clercq, van Loon et al. 2006b) monitoring Efficacy (ECG) T! T oxicity (GI effects; CBC, serial liver enzymes; thyroid function T! tests; blood pressure; pul monary radiographs if clinical signs such as dyspnea/cough occur) Client Information Because of the “experimental” nature (relatively few canine/equine T! patients have re ceived this agent) and the toxicity dangers associ-ated with its use, clients should give informed con sent before the drug is prescribed. Chemistry/Synonyms An iodinated benzofuran, amiodarone is unique structurally and pharmacologically from other antiarrhythmic agents. It occurs as a white to cream colored lipophilic powder having a p Ka of approxi-mately 6. 6. Amiodarone 200 mg tablets each contain approximately 75 mg of iodine. Amiodarone HCl may also be known as: amiodaroni hydrochlo-ridum, L-3428, 51087N, or SKF-33134-A; many trade names are available. Storage/Stability/Compatibility Tablets should be stored in tight containers, at room temperature and protected from light. A 3-year expiration date is assigned from the date of manufacture. Injection should be stored at room temperature and protected from light or excessive heat. While administering, light protection is not necessary. Use D5W as the IV diluent. Amiodarone is report-edly compatible with dobutamine, lidocaine, potassium chloride, procainamide, propafenone, and verapamil. Variable compatibility is reported with furosemide and quinidine gluconate. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Amiodarone Oral Tablets: 100 mg, 200 mg & 400 mg; Cordarone® (Wyeth-Ayerst); Pacerone® (Upsher Smith); generic; (Rx) Amiodarone Concentrate for Injection (for IV Infusion): 50 mg/m L in 3 m L amps & vials; Cordarone® (Wyeth-Ayerst); generic; (Rx) Amitraz — See the Topical Dermatologic Agents section in the appendix Amitriptyline hcl (a-mih-trip-ti-leen) Elavil® tricyclic beha vi Or m Odifier; anti-pruritic; neur Opathic p ain m Odifier Prescriber Highlights Tricyclic “antidepressant” used primarily for behavior dis-T T orders & neuropathic pain/pruritus in small animals May reduce seizure thresholds in epileptic animals T T Sedation & anticholinergic effects most likely adverse T T effects Overdoses can be very serious in both animals & humans T T Uses/Indications Amitriptyline has been used for behavioral conditions such as sepa-ration anxiety or generalized anxiety in dogs, and excessive groom-ing, spraying and anxiety in cats. Amitriptyline may be useful for adjunctive treatment of pruritus, or chronic pain of neuropathic origin in dogs and cats. In cats, it potentially could be useful for ad-junctive treatment of lower urinary tract disease. Amitriptyline has been tried to reduce feather plucking in birds. Pharmacology/Actions Amitriptyline (and its active metabolite, nortriptyline) has a com-plicated pharmaco logic profile. From a slightly oversimplified view-point, it has 3 main characteristics: blockage of the amine pump, thereby increasing neurotransmitter levels (principally serotonin, but also nore pinephrine), sedation, and central and peripheral anti-cholinergic activity. Other pharmacologic effects include stabilizing mast cells via H-1 receptor antagonism, and antagonism of gluta-mate receptors and sodium channels. In animals, tricyclic antide-pressants are similar to the actions of phenothiazines in altering avoidance behaviors.

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Am ITRIPTyl INE HCl 43 Pharmacokinetics Amitriptyline is rapidly absorbed from both the GI tract and from parenteral in jection sites. Peak levels occur within 2-12 hours. Amitriptyline is highly bound to plasma proteins, enters the CNS, and enters maternal milk in levels at, or greater than those found in maternal serum. The drug is metabolized in the liver to several me-tabolites, including nortriptyline, which is active. In humans, the terminal half-life is approximately 30 hours. Half-life in dogs has been reported to be 6-8 hours. Contraindications/Precautions/Warnings These agents are contraindicated if prior sensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxi dase inhibitors is generally contraindicated. Use with extreme caution in patients with seizure disorders as tricyclic agents may reduce sei-zure thresholds. Use with caution in patients with thyroid disor-ders, hepatic disorders, KCS, glaucoma, cardiac rhythm disorders, diabetes, or adrenal tumors. Adverse Effects The most predominant adverse effects seen with the tricyclics are re lated to their sedating and anticholinergic (constipation, urinary retention) properties. Occasionally, dogs exhibit hyperexcitability and, rarely, develop seizures. However, adverse effects can run the entire gamut of systems, including cardiac (dysrhythmias), hema-tologic (bone marrow suppression), GI (diarrhea, vomiting), en-docrine, etc. Cats may demonstrate the following adverse effects: sedation, hypersalivation, urinary retention, anorexia, thrombo-cytopenia, neutropenia, unkempt hair coat, vomiting, ataxia, dis-orientation and cardiac conductivity disturbances. Reproductive/Nursing Safety Isolated reports of limb reduction abnormalities have been noted; restrict use to pregnant animals only when the benefits clearly out-weigh the risks. In humans, the FDA categorizes this drug as cat-egory D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Overdosage/Acute Toxicity Overdosage with tricyclics can be life-threatening (arrhythmias, car diorespiratory collapse). Because the toxicities and therapies for treatment are complicated and con troversial, it is recommended to contact a poison control center for further information in any poten tial overdose situation. There were 25 exposures to amitriptyline reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases, 21 were cats with 5 showing clini-cal signs. Common findings recorded in decreasing frequency in-cluded: anorexia, mydriasis and adipsia. The remaining 4 cases were dogs with no reported clinical signs. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amitriptyline and may be of significance in veterinary patients: ANTICHOl INERg IC Ag ENTS!! : Increased effects; hyperthermia and ileus possible CIm ETIDINE!! : May inhibit tricyclic antidepressant metabolism and increase the risk of toxicity CISAPRIDE!! : May have additive effects on QTc interval; possible se-rious arrhythmias may result CNS !! DEPRESSANTS : Increased effects DIAz EPAm!! : Possible increased amitriptyline levelsm ONOAm INE Ox IDASE INHIb ITORS!! (including selegilene, amitraz ): Potential life threatening serotonin syndrome; use together not recommended SEl ECTIVE­SEROTONIN RE­UPTAKE INHIb ITORS !! (SSRIs, fluoxetine, etc. ): Potential increased amitriptyline levels, increased risk for sero-tonin syndrome; Note : SSRI's and TCA 's etc. amitriptyline are of-ten used together in veterinary behavior medicine, but enhanced monitoring for adverse effects is suggested) Sym PATHOm Im ETIC!! Ag ENTS : May increase the risk of cardiac effects (arrhythmias, hypertension, hyperpyrexia) THy ROID Ag ENTS!! : Increased risk for arrhythmias; monitor laboratory Considerations Tricyclics can widen QRS complexes, prolong PR intervals and T! in vert or flatten T-waves on ECg The response to T! metapyrone may be decreased by amitriptyline Tricyclics may alter (increase or decrease) T! blood glucose levels Doses DOg S:T! For adjunctive treatment of pruritus: a) 1-2 mg/kg PO q12h (Paradis and Scott 1992) b) For acral pruritic dermatitis: 2. 2 mg/kg PO twice daily; only occasionally effective. A 2-4 week trial is recommended (Rosychuck 1991) For behavior disorders amenable to tricyclics:a) For separation anxiety or generalized anxiety: 1-2 mg/kg PO q12h; with behavior modi fication (Shanley and Overall 1992); (Line 2000); (Overall 2000) b) 1-4 mg/kg PO q12h. Begin at 1-2 mg/kg PO q12h for 2 weeks, increase by 1 mg/kg up to maximum dosage (4 mg/kg) as necessary. If no clinical response, decrease by 1 mg/kg PO q12h for 2 weeks until at initial dosage. (Virga 2002) c) 2. 2-4. 4 mg/kg PO q12h (Reisner and Houpt 2000) d) 0. 25-1. 5 mg/kg PO every 12-24h (Crowell-Davis 1999) For neuropathic pain: a) 1-2 mg/kg PO q12-24h (Hardie 2000) b) For adjunctive treatment of pain associated with appendicu-lar osteosarcoma: 1-2 mg/kg PO q12-24h (Liptak and Eh-rhart 2005) CATS:T! For adjunctive treatment of behavior disorders amenable to tri-cyclics:a) 5-10 mg per cat PO once daily (Miller 1989), (Marder 1991), (Reisner and Houpt 2000) b) 0. 5-2 mg/kg PO q12-24h; start at 0. 5 mg/kg PO q12h (Overall 2000) c) 0. 5 -1 mg/kg PO q12-24h (Crowell-Davis 1999) d) 0. 5-1 mg/kg PO q12-24h. Allow 3-4 weeks for initial trial. (Virga 2002) For self-mutilation behaviors associated with anxiety:a) 5-10 mg per cat PO once to twice daily; with behavior mod-ification (Shanley and Overall 1992) b) 1-2 mg/kg PO q12h (Line 2000) For pruritus (after other more conventional therapies have failed): a) 5-10 mg per cat PO once daily or 2. 5-7. 5 mg/cat once to twice daily. When discontinu ing, taper dose over 1-3 weeks. (Messinger 2000)

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44 Aml ODIPINE b ESyl ATE For symptomatic therapy of idiopathic feline lower urinary tract disease:a) 2. 5-12. 5 mg (total dose) PO once daily at night (Bartges 2006e) b) 5-10 mg (total dose) PO once daily at night; the drug is in popular use at present and further studies are needed (Senior 2006) c) Reserved for cases with severe, recurrent signs; 2. 5-12. 5 mg (total dose) PO at the time the owner retires for the night. Dosage is adjusted to produce a barely perceptible calming effect on the cat. If no improvement is seen within 2 months, the medication may be gradually tapered and then stopped. (Buffington 2006) For neuropathic pain: a) 2. 5-12. 5 mg/cat PO once daily (Hardie 2000) b) 0. 5-2 mg/kg PO once daily; may be a useful addition to NSAIDs for chronic pain. (Lascelles, Robertson et al. 2003) b IRDS:T! For adjunctive treatment of feather plucking: a) 1-2 mg/kg PO q12-24 hours. Anecdotal reports indicate some usefulness. Barring side effects, may be worth a more prolonged course of therapy to determine efficacy. (Lightfoot 2001) monitoring Efficacy T! Adverse effects; it is recommended to perform a cardiac evalua-T! tion, CBC and serum chemistry panel prior to therapy For cats, some clinicians recommend that liver enzymes be mea-T! sured prior to therapy, one month after initial therapy, and yearly, thereafter Client Information All tricyclics should be dispensed in child-resistant packaging and T! kept well away from children or pets. Several weeks may be required before efficacy is noted and to con-T! tinue dosing as prescribed. Do not abruptly stop giving medica-tion without veterinarian's advice. Chemistry/Synonyms A tricyclic dibenzocycloheptene-derivative antidepressant, amitrip-tyline HCl occurs as a white or practically white, odorless or practi-cally odorless crystalline powder that is freely soluble in water or alcohol. It has a bitter, burning taste and a p K a of 9. 4. Amitriptyline may also be known as amitriptylini hydrochlo-ridum; many trade names are available. Storage/Stability Amitriptyline tablets should be stored at room temperature. The in-jection should be kept from freezing and protected from light. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Amitriptyline HCl Tablets: 10, 25, 50, 75, 100, 150 mg; generic; (Rx) There are also fixed dose oral combination products contain-ing amitriptyline and chlordiazepox ide, and amitriptyline and perphenazine. Amlodipine besyl A te (am-loe-di-peen) Norvasc® calcium channel bl Ocker Prescriber Highlights Calcium channel blocker used most often for treating T T hypertension, especially in cats Slight negative inotrope; use with caution in patients with T T heart disease, hepatic dysfunction Potentially may cause anorexia & hypotension in cats T T early in therapy Hypertension may rapidly reoccur if dosages are missed T T Uses/Indications Oral amlodipine appears to be a useful agent in the treatment of hypertension in cats and many consider it the drug of choice for this indication. In pharmacokinetic studies, amlodipine has decreased blood pressure in dogs with chronic renal disease, but its efficacy in treat ing hypertensive dogs has been disappointing. Hypertension in cats is usually secondary to other diseases (often renal failure or cardiac causes such as thyrotoxic cardiomyopathy or primary hypertrophic cardiomyopathy, etc. ) and is most often seen in middle-aged or geriatric cats. These animals often present with acute clinical signs such as blindness, seizures, collapse or paresis. A cat is generally considered hypertensive if systolic blood pressure is >160 mm Hg. Early reports indicate that if antihypertensive therapy is begun acutely, some vision may be restored in about 50% of cases of blindness secondary to hypertension. Pharmacology/Actions Amlodipine inhibits calcium influx across cell membranes in both cardiac and vas cular smooth muscle. It has a greater effect on vascu-lar smooth muscle, thereby acting as a periph eral arteriolar vasodila-tor and reducing afterload. Amlodipine also depresses impulse for-mation (automaticity) and conduction velocity in cardiac muscle. Pharmacokinetics No feline-specific data on the drug's pharmacokinetics was locat-ed. In humans, amlodipine's bioavailability does not appear to be altered by the presence of food in the gut. The drug is slowly but almost completely absorbed after oral administration. Peak plasma concentrations occur between 6-9 hours post-dose and effects on blood pressure are correspondingly delayed. The drug has very high plasma protein binding characteristics (approximately 93%). However, drug in teractions associated with potential displacement from these sites have not been elucidated. Am lodipine is slowly, but extensively metabolized to inactive compounds in the liver. T erminal plasma half-life is approximately 35 hours in healthy humans, but is prolonged in the elderly and in those patients with hypertension or hepatic dysfunction. Contraindications/Precautions/Warnings Because amlodipine may have slight nega tive inotropic effects, it should be used cautiously in patients with heart failure or cardio-genic shock. It should also be used cautiously in patients with he-patic disease or at risk for developing hypoten sion. A relative con-traindication for amlodipine exists for humans with advanced aortic stenosis.

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Aml ODIPINE b ESyl ATE 45 There is concern that using amlodipine alone for treating hy-pertension in cats with renal disease may expose glomeruli to higher pressures secondary to efferent arteriolar constriction. This is caused by localized increases in renin-angiotensin-aldosterone axis activity thereby allowing progressive damage to glomeruli. It is postulated that using an ACE inhibitor with amlodipine may help prevent this occurrence (Stepian 2006a). Adverse Effects Because of amlodipine's relatively slow onset of action, hypoten-sion and inappetence is usually absent in cats. Infrequently, cats may develop azotemia, lethargy, hypokalemia, reflex tachycardia and weight loss. In humans taking amlodipine, headache (7. 3% in-cidence) is the most frequent problem reported. Reproductive/Nursing Safety While no evidence of im paired fertility was noted in rats given 8X overdoses, amlodipine has been shown to be fetotoxic (intrauterine death rates increased 5 fold) in laboratory animals (rats, rabbits) at very high dosages. No evidence of teratogenicity or mutagenicity was observed in lab animal studies. In rats, amlodip ine prolonged labor. It is unknown whether amlodipine enters maternal milk. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity There were 69 exposures to amlodipine reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 59 were dogs with 7 showing clini-cal signs; the remaining 10 cases were cats with 2 showing clinical signs. Common findings in dogs, recorded in decreasing frequency included anorexia, lethargy, tachycardia, acidosis and bradycardia. Common findings in cats, recorded in decreasing frequency includ-ed lethargy and polydipsia. Limited experience with other calcium channel block ers in hu-mans has shown that profound hypotension and bradycardia may result. When possible, massive overdoses should be managed with gut emptying and supportive treatment. Beta-agonists and intrave-nous calcium may be beneficial. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amlodipine and may be of significance in veterinary patients: No clinically significant drug-drug interactions have been noted specifically with amlodipine at this time. However, concomitant use of diuretics, beta­blockers, other vasodila tors or other agents that may reduce blood pressure (e. g., fentanyl ) may cause hypotension if used with amlodipine. grapefruit juice/powder may alter bioavailability. laboratory Considerations No specific concerns were noted Doses CATS:T! For treatment of systemic hypertension:a) 0. 625 mg (1/4 of a 2. 5 mg tablet) PO once daily; some larger cats (>4 kg) or those with severe hypertension may require doses as high as 1. 25 mg PO twice daily. Titrate dosage care-fully, based upon BP determinations. (Brown and Henik 2000); (Trepanier 1999)b) 0. 625-1. 25 mg (total dose) PO once daily. Drug of choice; often successful as a single agent. Can be combined with an ACEI, beta-blocker or diuretic if needed. Maximum effect seen within 7 days of therapy. (Sparkes 2003a) DOg S:T! For adjunctive therapy for refractory heart failure:a) For treatment of advanced mitral valve degeneration as an afterload reducer after ACE inhibitor maintenance therapy has been established: 0. 2-0. 4 mg/kg PO twice daily. Initiate therapy at 0. 1 mg/kg PO twice daily and up-titrate weekly while monitoring blood pressure. (Kraus 2003) b) As an arterial vasodilator particularly in dogs moderately re-fractory, or recurrent CHF secondary to mitral regurgitation and maintained blood pressures: 0. 1 mg/kg q12-24h initial-ly; titrate up as needed to 0. 25 mg/kg PO q12-24h; monitor blood pressure. (De Francesco 2006) For treatment of systemic hypertension in dogs with chronic re-nal disease:a) 0. 05-0. 25 mg/kg PO once daily. In many dogs, amlodipine appears to be less effective, even at high doses (1 mg/kg/day). (Brown, Brown et al. 2006) b) 0. 1-0. 2 mg/kg PO q12-24h (Stepian 2006a) monitoring Blood pressure T! Ophthalmic exam T! Adverse effects T! Client Information May give with food T! Missing dosages can cause rapid redevelopment of symptoms T! and damage secondary to hypertension Chemistry/Synonyms Amlodipine besylate, a dihydropyridine calcium channel-blocking agent, occurs as a white crystalline powder that is slightly soluble in water and sparingly soluble in alcohol. Amlodipine Besylate may also as: amlodipini besilas, UK-48340-26, or UK-48340-11 (amlodipine maleate); many trade names are available. Storage/Stability Store amlodipine tablets at room temperature, in tight, light resis-tant containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Amlodipine Tablets: 2. 5 mg, 5 mg, 10 mg; Norvasc® (Pfizer); Am-vaz® (Reddy); (Rx) Fixed-dose combination products with benazepril (Lotrel ®) or atorvastatin (Caduet®) are available.

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46 Amm ONIUm CHl ORIDE Ammonium chloride (ah-moe-nee-um) Uroeze® acidifying agent Prescriber Highlights Urinary acidifier; treatment of metabolic alkalosis T T Contraindicated in patients with hepatic failure or uremia T T Potential adverse effects are primarily GI distress; IV use T T may lead to metabolic acidosis May increase excretion of quinidine; decrease efficacy of T T erythromycin or aminoglyco sides in urine Uses/Indications The veterinary indications for ammonium chloride are as a urinary acidifying agent to help prevent and dissolve certain types of uroliths (e. g., struvite), to enhance renal excretion of some types of toxins (e. g., strontium, strychnine) or drugs (e. g., quinidine), or to enhance the efficacy of cer tain antimicrobials (e. g., chlortetracycline, meth-enamine mandelate, nitrofurantoin, oxytetracycline, penicillin G or tetracycline) when treating urinary tract infections. Ammonium chloride has also been used intravenously for the rapid correction of metabolic alkalosis. Because of changes in feline diets to restrict struvite and as stru-vite therapeutic diets (e. g., s/d) cause aciduria, ammonium chloride is not commonly recommended for struvite uroliths in cats. Pharmacology/Actions The acidification properties of ammonium chloride are caused by its dissociation into chloride and ammonium ions in vivo. The am-monium cation is converted by the liver to urea with the release of a hydrogen ion. This ion combines with bicarbonate to form water and carbon dioxide. In the extracellular fluid, chloride ions combine with fixed bases and decrease the alkaline reserves in the body. The net effects are decreased serum bicarbonate levels and a decrease in blood and urine p H. Excess chloride ions presented to the kidney are not completely reabsorbed by the tubules and are excreted with cations (principally sodium) and water. This diuretic effect is usually compensated for in the kidneys after a few days of therapy. Pharmacokinetics No information was located on the pharmacokinetics of this agent in veterinary species. In humans, ammonium chloride is rapidly ab-sorbed from the GI. Contraindications/Precautions/Warnings Ammonium chloride is contraindicated in patients with severe he-patic disease as ammonia may accumulate and cause toxicity. In general, ammonium chloride should not be administered to uremic patients since it can intensify the metabolic acidosis already ex isting in some of these patients. As sodium depletion can occur, ammo-nium chloride should not be used alone in patients with se vere renal insufficiency and metabolic alkalosis secondary to vomiting hydrochloric acid. In these cases, sodium chloride repletion with or without ammonium chloride administration should be performed to correct both sodium and chloride deficits. Ammonium chlo ride is contraindicated in patients with urate calculi or respiratory acidosis and high total CO 2 and buffer base. Ammonium chloride alone can-not correct hypochloremia with secondary metabolic al kalosis due to intracellular potassium chloride depletion; potassium chloride must be administered to these patients. Do not administer subcutaneously, rectally or intraperitoneally. Use ammonium chloride with caution in patients with pulmo-nary insufficiency or cardiac edema. Adverse Effects Development of metabolic acidosis (sometimes severe) can occur un less adequate monitoring is performed. When used intravenously, pain at the injection site can de velop; slow administration lessens this effect. Gastric irritation, nausea and vomiting may be associ ated with oral dosing of the drug. Urinary acidification is associated with an increased risk for calcium oxalate urolith formation in cats. Overdosage/Acute Toxicity Clinical signs of overdosage may include: nausea, vomiting, exces-sive thirst, hyperventi lation, bradycardias or other arrhythmias, and progressive CNS depression. Profound acidosis and hypokalemia may be noted on laboratory results. Treatment should consist of correcting the acidosis by admin-istering sodium bicarbonate or sodium acetate intravenously. Hypokalemia should be treated by using a suitable oral (if possible) potassium product. Intense acid-base and electrolyte monitoring should be performed on an ongoing basis until the patient is stable. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ammonium chloride or other urinary acidifying agents and may be of significance in veteri-nary patients: Am INOgly COSIDES!! (e. g., gentamicin ) and ERy THROmy CIN : Are more effective in an alkaline medium; urine acidification may dimin-ish these drugs effectiveness in treating bacterial urinary tract infections QUINIDINE!! : Urine acidification may increase renal excretion Doses DOg S:T! For urine acidification: a) As adjunctive therapy for struvite uroliths: 20 mg/kg PO three times daily (Labato 2002b) b) T o enhance the renal elimination of certain toxins/drugs: 200 mg/kg/day divided four times daily (Grauer and Hjelle 1988) c) T o enhance elimination of strontium: 0. 2-0. 5 grams PO 3-4 times a day (used with cal cium salts) (Bailey 1986) For ATT (ammonia tolerance testing): a) 2 m L/kg of a 5% solution of ammonium chloride deep in the rectum, blood sampled at 20 minutes and 40 minutes; or oral challenge with ammonium chloride 100 mg/kg (maximum dose = 3 grams) either in solution: dissolved in 20-50 m L warm water or in gelatin capsules, blood sampled at 30 and 60 minutes. T est may also be done by comparing fasting and

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Amm ONIUm m Olyb DATE/Amm ONIUm TETRATHIOm Olyb DATE 47 6-hour postprandial samples without giving exogenous am-monium chloride. (Center 2004) CATS:T! For urine acidification: a) In struvite dissolution therapy if diet and antimicrobials do not result in acid urine or to help prevent idiopathic FUS in a non-obstructed cat: 20 mg/kg PO twice daily (Lage, Polzin, and Zenoble 1988) b) As adjunctive therapy for struvite uroliths: 20 mg/kg PO twice daily (Labato 2002b) c) 800 mg per day given in the food once daily (if diet and an-timicrobials do not reduce p H) (Lewis, Morris, and Hand 1987) HORSES:T! a) 4-15 grams PO (Swinyard 1975) b) Ammonium chloride as a urinary acidifier: 60-520 mg/kg PO daily. Ammonium salts are unpalatable and will have to be dosed via stomach tube or dosing syringe. Alterna tively, ammonium sulfate at 165 mg/kg PO per day is more pal-atable and may be ac cepted when mixed with grain or hay. (Jose-Cunilleras and Hinchcliff 1999) c) As a urinary acidifier to enhance renal excretion of strych-nine: 132 mg/kg PO (Schmitz 2004) CATTl E:T! For urolithiasis prevention: a) 200 mg/kg PO (Howard 1986) b) 15-30 grams PO (Swinyard 1975) SHEEP & g OATS:T! For urolithiasis prevention: a) 200 mg/kg PO (Howard 1986) b) 1-2 grams PO (Swinyard 1975) monitoring Urine p H (Urine p H's of T! ≤6. 5 are recommended as goals of therapy) Blood p H if there are clinical signs of toxicity or treating meta-T! bolic alkalosis Serum electrolytes, if using chronically or if treating metabolic T! acidosis Prior to IV use, it is recommended that the carbon dioxide com-T! bining power of the patient's serum be measured to insure that serious acidosis is prevented Client Information Contact veterinarian if animal exhibits signs of nausea, vomiting, T! excessive thirst, hyperventilation or progressive lethargy Powders may have a bitter taste and patients may not accept their T! food after mixing Chemistry/Synonyms An acid-forming salt, ammonium chloride occurs as colorless crys-tals or as white, fine or course, crystalline powder. It is somewhat hygroscopic, and has a cool, saline taste. When dis solved in water, the temperature of the solution is decreased. One gram is soluble in approximately 3 m L of water at room temperature; 1. 4 m L at 100°C. One gram is soluble in approximately 100 m L of alcohol. One gram of ammonium chloride contains 18. 7 m Eq of ammo-nium and chloride ions. The com mercially available concentrate for injection (26. 75%) contains 5 m Eq of each ion per m L and con tains disodium edetate as a stabilizing agent. The p H of the concentrate for injection is approxi mately 5. Ammonium chloride may also be known as muriate of ammo-nia and sal ammoniac. Storage/Stability/Compatibility Ammonium chloride for injection should be stored at room tem-perature; avoid freezing. At low temperatures, crystallization may occur; it may be resolubolized by warming to room temperature in a water bath. Ammonium chloride should not be titrated with strong oxidiz-ing agents etc. potassium chlorate) as explosive compounds may result. Ammonium chloride is reported to be physically compatible with all commonly used IV replace ment fluids and potassium chloride. It is incompatible with codeine phosphate, dimenhydrinate, metha-done HCl, nitrofurantoin sodium, sulfisoxazole diolamine, and warfarin sodium. It is also reportedly incompatible with alkalis and their hydroxides. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Ammonium Chloride Tablets: 200 mg, 400 mg; Uri Kare® 200, 400 Tablets (Neogen); (Rx). Approved for use in cats and dogs. Ammonium Chloride Granules: 200 mg per G teaspoonful pow-der; Uroeze ® 200 (Virbac), Uri Kare® 200 (Neogen); (Rx) Approved for cats and dogs. Ammonium Chloride Granules: 400 mg per G teaspoonful pow-der; Uroeze ® (Virbac), Uri Kare® 400 (Neogen); (Rx) Approved for cats and dogs. Ammonium chloride is also found in some veterinary labeled cough preparations e. g., Spect-Aid® Expectorant Granules (7% guaifenesin, 75% ammonium chloride, potassium iodide 2%) and in some cough syrups (also containing guaifenesin, pyrilamine and phenylephrine). When used in large animals, feed grade ammonium chloride can be obtained from feed mills. HUm AN­l Ab El ED PRODUCTS: Ammonium Chloride Injection: 26. 75% (5 m Eq/m L) in 20 m L (100 m Eq) vials. Must be diluted before infusion; generic; (Rx). Preparation of solution for IV administration: Dilute 1 or 2 vials (100-200 m Eq) in either 500 or 1000 m L of sodium chlo ride 0. 9% for injection. Do not administer at a rate greater than 5 m L/min (human adult). Ammonium molybd A te Ammonium tetr A thiomolybd A te (ah-moe-nee-um moe-lib-date; tet-ra-thye-oh-moe-lib-date) Molypen® c Opper p Ois Oning treatment Prescriber Highlights Used primarily to treat copper poisoning in food animals T T (esp. sheep) Consider contacting FDA for guidance in treating food T T animals

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48 Am Ox ICIll IN Uses/Indications Ammonium molybdate and ammonium tetrathiomolybdate (TTM) are used for the in vestigational or compassionate treatment of cop-per poisoning in food animals, primarily sheep. Adverse Effects After apparent successful treatment for copper poisoning with am-monium tetrathiomolybdate (TTM), a flock of sheep became infer-tile, progressively unthrifty, and died 2-3 years later. The authors concluded the TTM was retained in the CNS, pituitary and adrenal glands and caused a toxic endocrinopathy (Haywood, Dincer et al. 2004). Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Doses Note : In food animals, FARAD recommends a minimum 10 day pre-slaughter withdrawal time and a minimum 5 day milk withholding interval. (Haskell, Payne et al. 2005) Ammonium tetrathiomolybdate does not go into solution readily and ammonium molybdate administered orally is often preferred. SHEEP:T! For treatment of copper poisoning:a) Food animals: Ammonium molybdate: 200 mg per head PO once daily for 3 weeks. Ammonium tetrathiomolybdate: 1. 7-3. 4 mg per head IV or SC every other day for 3 treat-ments (Post and Keller 2000) b) 100 mg with 1-gram sodium sulfate by mouth daily (Debuf 1991) c) 200 mg ammonium or sodium molybdate plus 500 mg of so-dium thiosulfate given daily PO for up to 3 weeks (Thompson and Buck 1993) d) Ammonium tetrathiomolybdate: 1. 7 mg/kg IV or 3. 4 mg/kg SC every other day for 3 treatments. Alternatively, ammonium molybdate 50-500 mg PO once daily and sodium thiosulfate 300-1000 mg PO once daily for 3 weeks. (Plumlee 1996) Dosage Forms/Regulatory Status/Synonyms VETERINAR y­l Ab El ED PRODUCTS: None. Note : Ammonium Molybdate or ammonium tetrathiomolybdate can be obtained from various chemical supply houses, but it is rec-ommended to contact the FDA before treating for guidance when contemplating using molybdate. HUm AN­l Ab El ED PRODUCTS: Ammonium Molybdate Injection: 25 mcg/m L (as 46 mcg/m L am-monium molybdate tetrahydrate) in 10 m L vial); Molypen ® (Ameri-can Pharmaceutical Partners); generic; (Rx) Ammonium molybdate may also be known as: Molybdene Inject-able®, or Molypen ®. Ammonium tetrathiomolybdate may also be known as TTM. Amoxicillin (a-mox-i-sill-in) Amoxil®, Amoxi-Tabs® amin Openicillin Prescriber Highlights Bactericidal aminopenicillin with same spectrum as T T ampicillin (ineffective against bacteria that produce beta-lactamase) Most likely adverse effects are GI-related, but hypersensi-T T tivity & other adverse effects rarely occur Available in oral & parenteral dosage forms in USA T T Uses/Indications The aminopenicillins have been used for a wide range of infections in various species. FDA-approved indications/species, as well as non-approved uses, are listed in the Dosages section below. Pharmacology/Actions Like other penicillins, amoxicillin is a time-dependent, bactericidal (usually) agent that acts by inhibiting cell wall synthesis. Although there may be some slight differences in activity against certain or-ganisms, amoxicillin generally shares the same spectrum of activity and uses as ampicillin. Because it is better absorbed orally (in non-ruminants), higher serum levels may be attained than with ampicil-lin. Penicillins are usually bactericidal against susceptible bacteria and act by inhibiting mucopeptide synthesis in the cell wall resulting in a defective barrier and an osmotically unstable spheroplast. The ex-act mechanism for this effect has not been definitively determined, but beta-lactam antibiotics have been shown to bind to several en-zymes (carboxypeptidases, transpeptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that various beta-lactam antibiotics have for these enzymes (also known as penicillin-binding proteins; PBPs) help explain the differences in spectrums of activity the drugs have that are not explained by the influence of beta-lactamases. Like other beta-lactam antibiotics, penicillins are generally considered more effective against actively growing bacteria. The aminopenicillins, also called the “broad-spectrum” or am-picillin penicillins, have increased ac tivity against many strains of gram-negative aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus. Like the natural penicillins, they are susceptible to inactivation by beta-lactamase-producing bacteria (e. g., Staph aureus). Although not as active as the natural penicil-lins, they do have activity against many anaerobic bacteria, including Clostridial organisms. Organisms that are generally not suscepti-ble include Pseudomonas aeruginosa, Serratia, Indole-positive Proteus (Proteus mirabilis is suscep tible), Enterobacter, Citrobacter, and Acinetobacter. The aminopenicillins also are inactive against Rickettsia, mycobacteria, fungi, Mycoplasma, and viruses. In order to reduce the inactivation of penicillins by beta-lacta-mases, potassium clavulanate and sul bactam have been developed to inactivate these enzymes and thus extend the spectrum of those penicillins. When used with a penicillin, these combinations are of-ten effective against many beta-lactamase-producing strains of oth-erwise resistant E. coli, Pasturella spp., Staphylococcus spp., Kleb siella, and Proteus. Type I beta-lactamases that are often associated with E. coli, Enterobacter, and Pseudomonas are not generally inhibited by clavulanic acid.

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Am Ox ICIll IN 49 Pharmacokinetics Amoxicillin trihydrate is relatively stable in the presence of gastric acid. After oral administration, it is about 74-92% absorbed in hu-mans and monogastric animals. Food will decrease the rate, but not the extent of oral absorption and many clinicians suggest giving the drug with food, particularly if there is concomitant associated GI distress. Amoxicillin serum levels will generally be 1. 5-3 times greater than those of ampicillin after equivalent oral doses. After absorption, the volume of distribution for amoxicillin is approximately 0. 3 L/kg in humans and 0. 2 L/kg in dogs. The drug is widely distributed to many tissues, including liver, lungs, pros-tate (human), muscle, bile, and ascitic, pleural and synovial fluids. Amoxicillin will cross into the CSF when meninges are inflamed in concentrations that may range from 10-60% of those found in serum. Very low levels of the drug are found in the aqueous humor, and low levels found in tears, sweat and saliva. Amoxicillin crosses the placenta, but it is thought to be relatively safe to use during preg nancy. It is approximately 17-20% bound to human plasma proteins, primarily albumin. Protein binding in dogs is approxi-mately 13%. Milk levels of amoxicillin are considered low. Amoxicillin is eliminated primarily through renal mechanisms, principally by tubular secretion, but some of the drug is metabo-lized by hydrolysis to penicilloic acids (inactive) and then excreted in the urine. Elimination half-lives of amoxicillin have been report-ed as 45-90 minutes in dogs and cats, and 90 minutes in cattle. Clearance is reportedly 1. 9 m L/kg/min in dogs. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, carbapenems). Do not administer penicillins, cephalosporins, or macrolides to rabbits, guinea pigs, chinchillas, hamsters, etc. or serious enteritis and clostridial enterotoxemia may occur. Do not administer systemic antibiotics orally in patients with septicemia, shock, or other grave ill nesses as absorption of the medi-cation from the GI tract may be significantly delayed or diminished. Parenteral (preferably IV) routes should be used for these cases. Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, neu-tropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymphadenopathy, or full-blown anaphylaxis. When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). High doses or very prolonged use have been associated with neurotoxicity (e. g., ataxia in dogs). Al though the penicillins are not considered hepatotoxic, elevated liver enzymes have been re ported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta; safe use during pregnancy has not been firmly established, but neither have there been any documented teratogenic problems associated with these drugs. However, use only when the potential benefits outweigh the risks. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimes-ters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity Acute oral penicillin overdoses are unlikely to cause significant problems other than GI distress but other effects are possible (see Adverse Effects). In humans, very high dosages of parenteral peni-cillins, especially in patients with renal disease, have induced CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amoxicillin and may be of significance in veterinary patients: b ACTERIOSTATIC ANTIm ICROb IAl S !! (e. g., chloramphenicol, erythromy­ cin and other macrolides, tetracyclines, sulfonamides, etc. ): Because there is evidence of in vitro antagonism between beta-lactam antibiotics and bacteriostatic antibiotics, use together has been generally not recommended, but actual clinical importance is not clear m ETHOTREx ATE!! : Amoxicillin may decrease the renal excretion of MTX causing increased levels and potential toxic effects PROb ENECID!! : Competitively blocks the tubular secretion of most penicillins, thereby increasing serum levels and serum half-lives laboratory Considerations Amoxicillin may cause false-positive T! urine glucose de terminations when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by amoxicillin. As penicillins and other beta-lactams can inactivate T! aminogly­ cosides in vitro (and in vivo in pa tients in renal failure), serum concentrations of aminoglycosides may be falsely decreased if the pa tient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recom mended that if the assay is delayed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. Doses DOg S:T! For susceptible infections:a) For Gram-positive infections: 10 mg/kg PO, IM, SC twice daily for at least 2 days after symp toms subside. For Gram-negative infections: 20 mg/kg PO three times daily or IM, SC twice daily for at least 2 days after symptoms sub-side (Aucoin 2000) b) For susceptible UTI's: 10-20 mg/kg PO q12h for 5-7 days. For susceptible systemic in fections (bacteremia/sepsis): 22-30 mg/kg IV, IM, SC q8h for 7 days. For susceptible orthopedic infections: 22-30 mg/kg IV, IM, SC, or PO q6-8h for 7-10 days. (Greene, Hartmannn et al. 2006) c) For Lyme disease: 22 mg/kg PO q12h for 21-28 days (Appel and Jacobson 1995)

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50 Am Ox ICIll IN CATS:T! For susceptible infections: a) For Gram-positive infections: 10 mg/kg PO, IM, SC twice daily for at least 2 days after symp toms subside. For Gram-negative infections: 20 mg/kg PO three times daily or IM, SC twice daily for at least 2 days after symptoms sub-side (Aucoin 2000) b) For susceptible UTI's and soft tissue infections: 50 mg (total dose per cat) or 11-22 mg/kg PO once daily for 5-7 days. For sepsis: 10-20 mg/kg IV, SC, or PO q12h for as long as necessary. Note : Duration of treatment are general guidelines, generally treat for at least 2 days after all signs of infection are gone. (Greene, Hartmannn et al. 2006) c) C. perfringens, bacterial overgrowth (GI): 22 mg/kg PO once daily for 5 days (Lappin 2000) d) C. perfringens enterotoxicosis: 11-22 mg/kg PO two to three times daily for 7 days (Leib 2004a) e) For treating H. pylori infections using triple therapy: amoxi-cillin 20 mg/kg PO twice daily for 14 days; metronidazole 10-15 mg/kg PO twice daily; clarithromycin 7. 5 mg/kg PO twice daily (Simpson 2003b) FERRETS:T! For eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 22 mg/kg, amoxicillin 22 mg/kg and bismuth subsalicylate (original Pepto-Bismol®) 17. 6 mg/kg PO. Give each 3 times daily for 3-4 weeks. (Hall 2000) b) Using triple therapy: Metronidazole 20 mg/kg PO q12h, amoxicillin 20 mg/kg PO q12h and bismuth subsalicylate 17. 5 mg/kg PO q8h. Give 21 days. Sucralfate (25 mg/kg PO q8h) and famotidine (0. 5 mg/kg PO once daily) are also used. Fluids and assisted feeding should be continued while the pri-mary cause of disease is investigated. (Johnson 2006c) For susceptible infections:a) 10-35 mg/kg PO or SC twice daily (Williams 2000) RAbb ITS/RODENTS/Sm All m Amm Al S:T! Note : See warning above in Contraindications a) Hedgehogs: 15 mg/kg IM or PO q12h (Smith 2000) CATTl E:T! For susceptible infections:a) 6-10 mg/kg SC or IM q24h (Withdrawal time = 30 days) (Jenkins 1986) b) For respiratory infections: 11 mg/kg IM or SC q12h (Hjerpe 1986), (Beech 1987b) c) Calves: Amoxicillin trihydrate: 7 mg/kg PO q8-12h (Baggot 1983) HORSES:T! For susceptible infections:a) For respiratory infections: 20-30 mg/kg PO q6h (Beech 1987b) b) Foals: Amoxicillin Sodium: 15-30 mg/kg IV or IM q6-8h; amoxicillin trihydrate sus pension: 25-40 mg/kg PO q8h; amoxicillin/clavulanate 15-25 mg/kg IV q6-8h (Brumbaugh 1999) b IRDS:T! For susceptible infections:a) For most species: 150-175 mg/kg PO once to twice daily (us-ing 50 mg/m L suspension) (Clubb 1986) b) 100 mg/kg q8h PO (Bauck and Hoefer 1993)c) 100 mg/kg q8h, IM, SC, PO (Hoeffer 1995) d) Ratites: 15-22 mg/kg PO twice daily; in drinking water: 250 mg/gallon for 3-5 days (Jenson 1998) REPTIl ES:T! For susceptible infections: a) For all species: 22 mg/kg PO q12-24h; not very useful unless used in combination with aminoglycosides (Gauvin 1993) monitoring Because penicillins usually have minimal toxicity associated with T! their use, monitoring for efficacy is usually all that is required un-less toxic signs develop. Serum levels and therapeutic drug moni-toring are not routinely done with these agents. Client Information The oral suspension should preferably be refrigerated, but refrig-T! eration is not absolutely necessary; any unused oral suspension should be discarded after 14 days Amoxicillin may be administered orally without regard to feeding T! status If the animal develops gastrointestinal symptoms ( T! e. g., vomiting, anorexia), giving with food may be of benefit Chemistry/Synonyms An aminopenicillin, amoxicillin is commercially available as the tri-hydrate. It occurs as a practically odorless, white, crystalline powder that is sparingly soluble in water. Amoxicillin dif fers structurally from ampicillin only by having an additional hydroxyl group on the phenyl ring. Amoxicillin may also be known as: amoxycillin, p-hydroxyampi-cillin, or BRL 2333; many trade names are available. Storage/Stability/Compatibility Amoxicillin capsules, tablets, and powder for oral suspension should be stored at room temperature (15-30°C) in tight containers. After reconstitution, the oral suspension should preferably be refrigerated (refrigeration not absolutely necessary) and any unused product discarded after 14 days. Dosage Forms/Regulatory Status/Withdrawal Times VETERINAR y­l Ab El ED PRODUCTS: Amoxicillin Oral Tablets: 50 mg, 100 mg, 150 mg, 200 mg, & 400 mg; Amoxi-Tabs® (Pfizer); (Rx). Approved for use in dogs and cats. Amoxicillin Powder for Oral Suspension 50 mg/m L (after reconsti-tution) in 15 m L or 30 m L bottles; Amoxi-Drop® (Pfizer); (Rx). Ap-proved for use in dogs and cats. Amoxicillin Intramammary Infusion 62. 5 mg/syringe in 10 m L sy-ringes; Amoxi-Mast® (Schering-Plough); (Rx). Approved for use in lactating dairy cattle. Slaughter withdrawal (when administered as la beled) = 12 days; Milk withdrawal (when administered as labeled) = 60 hours. HUm AN­l Ab El ED PRODUCTS: Amoxicillin Tablets (chewable) (as trihydrate): 125 mg, 200 mg, 250 mg, & 400 mg; Amoxil® (Glaxo Smith Kline); generic; (Rx) Amoxicillin Tablets (as trihydrate): 500 mg & 875 mg; Amoxil® (Glaxo Smith Kline); generic; (Rx) Amoxicillin Capsules (as trihydrate): 250 mg, & 500 mg; Amoxil® (Glaxo Smith Kline); generic; (Rx)Amoxicillin (as trihydrate) Powder for Oral Suspension: 50 mg/m L (in 15 and 30 m L bottles), 125 mg/5 m L in 80 m L & 150 m L; 200 mg/5 m L in 50 m L, 75 m L & 100 m L; 250 mg/5 m L in 80 m L, 100 m L & 150 m L; 400 mg/5 m L in 50 m L, 75 m L & 100 m L; Amoxil® &

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Am Ox ICIll IN/Cl AVUl ANATE 51 Amoxil® Pediatric Drops (Glaxo Smith Kline); (Apothecon), Trimox® (Sandoz); generic; (Rx) Amoxicillin Tablets for Oral Suspension: 200 mg & 400 mg; Disper-Mox ® (Ranbaxy); (Rx) Amoxicillin/cl A vul An A te pot Assium Amoxicillin/cl A vul Anic Acid (a-mox-i-sill-in clav-yue-lan-ate) Clavamox®, Augmentin® p Otentiated amin Openicillin Prescriber Highlights Bactericidal aminopenicillin with beta-lactamase inhibi-T T tor that expands its spectrum. Not effective against Pseudomonas or Enterobacter Most likely adverse effects are GI related, but hypersensi-T T tivity & other adverse effects rarely occur Uses/Indications Amoxicillin/potassium clavulanate tablets and oral suspension products are ap proved for use in dogs and cats for the treatment of urinary tract, skin and soft tissue infections caused by susceptible organisms. It is also indicated for canine periodontal disease due to susceptible strains of bacteria. Pharmacology/Actions For information on the pharmacology/actions of amoxicillin, refer that monograph. Clavulanic acid has only weak antibacterial activity when used alone and presently it is only available in fixed-dose combinations with either amoxicillin (oral) or ticarcillin (parenteral). Clavulanic acid acts by competitively and irreversibly binding to beta-lactama-ses, including types II, III, IV, and V, and penicillinases produced by Staphylococcus. Staphylococci that are resistant to penicilli-nase-resistant penicillins (e. g., oxacillin) are considered resistant to amoxi cillin/potassium clavulanate, although susceptibility test-ing may indicate otherwise. Amoxi cillin/potassium clavulanate is usually ineffective against type I cephalosporinases. These plasmid-mediated cephalosporinases are often produced by members of the family Enterobacteriaceae, par ticularly Pseudomonas aeruginosa. When combined with amoxicillin, there is little if any synergistic activity against organisms already susceptible to amoxicillin, but amoxicillin-resistant strains (due to beta-lactamase inactivation) may be covered. When performing Kirby-Bauer susceptibility testing, the Augmentin® (human-product trade name) disk is often used. Because the amoxicillin:clavulanic acid ratio of 2:1 in the suscep-tibility tests may not correspond to in vivo drug levels, suscepti-bility testing may not always accurately predict efficacy for this combination. Pharmacokinetics The pharmacokinetics of amoxicillin are presented in that drug's monograph. There is no evidence to suggest that the addition of clavulanic acid significantly alters amoxicillin pharmacokinetics. Clavulanate potassium is relatively stable in the presence of gas-tric acid and is readily absorbed. In dogs, the absorption half-life is reportedly 0. 39 hours with peak levels occurring about 1 hour after dosing. Specific bioavailability data for dogs or cats was not located. Clavulanic acid has an apparent volume of distribution of 0. 32 L/kg in dogs and is distributed (with amoxicillin) into the lungs, pleural fluid and peritoneal fluid. Low concentrations of both drugs are found in the saliva, sputum and CSF (uninflamed menin-ges). Higher concentrations in the CSF are expected when menin-ges are inflamed, but it is questionable whether therapeutic levels are attain able. Clavulanic acid is 13% bound to proteins in dog se-rum. The drug readily crosses the placenta but is not believed to be teratogenic. Clavulanic acid and amoxicillin are both found in milk in low concentrations. Clavulanic acid is apparently extensively metabolized in the dog (and rat) primarily to 1-amino-4-hydroxybutan-2-one. It is not known if this compound possesses any beta-lactamase inhibiting activity. The drug is also excreted unchanged in the urine via glom-erular filtration. In dogs, 34-52% of a dose is excreted in the urine as unchanged drug and metabolites, 25-27% eliminated in the fe-ces, and 16-33% into respired air. Urine levels of active drug are considered high, but may be only 1/5th of those of amoxicillin. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, carbapenems). Do not administer systemic antibiotics orally in patients with septicemia, shock, or other grave ill nesses as absorption of the medication from the GI tract may be significantly delayed or diminished. Do not administer penicillins, cephalosporins, or macrolides to rabbits, guinea pigs, chinchillas, hamsters, etc. or serious enteritis and clostridial enterotoxemia may occur. Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, neu-tropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymphadenopathy, or full-blown anaphylaxis. When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). Neurotoxicity (e. g., ataxia in dogs) has been associated with very high doses or very prolonged use. Al though the penicillins are not considered hepatotoxic, elevated liver enzymes have been re ported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia.

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52 Am Ox ICIll IN/Cl AVUl ANATE Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and fe-line pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity Acute oral penicillin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects). In humans, very high dosages of parenteral peni-cillins, especially in patients with renal disease, have induced CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amoxicillin-clavulanate and may be of significance in veterinary patients: b ACTERIOSTATIC ANTIm ICROb IAl S !! (e. g., chloramphenicol, erythromycin and other macrolides, tetracyclines, sulfonamides, etc. ): Because there is evidence of in vitro antagonism between beta-lactam antibiotics and bacteriostatic antibiotics, use together has been generally not recommended, but actual clinical importance is not clear m ETHOTREx ATE!! : Amoxicillin may decrease the renal excretion of MTX causing increased levels and potential toxic effects PROb ENECID!! : Competitively blocks the tubular secretion of most penicillins, thereby increasing serum levels and serum half-lives laboratory Considerations Amoxicillin may cause false-positive T! urine glucose de terminations when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by amoxicillin. As penicillins and other beta-lactams can inactivate T! aminogly­ cosides in vitro (and in vivo in pa tients in renal failure), serum concentrations of aminoglycosides may be falsely decreased if the pa tient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recom mended that if the assay is de-layed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. Doses Note : All doses are for combined quantities of both drugs (unless noted otherwise). DOg S:T! For susceptible infections:a) 13. 75 mg/kg PO twice daily; do not exceed 30 days of therapy (Package insert; Clavamox® —Pfizer) b) For susceptible UTI's: 12. 5 mg/kg PO q12h for 5-7 days For susceptible skin, soft tissue infections: 12. 5 mg/kg PO q12h for 5-7 days (may need to extend to 21 days; do not exceed past 30 days). Much higher doses have been recom-mended for resistant skin infections. For susceptible deep pyodermas: 12. 5 mg/kg PO q12h for 14-120 days For systemic bacteremia: 22 mg/kg PO q8-12h for 7 days Note : Duration of treatments are general guidelines; gener-ally treat for at least 2 days after all signs of infection are gone. (Greene, Hartmannn et al. 2006) c) For Gram-positive infections: 10 mg/kg PO twice daily For Gram-negative infections: 20 mg/kg PO three times daily (Aucoin 2000) d) For non-superficial pyoderma: 10-25 mg/kg PO twice daily for 3-6 weeks. Maximum dose is 650 mg twice daily. Increase to three times daily if no response in 1 week. If no response by the 2nd week, discontinue. (Aucoin 2002a) e) For recurrent pyoderma: 13. 75-22 mg/kg PO q8-12h (Hilli-er 2006b) CATS:T! For susceptible infections:a) 62. 5 mg PO twice daily; do not exceed 30 days of therapy (Package insert; Clavamox® —Pfizer) b) For Gram-positive infections: 10 mg/kg PO twice daily; For Gram-negative infections: 20 mg/kg PO three times daily (Aucoin 2000) c) For susceptible UTI's: 62. 5 mg/cat (total dose) PO q12h for 10-30 days; For susceptible skin, soft tissue infections: 62. 5 mg/cat (total dose) or 10-20 mg/kg PO q12h for 5-7 days; For susceptible sepsis, pneumonia: 10-20 mg/kg PO q8h for 7-10 days Note : Duration of treatment are general guidelines, generally treat for at least 2 days after all signs of infection are gone. (Greene, Hartmannn et al. 2006) FERRETS:T! For susceptible infections: a) 10-20 mg/kg PO 2-3 times daily (Williams 2000) b IRDS:T! For susceptible infections:a) 50-100 mg/kg PO q6-8h (Hoeffer 1995) b) Ratites: 10-15 mg/kg PO twice daily (Jenson 1998) Client Information The oral suspension should preferably be refrigerated, but refrig-T! eration is not absolutely necessary; any unused oral suspension should be discarded after 10 days Amoxicillin/clavulanate may be administered orally without re-T! gard to feeding status If the animal develops gastrointestinal symptoms ( T! e. g., vomiting, anorexia), giving with food may be of benefit monitoring Because penicillins usually have minimal toxicity associated with T! their use, monitoring for efficacy is usually all that is required un-less toxic signs or symptoms develop. Serum levels and therapeutic drug monitoring are not routinely performed with these agents. Chemistry/Synonyms A beta-lactamase inhibitor, clavulanate potassium occurs as an off-white, crystalline powder that has a p K a of 2. 7 (as the acid) and is very soluble in water and slightly soluble in alcohol at room temper-atures. Although available in commercially available preparations as the potassium salt, potency is expressed in terms of clavulanic acid. Amoxicillin may also be known as: amoxycillin, p-hydroxyam-picillin, or BRL 2333; many trade names are available. Clavulanate potassium may also be known as: clavulanic acid, BRL-14151K, or kalii clavulanas.

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Am PHOTERICIN b 53 Storage/Stability/Compatibility Clavulanate products should be stored at temperatures less than 24°C (75°F) in tight containers. Potassium clavulanate is reportedly very susceptible to moisture and should be protected from excessive hu midity. After reconstitution, oral suspensions are stable for 10 days when refrigerated. Unused portions should be discarded after that time. If kept at room temperature, suspensions are reportedly stable for 48 hours. The veterinary oral suspension should be reconstituted by adding 14 m L of water and shaking vigorously; refrigerate and discard any unused portion after 10 days. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Oral Tablets (4:1 ratio): 62. 5 mg: Amoxicillin 50 mg/12. 5 mg clavulanic acid (as the potas-sium salt) 125 mg: Amoxicillin 100 mg/25 mg clavulanic acid (as the potas-sium salt) 250 mg: Amoxicillin 200 mg/50 mg clavulanic acid (as the potas-sium salt) 375 mg: Amoxicillin 300 mg/75 mg clavulanic acid (as the potas-sium salt); Clavamox Tablets® (Pfizer); (Rx). Approved for use in dogs and cats. Powder for Oral Suspension: Amoxicillin 50 mg/12. 5 mg clavulanic acid (as the potassium salt) per m L in 15 m L dropper bot tles; Clavamox® Drops (Pfizer); (Rx). Approved for use in dogs and cats. HUm AN­l Ab El ED PRODUCTS: Note : Human-labeled amoxicillin/clavulanate products have vary-ing ratios of amoxicillin:clavulanate ranging from 2:1 to 7:1. Amoxicillin (as trihydrate)/Clavulanic Acid (as potassium salt) Tablets: Amoxicillin 250 mg/125 mg clavulanic acid; Amoxicillin 500 mg/125 mg clavulanic acid; Amoxicillin 875 mg/125 mg clavu-lanic acid; Augmentin® (Glaxo Smith Kline); generic (Rx) Chewable Tablets: Amoxicillin 125 mg/31. 25 mg clavulanic acid; Amoxicillin 200 mg/28. 5 mg clavulanic acid; 250 mg/62. 5 mg cla-vulanic acid & 400 mg/57 mg clavulanic acid; Augmentin® (Glaxo S-mith Kline); generic; (Rx) Powder for Oral Suspension—Amoxicillin/Clavulanic Acid (as po-tassium salt) after reconstitution: Amoxicillin 125 mg/31. 25 mg cla-vulanic acid per 5 m L in 75 m L, 100 m L & 150 m L; Amoxicillin 200 mg/28. 5 mg clavulanic acid per 5 m L in 50 m L, 75 m L &100 m L; Amoxicillin 250 mg/62. 5 mg clavulanic acid per 5 m L in 75 m L, 100 m L & 150 m L; Amoxicillin 400 mg/57 mg clavulanic acid per 5 m L in 50 m L, 75 m L & 100 m L; 600 mg/42. 9 mg clavulanic acid per 5 m L in 75 m L, 100 m L, 125 m L & 200 m L; Augmentin® & Augmentin ES-600® (Glaxo Smith Kline); Amoclan® (West-ward); generic; (Rx)Amphotericin b desoxychol A te Amphotericin b lipid-b Ased (am-foe-ter-i-sin bee) Abelcet®, Fungizone® antifungal Prescriber Highlights Systemic antifungal used for serious mycotic infections T T Must be administered IVT T Nephrotoxicity is biggest concern, particularly with the T T deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive Renal function monitoring essential T T Drug interactions T T Uses/Indications Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of ampho tericin has been primarily in dogs, but other species have been treated successfully. For further in formation on fungal diseases treated, see the Pharmacology and Dosage sections. The liposomal form of amphotericin B can be used to treat Leishmaniasis. Pharmacology/Actions Amphotericin B is usually fungistatic, but can be fungicidal against some organ isms depending on drug concentration. It acts by bind-ing to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out. ” Because bacteria and rickettsia do not contain sterols, ampho tericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug's toxicity may be a re-sult of a similar mechanism of action, al though amphotericin binds less strongly to cholesterol than ergosterol. Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfacto-rily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp. It has been reported that amphotericin B has immunoadjuvant properties but further work is neces sary to confirm the clinical sig-nificance of this effect. Pharmacokinetics Pharmacokinetic data on veterinary species is apparently unavail-able. In hu mans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infec-tions. After in travenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and

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54 Am PHOTERICIN b peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form. The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been de scribed. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Ap proximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form. Contraindications/Precautions/Warnings Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available. Because of the serious nature of the diseases treated with systemic amphotericin, it is not con traindicated in patients with renal disease, but it should be used cautiously with adequate monitoring. Adverse Effects Amphotericin B is notorious for its nephrotoxic effects; most ca-nine patients will show some degree of renal toxicity after receiving the drug. The proposed mecha nism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtra-tion rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in pa-tients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require sev eral months to do so. Newer forms of lipid-complexed and liposome-encapsulated amphotericin B sig nificantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that ampho-tericin B lipid complex was 8-10 times less nephrotoxic than the conventional form. The patient's renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recom-mend stopping, at least temporarily, ampho tericin treatment if the BUN reaches 30-40 mg/d L, serum creatinine >3 mg/d L or if other clinical signs of systemic toxicity develop such as serious depression or vomiting. At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12. 5 grams or 0. 5-1 g/kg) given concurrently with am-photericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubu loglomerular feedback mechanism that in-duces vasoconstriction and decreased GFR has been postu lated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 m L/kg of normal saline given in two portions, before and after am-photericin B dosing and states that is has been “. .. helpful in averting renal insufficiency.... ”Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clini cians recommend using reduced dosages in this species (see Dosage section). Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse. Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hy pokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regen-erative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been re-ported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels. Reproductive/Nursing Safety The safety of amphotericin B during pregnancy has not been estab-lished, but there are apparently no reports of teratogenicity associ-ated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage cal-culations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity may be minimized by administering fluids and mannitol as outlined above in the Adverse Effects section. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amphotericin B and may be of significance in veterinary patients: CORTICOSTEROIDST! : May exacerbate the potassium-losing effects of amphotericin DIg Ox INT! : Amphotericin B-induced hypokalemia may exacerbate digoxin toxicity Fl UCy TOSINET! : Synergy (in vitro) between amphotericin and flucy-tosine may occur against strains of Cryptococcus and Candida, but increased flucytosine toxicity may also occur NEPHROTOx IC DRUg ST! (aminoglycosides, polymyxin b, colistin, cispla­ tin, cyclosporine, methoxyflurane or vancomycin ): Since the renal ef-fects of other nephrotoxic drugs may be additive with ampho-tericin B, avoid, if possible the concurrent or sequential use of these AGENTS POTASSIUm­DEPl ETINg DRUg ST! (e. g., thiazide or loop diuretics ) SAl INE SOl UTIONS OR WITH SOl UTIONS CONTAININg A PRESERVATIVE T! : Reconstituting amphotericin B with these solutions may cause pre cipitation SKEl ETAl m USCl E REl Ax ANTS T! (tubocurarine ): Amphotericin B-in-duced hypokalemia may enhance curariform effects

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Am PHOTERICIN b 55 Doses All dosages are for amphotericin B desoxycholate (regular amphot-ericin B) unless specifi cally noted for the lipid-based products. Note : Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, tem-perature, and if possible, blood pressure. If a febrile reaction oc-curs some clinicians recommend adding a glu cocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial. A published study (Rubin et al. 1989) demonstrated less renal impairment and systemic adverse effects in dogs who received am-photericin B IV slowly over 5 hours in 1 L of D 5W than in dogs who received the drug IV in 25 m L of D 5W over 3 minutes. DOg S:T! For treatment of susceptible systemic fungal infections:a) Two regimens can be used; after diluting vial (as outlined be-low in preparation of solu tion section), either: 1) Rapid-Infusion T echnique: Dilute quantity of stock solu-tion to equal 0. 25 mg/kg in 30 m L of 5% dextrose. Using butterfly catheter, flush with 10 m L of D 5W. Infuse am-photericin B solution IV over 5 minutes. Flush catheter with 10 m L of D 5W and remove catheter. Repeat above steps us ing 0. 5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. 2) Slow IV Infusion T echnique: Dilute quantity of stock so-lution to equal 0. 25 mg/kg in 250-500 m L of D5W. Place in dwelling catheter in peripheral vein and give total vol-ume over 4-6 hours. Flush catheter with 10 m L of D 5W and remove catheter. Repeat above steps using 0. 5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. (Noxon 1989) b) In dehydrated, sodium-depleted animals, must rehydrate be-fore administration. Dosage is 0. 5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 m L of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 m L or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer ev ery other day if BUN remains below 50 mg/dl. If BUN ex-ceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8-10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, asper-gillosis and other fungal diseases require a greater cumulative dosage. (Legendre 1995) c) For treating systemic mycoses using the lipid-based products: Am Bisome®, Amphocil® or Abelcet ®: Give test dose of 0. 5 mg/ kg; then 1-2. 5 mg/kg IV q48h (or Monday, Wednesday, Fri-day) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more re-sistant filamentous fungal infections (e. g., pythiosis) use the higher dose 2-2. 5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. (Greene and Watson 1998) d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; A b e l c e t®) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/m L in dextrose 5% (D5W) and infuse over 1-2 hours (Grooters 1999) e) For systemic mycoses using amphotericin B lipid complex (Abelcet ®): Dilute in 5% dextrose to a final concentration of 1 mg/m L and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg (Schulman and Marks 2005)For blastomycosis (see general dosage guidelines above):a) Amphotericin B 0. 5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months (Foil 1986) b) Amphotericin B 0. 15-0. 5 mg/kg IV 3 times a week with ke-toconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involve-ment (for at least 2-3 months or until remission then start maintenance). When a total dose of ampho tericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketocon-azole at 2. 5-5 mg/kg PO once daily. If CNS/ocular involve-ment use keto conazole at 20-40 mg/kg PO divided twice daily (Greene, O'Neal, and Barsanti 1984) c) For severe cases, using amphotericin B lipid complex (Abel-cet®): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg (Taboada 2000) For cryptococcosis (see general dosage guidelines above): a) Amphotericin B 0. 5-0. 8 mg/kg SC 2-3 times per week. Dose is diluted in 0. 45% Na Cl with 2. 5% dextrose (400 m L for cats, 500 m L for dogs less than 20 kg and 1000 m L for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. (Taboada 2000) For histoplasmosis (see general dosage guidelines above):a) Amphotericin B 0. 15-0. 5 mg/kg IV 3 times a week with ke-toconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start mainte nance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2. 5-5 mg/kg PO once daily (Greene, O'Neal, and Barsanti 1984) b) As an alternative to ketoconazole treatment: 0. 5 mg/kg IV given over 6 -8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7. 5-8. 5 mg/kg cumulative dose is achieved (Macy 1987) For Leishmaniasis:a) Using the liposomal form of Amphotericin B: 3-3. 3 mg/kg IV 3 times weekly for 3-5 treatments (Lappin 2000) b) Using Am Bisome® (lipid-based product): Give initial test dose of 0. 5 mg/kg, then 3-3. 3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. (Greene, Hartmannn et al. 2006) For gastrointestinal pythiosis:a) Resect lesions that are surgically removable to obtain 5-6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet ®) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. (Taboada 1999) CATS:T! For treatment of susceptible systemic fungal infections:a) Rapid-Infusion T echnique: After diluting vial (as outlined below in preparation of solu tion section), dilute quantity of stock solution to equal 0. 25 mg/kg in 30 m L of 5% dex trose. Using butterfly catheter, flush with 10 m L of D 5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 m L of D 5W and remove catheter. Repeat above steps

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56 Am PHOTERICIN b using 0. 25 mg/kg 3 times a week until 9-12 mg/kg accumu-lated dosage is given. (Noxon 1989) For cryptococcosis (see general dosage guidelines above): a) As an alternative therapy to ketoconazole: Amphotericin B: 0. 25 mg/kg in 30 m L D 5W IV over 15 minutes q48h with flu-cytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989) b) Amphotericin B 0. 15-0. 4 mg/kg IV 3 times a week with flu-cytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start main tenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily (Greene, O'Neal, and Barsanti 1984) c) Amphotericin B 0. 5-0. 8 mg/kg SC 2-3 times per week. Dose is diluted in 0. 45% Na Cl with 2. 5% dextrose (400 m L for cats, 500 m L for dogs less than 20 kg and 1000 m L for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in lo-cal irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. (Taboada 2000) d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; A b e l c e t®) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/m L in dextrose 5% (D5W) and infuse over 1-2 hours (Grooters 1999) For histoplasmosis (see general dosage guidelines above):a) Amphotericin B: 0. 25 mg/kg in 30 m L D 5W IV over 15 min-utes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN in-creases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of dura-tion. (Legendre 1989) b) Amphotericin B 0. 15-0. 5 mg/kg IV 3 times a week with ke-toconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start mainte-nance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2. 5-5 mg/kg PO once daily (Greene, O'Neal, and Barsanti 1984) For blastomycosis (see general dosage guidelines above):a) Amphotericin B: 0. 25 mg/kg in 30 m L D 5W IV over 15 min-utes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumu-lative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not de velop, may increase dose to 0. 5 mg/ kg of amphotericin B. (Legendre 1989) b) Amphotericin B 0. 15-0. 5 mg/kg IV 3 times a week with ke-toconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start mainte-nance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2. 5-5 mg/kg PO once daily. If CNS/ocular involvement, use keto-conazole at 20-40 mg/kg PO divided twice daily. (Greene, O'Neal, and Barsanti 1984) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: 1 mg/kg/day IV (Ivey and Morrisey 2000)HORSES:T! For treatment of susceptible systemic fungal infections:a) For fungal pneumonia: Day 1: 0. 3 mg/kg IV; Day 2: 0. 4 mg/kg IV; Day 3: 0. 6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6. 75 mg/kg has been administered (Foreman 1999) b) For phycomycoses and pulmonary mycoses: After reconstitu-tion (see below) transfer ap propriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0. 3 mg/kg IV; Day 2: 0. 45 mg/kg IV; Day 3: 0. 6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. (Brumbaugh 1987) For intrauterine infusion: 200-250 mg. Little science is avail-able for recommending doses, volume infused, frequency, di-luents, etc. Most intrauterine treatments are com monly per-formed every day or every other day for 3-7 days. (Perkins 1999) ll Am AS:T! For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then ini-tially at 0. 3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1. 5 m L of B-Complex and 20 m Eq of KCl added. Subse-quent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coc-cidioidomycosis). (Fowler 1989) b IRDS:T! For treatment of susceptible systemic fungal infections:a) For raptors and psittacines with aspergillosis: 1. 5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/m L of saline) for 15 min-utes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. (Clubb 1986) b) 1. 5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0. 3-1 mg/m L nebulized for 15 minutes 2-4 times daily (Flammer 2003a) REPTIl ES:T! For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intra-tracheally once daily for 14-28 treatments (Gauvin 1993) monitoring Also see Adverse Effects section BUN and serum creatinine every other day while dosage is being T! increased, and at least weekly thereafter during therapy Serum electrolytes (sodium, potassium and magnesium) weekly T! Liver function tests weekly T! CBC weekly T! Urinalysis weekly T! TPP at least weekly T! Animal's weight T! Client Information Clients should be informed of the potential seriousness of toxic T! effects that can occur with amphotericin B therapy The costs associated with therapy T!

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Am PICIll IN 57 Chemistry/Synonyms A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of ampho-tericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concen-trations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent. Newer lipid-based amphotericin B products are available that have less toxicity than the conven tional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec®), amphotericin B lipid complex (ABLC, Abelcet ®), and amphotericin B liposomal (ABL, L-AMB, Ambisome®). Amphotericin B may also be known as: amphotericin; amphot-ericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available. Storage/Stability/Compatibility Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives—see directions for preparation in the Dosage Form section below). After reconstitution, if protected from light, the solution is sta-ble for 24 hours at room temperature and for 1 week if kept refrig-erated. After diluting with D 5W (must have p H >4. 3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies how ever, have shown that potency remains largely unaffected if the solution is ex-posed to light for 8-24 hours. Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D 5W, D 5W in sodium chloride 0. 2%, heparin sodium, heparin sodium with hydrocortisone so-dium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate. Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer's, D 5-normal saline, D 5-lactated Ringer's, amino acids 4. 25%-dex trose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodi-um, chlorpromazine HCl, cimetidine HCl, diphenhydramine HCl, dopamine HCl, edetate calcium disodium (Ca EDTA), gen tamicin sulfate, kanamycin sulfate, lidocaine HCl, metaraminol bitartrate, methyldopate HCl, nitro furantoin sodium, oxytetracycline HCl, penicillin G potassium/sodium, polymyxin B sulfate, potas sium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracy-cline HCl, and verapamil HCl. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific in formation. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin® (Gensia Sicor); Fungizone® Intravenous (Apoth-econ); generic (Pharma-T ek); (Rx) Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 m L of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/m L colloidal solution results. Further dilute (1:50) for administration to a concentration of 0. 1 mg/m L with 5% dextrose in water (p H >4. 2). An in-line filter may be used during adminis-tration, but must have a pore diameter >1 micron. Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 m L (as lipid complex) in 10 m L & 20 m L vials with 5 micron filter needles: Abelcet ® (Enzon); (Rx) Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 m L vials; 100 mg (as cholesteryl) in 50 m L vi-als; Amphotec® (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; Am Bisome® (Fujisawa; (Rx) Amphotericin B is also available in topical formulations: Fungi-zone® (Apothecon); (Rx) Ampicillin Ampicillin sodium Ampicillin trihydr A te (am-pi-sill-in; sul-bak-tam) Polyflex® amin Openicillin Prescriber Highlights Bactericidal aminopenicillin with same spectrum as T T amoxicillin (ineffective against bacteria that produce beta-lactamase) Most likely adverse effects are GI-related, but hypersen-T T sitivity & other adverse effects rarely occur; may cause more GI effects than amoxicillin when used orally More susceptible than is amoxicillin to food reducing oral T T absorption Available in both parenteral & oral forms T T Uses/Indications In dogs and cats, ampicillin is not as well absorbed after oral ad-ministration as amoxicillin and its oral use has largely been sup-planted by amoxicillin. It is used commonly in par enteral dosage forms when an aminopenicillin is indicated in all species. The aminopenicillins, also called the “broad-spectrum” or am-picillin penicillins, have increased ac tivity against many strains of gram-negative aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus. Pharmacology/Actions Like other penicillins, ampicillin is a time-dependent, bactericidal (usually) agent that acts via inhibiting cell wall synthesis. Ampicillin and the other aminopenicillins have increased activity against many strains of gram-negative aerobes not covered by either the natural penicillins or penicillinase-resis tant penicillins, including some strains of E. coli, Klebsiella and Haemophilus. Like the natural penicillins, they are susceptible to inactivation by beta-lactamase-producing bacteria (e. g., Staph au reus). Although not as active as the natural penicillins, they do have activity against many anaero-bic bacteria, including Clostridial organisms. Organisms that are

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58 Am PICIll IN generally not susceptible include Pseu domonas aeruginosa, Serratia, Indole-positive Proteus (Proteus mirabilis is susceptible), Enterobac-ter, Citrobacter, and Acinetobacter. The aminopenicillins also are inactive against Rickettsia, my cobacteria, fungi, Mycoplasma, and viruses. In order to reduce the inactivation of penicillins by beta-lacta-mases, potassium clavulanate and sul bactam have been developed to inactivate these enzymes and extend the spectrum of those penicil-lins. See the ampicillin/sulbactam or amoxicillin/clavulanate mono-graphs for more information. Pharmacokinetics Ampicillin anhydrous and trihydrate are relatively stable in the pres-ence of gastric acid. After oral administration, ampicillin is about 30-55% absorbed in humans (empty stom ach) and monogastric animals. Food will decrease the rate and extent of oral absorption. When administered parenterally (IM, SC) the trihydrate salt will achieve serum levels of approxi mately H those of a comparable dose of the sodium salt. The trihydrate parenteral dosage form should not be used where higher MIC's are required for treating systemic infections. After absorption, the volume of distribution for ampicillin is ap-proximately 0. 3 L/kg in humans and dogs, 0. 167 L/kg in cats, and 0. 16-0. 5 L/kg in cattle. The drug is widely distributed to many tis-sues, including liver, lungs, prostate (human), muscle, bile, and as-citic, pleural and synovial fluids. Ampicillin will cross into the CSF when meninges are inflamed in concentrations that may range from 10-60% those found in serum. Very low levels of the drug are found in the aqueous humor; low levels are found in tears, sweat and saliva. Ampicillin crosses the placenta, but is thought to be relatively safe to use during pregnancy. Ampicillin is approximately 20% bound to plasma pro teins, primarily albumin. Milk levels of ampicillin are considered low. In lactating dairy cattle, the milk to plasma ratio is about 0. 3. Ampicillin is eliminated primarily through renal mechanisms, principally by tubular secretion, but some of the drug is metabo-lized by hydrolysis to penicilloic acids (inactive) and then excreted in the urine. Elimination half-lives of ampicillin have been reported as 45-80 minutes in dogs and cats, and 60 minutes in swine. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, car-bapenems). Do not administer systemic antibiotics orally in patients with septicemia, shock, or other grave ill nesses as absorption of the medi-cation from the GI tract may be significantly delayed or diminished. Parenteral (preferably IV) routes should be used for these cases. Do not administer penicillins, cephalosporins, or macrolides to rabbits, guinea pigs, chinchillas, hamsters, etc., or serious enteritis and clostridial enterotoxemia may occur. Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and manifest as rashes, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymph-adenopathy, or full-blown anaphylaxis. In humans, it is estimated that up to 15% of patients hypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of cross-re activity in veterinary patients is unknown. When given orally penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may also alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). Neurotoxicity (e. g., ataxia in dogs) has been associated with very high doses or very prolonged use. Al though the penicillins are not considered hepatotoxic, elevated liver enzymes have been re ported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta; safe use during pregnancy has not been firmly established, but neither have there been any documented teratogenic problems associated with these drugs. However, use only when the potential benefits outweigh the risks. In humans, the FDA categorizes ampicillin as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimes-ters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity Acute oral penicillin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects). In humans, very high dosages of parenteral peni-cillins, particularly in patients with renal disease, have induced CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ampicillin and may be of significance in veterinary patients: b ACTERIOSTATIC ANTIm ICROb IAl S T! (e. g., chloramphenicol, erythromycin and other macrolides, tetracyclines, sulfonamides, etc. ): Because there is evidence of in vitro antagonism between beta-lactam antibiotics and bacteriostatic antibiotics, use together has been generally not recommended, but actual clinical importance is not clear m ETHOTREx ATET! : Ampicillin may decrease the renal excretion of MTX causing increased levels and potential toxic effects PROb ENECIDT! : Competitively blocks the tubular secretion of most penicillins thereby increasing serum levels and serum half-lives laboratory Considerations Ampicillin may cause false-positive T! urine glucose determina tions when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose ox idase (Tes-Tape®, Clinistix®) are not affected by ampicillin. As penicillins and other beta-lactams can inactivate T! aminogly­ cosides in vitro (and in vivo in pa tients in renal failure), serum concentrations of aminoglycosides may be falsely decreased if the pa tient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recom mended that if the assay is de-layed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough.

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Am PICIll IN 59 Doses DOg S:T! For susceptible infections: a) For Gram-positive infections: 10-20 mg/kg PO twice daily; 5 mg/kg IM, SC twice daily; 5 mg/kg IV three times daily For Gram-negative infections: 20-30 mg/kg PO three times daily; 10 mg/kg IM, SC three times daily; 10 mg/kg IV four times daily (Aucoin 2000) b) For susceptible UTI's: 12. 5 mg/kg PO q12h for 3-7 days, 6. 6 mg/kg IM or SC q12h for 3-7 days; For susceptible soft tissue infections: 10-20 mg/kg PO, IM or SC q8h for 7 days; For pneumonia, systemic: 22 mg/kg PO, IV or SC q8h for 7-14 days; For meningitis, orthopedic infections: 22 mg/kg PO, IV, IM, SC q6-8h as long as necessary; For susceptible sepsis, bacteremia: 20-40 mg/kg IV, IM or SC q6-8h for as long as nec essary; For neonatal sepsis: 50 mg/ kg IV or intraosseous q4-6h as long as necessary; For susceptible orthopedic infections or meningitis: 22 mg/ kg IV, IM, SC, or PO q6-8h for as long as necessary (Greene, Hartmannn et al. 2006) c) For sepsis: 20-40 mg/kg IV q6-8h (Hardie 2000) d) For susceptible UTI's: 25 mg/kg PO q8h (Polzin 2005c) e) T o eliminate the leptospiremic phase of leptospirosis: 22 mg/kg q6-8h IV during the acute illness until patient is eating, then amoxicillin 22 mg/kg PO q8h (Lunn 2006) CATS:T! For susceptible infections:a) For Gram-positive infections: 10-20 mg/kg PO twice daily; 5 mg/kg IM, SC twice daily; 5 mg/kg IV three times daily; For Gram-negative infections: 20-30 mg/kg PO three times daily; 10 mg/kg IM, SC three times daily; 10 mg/kg IV four times daily (Aucoin 2000) b) For susceptible UTI's: 20 mg/kg PO q8-12h for 7-14 days; For soft tissue infections 20-40 mg/kg PO q8-12h for 14 days; For systemic infections: 7-11 mg/kg IV, IM or SC q8-12h for as long as necessary; (Greene, Hartmannn et al. 2006) c) For sepsis: 20-40 mg/kg IV q6-8h (Hardie 2000) CATTl E:T! For susceptible infections: a) For respiratory infections: Ampicillin trihydrate (Polyflex®): 22 mg/kg SC q12h (60 day slaughter withdrawal suggested) (Hjerpe 1986) b) For respiratory infections: Ampicillin sodium 22 mg/kg SC q12h; Ampicillin trihydrate: 11 mg/kg IM q24h (Beech 1987b) HORSES:T! For susceptible infections:a) Ampicillin sodium: 10-50 mg/kg IV or IM three times daily Ampicillin trihydrate: 5-20 mg/kg IM twice daily (Robinson 1987) Ampicillin sodium: 11-15 mg/IM or IV three to four times daily (Beech 1987a) b) Foals: Ampicillin sodium 11 mg/kg q6h IM or IV (Furr 1999) c) Foals: Ampicillin sodium 15-30 mg/kg IV or IM q 6-8h (Brumbaugh 1999)d) For intrauterine infusion: 1-3 grams. Little science is avail-able for recommending doses, volume infused, frequency di-luents, etc. Most treatments are commonly performed every day or every other day for 3-7 days. (Perkins 1999) FERRETS:T! For susceptible infections: 5-10 mg/kg IM, SC or IV twice daily (Williams 2000) RAbb ITS/RODENTS/Sm All m Amm A l S: T! a) Rabbits: Not recommended as it can cause a fatal enteritis (Ivey and Morrisey 2000) b) Gerbils, Mice, Rats: 20-100 mg/kg PO, SC, IM q8-12h c) Guinea pigs, Chinchillas, Hamsters: Do NOT use as it may cause enterocolitis (Adamcak and Otten 2000) d) Hedgehogs: 10 mg/kg IM or PO once daily (Smith 2000) SWINE:T! For susceptible infections: a) Ampicillin sodium: 6-8 mg/kg SC or IM q8h (Baggot 1983) b IRDS:T! For susceptible infections:a) Amazon parrots: 150-200 mg/kg PO twice daily-three times daily (poorly absorbed PO); 100 mg/kg IM (as the tri-hydrate/Polyflex®) q4h. Pet birds: 250 mg capsule in 8 oz. of drinking water (poorly absorbed; rapidly excreted) Chickens: 1. 65 g/L drinking water (see above) Most birds: 250 mg/kg via feed for 5-10 days. Sprinkle on favorite food, or add to mash or corn mix. (Clubb 1986) b) 100 mg/kg IM or IM q8h (Hoeffer 1995) c) Ratites: 11-15 mg/kg PO or IV 3 times daily; 15-20 mg/kg IM twice daily (Jenson 1998) REPTIl ES:T! For susceptible infections:a) All species: 3-6 mg/kg PO, SC or IM every 12-24 hours for 2 weeks; not very useful unless used in combination with aminoglycosides (Gauvin 1993) b) For Chelonians (turtles et al): 50 mg/kg IM q12h (Jacobson 2000) monitoring Because penicillins usually have minimal toxicity associated with T! their use, monitoring for efficacy is usually all that is required un-less toxic signs or symptoms develop. Serum levels and therapeu-tic drug monitoring are not routinely done with these agents. Client Information Unless otherwise instructed by the veterinarian, this drug should T! be given orally on an empty stomach, at least 1 hour before feed-ing or 2 hours after. Keep oral suspension in the refrigerator and discard any unused T! suspension after 14 days. If stored at room temperature, dis card unused suspension after 7 days. Chemistry/Synonyms A semi-synthetic aminopenicillin, ampicillin anhydrous and tri-hydrate occur as practi cally odorless, white, crystalline powders that are slightly soluble in water. At usual temperatures (<42°C), ampicillin anhydrous is more soluble in water than the trihydrate (13 mg/m L vs. 6 mg/m L at 20°C). Ampicillin anhydrous or tri-hydrate oral suspensions have a p H of 5-7. 5 after reconstitution with water. Ampicillin sodium occurs as an odorless or practically odor-less, white to off-white, crystalline hy groscopic powder. It is very

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60 Am PICIll IN + SUlb ACTAm soluble in water or other aqueous solutions. After reconstitution, ampi cillin sodium has a p H of 8-10 at a concentration of 10 mg/ m L. Commercially available ampicillin sodium for injection has ap-proximately 3 m Eq of sodium per gram of ampicillin. Potency of the ampicillin salts is expressed in terms of ampicillin anhydrous. Ampicillin may also be known as: aminobenzylpenicillin, ampi-cillinum, ampicillinum anhydricum, anhydrous ampicillin, AY-6108, BRL-1341, NSC-528986, or P-50; many trade names are available. Storage/Stability/Compatibility Ampicillin anhydrous or trihydrate capsules and powder for oral suspension should be stored at room temperature (15-30°C). After reconstitution, the oral suspension is stable for 14 days if refriger-ated (2-8°C); 7 days when kept at room temperature. Ampicillin trihydrate for injection (Polyflex®) is stable for 12 months if refrigerated (2-8°C); 3 months when kept at room temperature. Ampicillin sodium for injection is relatively unstable after recon-stitution and should generally be used within 1 hour of reconstitu-tion. As the concentration of the drug in solution increases, the sta-bility of the drug decreases. Dextrose may also speed the destruction of the drug by acting as a cata lyst in the hydrolysis of ampicillin. While most sources recommend using solutions of ampicillin sodium immediately, studies have demonstrated that at concentra-tions of 30 mg/m L, ampicillin sodium solutions are stable up to 48 hours at 4°C in sterile water for injection or 0. 9% sodium chloride (72 hours if concentrations are 20 mg/m L or less). Solutions with a concentration of 30 mg/m L or less have been shown to be stable up to 24 hours in solutions of lactated Ringer's solution if kept at 4°C. Solutions of 20 mg/m L or less are reportedly stable up to 4 hours in D5W if refrigerated. Ampicillin sodium is reportedly compatible with the following additives (see the above paragraph for more information): hepa-rin sodium, chloramphenicol sodium succinate, procaine HCl and vera pamil HCl. Ampicillin sodium is reportedly incompatible with the following additives: amikacin sulfate, chlorpromazine HCl, dopamine HCl, erythromycin lactobionate, gentamicin HCl, hydralazine HCl, hy-drocortisone sodium succinate, kanamycin sulfate, lincomycin HCl, oxytetracycline HCl, polymyxin B sulfate, prochlorperazine edisy-late, sodium bicarbonate and tetracycline HCl. Compat ibility is de-pendent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific in formation. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Ampicillin Trihydrate Injection Powder for Suspension: 10 g and 25 g (of ampicillin) vials; Polyflex® (Fort Dodge); (Rx). Approved for use in dogs, cats, and cattle. Withdrawal times at labeled doses (cat-tle; do not treat for more than 7 days): Milk = 48 hours; Slaughter = 6 days (144 hours). HUm AN­l Ab El ED PRODUCTS: Ampicillin Sodium Powder for Injection: 250 mg, 500 mg, 1 g, & 2 g in vials; generic; (Rx) Ampicillin Capsules (as trihydrate): 250 mg, & 500 mg; Principen® (Geneva); generic; (Rx)Ampicillin (as the trihydrate) Powder for Oral Suspension: 125 mg/5 m L & 250 mg/5 m L when reconstituted in 100 m L and 200 m L; Principen® (Geneva); (Rx)Ampicillin sodium + sulb Act Am sodium (am-pi-sill-in; sul-bak-tam) Unasyn® injectable p O tentiated amin Openicillin Prescriber Highlights Parenteral potentiated aminopenicillin that may be used T T for infections where amoxicillin/clavulanate would be ap-propriate but when an injectable antibiotic is required Hypersensitivity reactions possible; contraindicated in T T patients with documented severe hypersensitivity to penicillins Usually dosed IM or IV q6-8h T T Uses/Indications Ampicillin sodium/sulbactam sodium in a 2:1 ratio is effective when used parenterally for several types of infections caused by many beta-lactamase-producing bacterial strains of otherwise resistant E. coli, Pasturella spp., Staphylococcus spp., Klebsiella, and Proteus. Other aerobic bacteria commonly susceptible to this combination include Streptococcus, Listeria monocytogenes, Bacillus anthracis, Salmonella, Pasturella, and Acinetobacter. Anaerobic bacterial infections caused by Clostridium, Bacteroides, Fusobacterium, Peptostreptococcus or Propionibacterium may be effectively treated with ampicillin/sulbac-tam. Type I beta-lactamases that may be associated with Citrobacter, Enterobacter, Serratia and Pseudomonas are not generally inhibited by sulbactam or clavulanic acid. Ampicillin/sulbactam is ineffective against practically all strains of Pseudomonas aeruginosa. In dogs and cats, ampicillin/sulbactam therapy may be consid-ered when oral amoxicillin/clavulanate treatment is not viable (pa-tient NPO, critically ill) or when large parenteral doses would be desirable (sepsis, pneumonia, other severe infections) for treating susceptible bacterial infections or prophylaxis. Ampicillin/sulbactam has been used successfully to treat experi-mentally induced Klebsiella pneumonia in foals. Pharmacology/Actions When sulbactam is combined with ampicillin it extends its spec-trum of activity to those bacteria that produce beta-lactamases of Richmond-Sykes types II-VI that would otherwise render ampicillin ineffective. Sulbactam binds to beta-lactamases thereby “protecting” the beta-lactam ring of ampicillin from hydrolysis. Sulbactam has some intrinsic antibacterial activity against some bacteria (Neisseria, Moraxella, Bacteroides) at achievable levels. Sulbactam binding to certain penicillin-binding proteins (PBPs) may explain its activity. For most bacteria, sulbactam alone does not achieve levels sufficient to act alone as an antibacterial but when used in combination with ampicillin, synergistic effects may result. On a mg for mg basis, clavulanic acid is a more potent beta-lac-tamase inhibitor than is sulbactam, but sulbactam has advantages of reduced likelihood of inducing chromosomal beta-lactamases, greater tissue penetration and greater stability. For further information on the pharmacology of ampicillin, refer to that monograph.

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Am PICIll IN + SUlb ACTAm 61 Pharmacokinetics As sulbactam sodium is not appreciably absorbed from the GI tract, this medication must be given parenterally. A covalently linked double ester form of ampicillin/sulbactam (sultamicillin) is orally absorbed, but this combination is not commercially available in the USA. When administered parenterally (IV/IM), sulbactam's pharmacokinetic profile closely mirrors that of ampicillin in most species studied. During the elimination phase in calves, plasma concentrations of sulbactam were consistently higher than those of ampicillin, leading the authors of the study to propose using a higher ratio (than 2:1 ampicillin/sulbactam) if the combination is used in calves. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of severe hypersensitivity (e. g., anaphylaxis) to them. Because there may be cross-reactivity, use penicillins cautiously in patients who are docu-mented hypersensitive to other beta-lactam antibiotics (e. g., cepha-losporins, cefamycins, carbapenems). Patients with severe renal dysfunction may require increased pe-riods of time between doses. Adverse Effects Intramuscular injections may be painful. Intravenous injections may cause thrombophlebitis. Hypersensitivity reactions to penicil-lins occur infrequently in animals, but can be severe (anaphylaxis), particularly after IV administration. High doses or very prolonged use of penicillins have been asso-ciated with neurotoxicity (e. g., ataxia in dogs). Although the peni-cillins are not considered hepatotoxic, elevated liver enzymes have been reported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta and safe use during pregnancy has not been firmly established, but neither have there been any documented teratogenic problems associated with these drugs; however, use only when the potential benefits outweigh the risks. In humans, the FDA categorizes ampicillin as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimes-ters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), ampicillin is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) It is unknown if sulbactam crosses the placenta and safe use dur-ing pregnancy has not been established. Both ampicillin and sulbactam are distributed into human breast milk in low concentrations. For humans, the World Health Organization (WHO) rates ampicillin as being compatible with breastfeeding and the American Academy of Pediatrics lists sulbac-tam as compatible with breastfeeding. Overdosage/Acute Toxicity Neurological effects (ataxia) have rarely been reported in dogs re-ceiving very high dosages of penicillins; should these develop, weigh the risks of continued use versus those of dosage reduction or using a different antibiotic. In humans, very high dosages of parenteral penicillins, especially in those with renal disease, have induced CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ampicillin/sulbactam and may be of significance in veterinary patients: Am INOgly COSIDEST! (amikacin, gentamicin, tobramycin ): In vitro stud-ies have demonstrated that penicillins can have synergistic or additive activity against certain bacteria when used with amino-glycosides. However, beta-lactam antibiotics can inactivate amin-oglycosides in vitro and in vivo in patients in renal failure or when penicillins are used in massive dosages. Amikacin is considered the most resistant aminoglycoside to this inactivation. PROb ENECIDT! : Can reduce the renal tubular secretion of both ampi-cillin and sulbactam, thereby maintaining higher systemic levels for a longer period of time. This potential “beneficial” interaction requires further investigation before dosing recommendations can be made for veterinary patients. laboratory Considerations Ampicillin may cause false-positive T! urine glucose determina tions when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose ox idase (Test-Tape®, Clinistix®) are not affected by ampicillin. As penicillins and other beta-lactams can inactivate T! aminogly­ cosides in vitro (and in vivo in pa tients in renal failure or when penicillins are used in massive dosages), serum concentrations of aminoglycosides may be falsely decreased particularly when the serum is stored prior to analysis. It is recom mended that if the aminoglycoside assay is delayed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. Doses DOg S:T! For susceptible infections:a) For respiratory infections: 50 mg/kg (combined) IV q8h (Hawkins 2003) b) For respiratory infections: 20 mg/kg IV or IM q6-8h (Greene and Reinero 2006) c) As adjunctive treatment of serious bite wounds: 30-50 mg/ kg q8h IV (Bateman 2005b) d) For intra-abdominal infections: 20 mg/kg IV or IM q6-8h (Extrapolation of human dose with limited studies in dogs and cats) (Greene 2006) CATS:T! For susceptible infections:a) For respiratory infections using ampicillin/sulbactam (Un-asyn®): 50 mg/kg (combined) IV q8h (Hawkins 2003) b) As adjunctive treatment of serious bite wounds: 30-50 mg/ kg q8h IV (Bateman 2005b) c) For intra-abdominal infections: 20 mg/kg IV or IM q6-8h (Extrapolation of human dose with limited studies in dogs and cats) (Greene 2006) monitoring Because penicillins usually have minimal toxicity associated with T! their use, monitoring for efficacy is usually all that is required unless toxic signs or symptoms develop Serum levels and therapeutic drug monitoring are not routinely T! performed with these agents Client Information Because of the dosing intervals required this drug is best admin-T! istered to inpatients only

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62 Am PROl IUm Hy DROCHl ORIDE Chemistry/Synonyms Ampicillin sodium and sulbactam sodium for injection occurs as a white to off-white powder that is freely soluble in water or other aqueous solutions. Ampicillin/Sulbactam may also be known as: Ampibactan®, Bacimex®, Begalin-P®, Bethacil®, Comabactan®, Galotam®, Loricin®, Sulam®, Sulperazon®, Synergistin®, Unacid®, Unacim®, Unasyn® or Unasyna®. Storage/Stability/Compatibility The unreconstituted powder should be stored at temperatures at, or below, 30°C. Diluents for reconstituting the powder for injection for IV use that are reported compatible with ampicillin/sulbactam include ster-ile water for injection, and 0. 9% sodium chloride. If reconstituted to a concentration of 45 mg/m L (30/15), the resulting solution is stable for 8 hours at room temperature and for 48 hours at 4°C. If reconstituted to a concentration of 30 mg/m L (20/10), the resulting solution is stable for 72 hours at 4°C. After reconstitution and be-fore administering, the solution should be further diluted into a 50 or 100 m L bag of 0. 9% sodium chloride and administered IV over 15-30 minutes. Diluted solutions for IV administration are stable at room temperature for 8 hours. When reconstituting for IM use, sterile water for injection or 0. 5% or 2% lidocaine HCl injection may be used. 3. 2 m L of diluent is added to the 1. 5 g vial; 6. 4 m L of diluent to the 3 g vial. After re-constituting, the solution should be administered within 1 hour. Ampicillin/sulbactam injection is not compatible with aminogly-coside antibiotics (e. g., gentamicin, amikacin) and should not be mixed with these agents. Ampicillin/sulbactam is compatible with vancomycin when mixed at concentrations of 50/25 mg/m L of ampicillin/sulbactam and 20 mg/m L or less of vancomycin. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Ampicillin Sodium/Sulbactam Sodium Powder (injection): 1. 5 g (1 g ampicillin sodium/0. 5 g sulbactam sodium), 3 g (2 g ampicil-lin sodium/1 g sulbactam sodium) in vials, piggyback bottles and ADD-Vantage vials, and 10 g (10 g ampicillin sodium/5 g sulbactam sodium) in bulk; Unasyn® (Roerig); (Rx) Amprolium hydrochloride (am-proe-lee-um) Amprovine®, Corid® antic Occidial Prescriber Highlights Thiamine analog antiprotozoal (coccidia)T T Prolonged high dosages may cause thiamine deficiency; T T treatment is usually no longer than 14 days Occasionally may cause GI or neurologic effects T T May be unpalatable T T Uses/Indications Amprolium has good activity against Eimeria tenella and E. acer-vulina in poultry and can be used as a therapeutic agent for these organisms. It only has marginal activity or weak ac tivity against E. maxima, E. mivati, E. necatrix, or E. brunetti. It is often used in combination with other agents (e. g., ethopabate) to improve control against those organisms. In cattle, amprolium has approval for the treatment and preven-tion of E. bovis and E. zurnii in cattle and calves. Amprolium has been used in dogs, swine, sheep, and goats for the control of coccidiosis, although there are no approved products in the USA for these species. Pharmacology/Actions By mimicking its structure, amprolium competitively inhibits thia-mine utilization by the parasite. Prolonged high dosages can cause thiamine deficiency in the host; excessive thi amine in the diet can reduce or reverse the anticoccidial activity of the drug. Amprolium is thought to act primarily upon the first generation schizont in the cells of the intestinal wall, preventing differentiation of the metrozoites. It may suppress the sexual stages and sporu lation of the oocysts. Pharmacokinetics No information was located for this agent. Contraindications/Precautions/Warnings Not recommended to be used for more than 12 days in puppies. Adverse Effects In dogs, neurologic disturbances, depression, anorexia, and diarrhea have been reported but are rare and are probably dose-related. See Overdosage section below for treat ment recommendations. The un-diluted liquid or pastes are reportedly unpalatable. Overdosage/Acute Toxicity Amprolium has induced polioencephalomalacia (PEM) in sheep when administered at 880 mg/kg PO for 4-6 weeks and at 1 gram/ kg for 3-5 weeks. Erythrocyte production also ceased in lambs re-ceiving these high dosages. It is reported that overdoses of amprolium will produce neuro-logic clinical signs in dogs. Treatment should consist of stopping amprolium therapy and administering parenteral thiamine (1-10 mg/day IM or IV). Drug Interactions The following drug interactions have either been reported or are theoretical in animals receiving amprolium and may be of signifi-cance in veterinary patients: THIAm INET! : Exogenously administered thiamine in high doses may reverse or reduce the efficacy of amprolium Doses DOg S:T! For coccidiosis:a) Small Pups (< 10 kg adult weight): 100 mg (using the 20% powder) in a gelatin capsule PO once daily for 7-12 days. Large pups (>10 kg adult weight): 200 mg (using the 20% powder) in a gelatin capsule PO once daily for 7-12 days. In food, for pups or bitches: 250-300 mg total dose using the 20% powder on food once daily for 7-12 days. In water, for pups or bitches: 30 m L of the 9. 6% solution in one gallon of water (no other water provided) for 7-10 days (Greene, Hartmannn et al. 2006) b) Prophylaxis: 30 m L of 9. 6% solution in one gallon (3. 8 L) of drinking water or 1. 25 grams of 20% powder in food to feed 4 pups daily. Give as sole source of food or water for 7 days prior to shipping. Bitches may be given medicated water (as above) as the sole source of water for 10 days prior to whelp-ing. (USPC 1989)

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ANTIVENIN (CROTAl IDAE) 63 c) Prophylaxis: 0. 075% solution as drinking water (Matz 1995) d) 150 mg/kg of amprolium and 25 mg/kg of sulfadimethoxine for 14 days (Blagburn 2003b) e) For control of coccidiosis: 1. 5 tablespoonful (22. 5 m L) of the 9. 6% solution per one gallon of water to be used as the sole drinking water source, not to exceed 10 days. Monitor water consumption both for treatment and hydration assurance; rarely some dogs may not drink the amprolium water due to its bitter taste. In situations where dogs are co-habitants, it is necessary to place enough water for all to have access. (Blag-burn 2005a), (Blagburn 2007) CATS:T! For coccidiosis:a) For Cystoisospora spp. : 60-100 mg total dose PO once daily for 7 days (Lappin 2000) b) On food : 300-400 mg/kg on food once daily for 5 days or 110-220 mg/kg on food once daily for 7-12 days. In water: 1. 5 teaspoonsful (7. 5 m L) of the 9. 6% solution in one gallon of water per day for 10 days. In combination: amprolium at 150 mg/kg PO once daily with sulfadimethoxine (25 mg/kg PO once daily) for 14 days (Greene, Hartmannn et al. 2006) FERRETS:T! For coccidiosis: a) 19 mg/kg PO once daily (Lennox 2006) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits for coccidiosis: Using 9. 6% solution: 1 m L/7 kg BW PO once daily for 5 days; in drinking water: 0. 5 m L/500 m L for 10 days (Ivey and Morrisey 2000) b) Gerbils, Mice, Rats, Hamsters: 10-20 mg/kg total daily dose divided q8-24h SC or IM. Chinchillas: 10-15 mg/kg per day divided q8-24h SC, IM or IV (Adamcak and Otten 2000) CATTl E:T! For coccidiosis: a) Treatment: 10 mg/kg PO for 5 days; 5 mg/kg for 21 days for prophylaxis (T odd, Dipi etro, and Guterbock 1986) SWINE:T! For coccidiosis:a) Treatment: 25-65 mg/kg PO once or twice daily for 3-4 days (T odd, Dipietro, and Guterbock 1986) b) 100 mg/kg/day in food or water (Howard 1986) SHEEP & g OATS:T! For coccidiosis: a) Lambs: 55 mg/kg daily PO for 19 days (T odd, Dipietro, and Guterbock 1986) b IRDS:T! a) For coccidiosis in pet birds: 2 m L (using the 9. 6% solution)/gallon of water for 5 days or longer. Cages should be steam cleaned to prevent reinfection. Supplement diet with B vita-mins. Some strains resistant in T oucans and Mynahs. (Clubb 1986) b) For chickens (broilers or layers), turkeys, and pheasants: Re-fer to individual product instruc tions. monitoring Clinical efficacy T! Chemistry/Synonyms A structural analogue of thiamine (vitamin B 1), amprolium hydro-chloride occurs as a white or almost white, odorless or nearly odor-less powder. One gram is soluble in 2 m L of water and is slightly soluble in alcohol. Amprolium may also be known as amprocidi, Amprol ®, Corid®, Coxoid®, Coxiprol ® or Nemapro®. Storage/Stability Unless otherwise instructed by the manufacturer, amprolium prod-ucts should be stored at room temperature (15-30°C). Dosage Forms/Regulatory Status/Withdrawal Times VETERINAR y­l Ab El ED PRODUCTS: Amprolium 9. 6% (96 mg/m L) Oral Solution in 1 gal jugs; Corid® 9. 6% Oral Solution (Merial); (OTC). Approved for use in calves (not veal calves). Slaughter withdrawal (when used as la beled) = 24 hours; a withdrawal period has not been established for pre-ruminating calves. Amprolium 9. 6% (96 mg/m L) Oral Solution in 1 gal jugs; Amprol ® 9. 6% Oral Solution (Merial Select); (OTC). Approved for use in growing chickens, turkeys and laying hens. No meat or egg with-drawal when used as directed. Amprolium 20% Soluble Powder; Amprol ® 128 20% Soluble Pow-der (Merial Select); (OTC). Approved for use in growing chickens, turkeys and laying hens. No meat or egg withdrawal when used as directed. Amprolium 20% Soluble Powder; Corid® 20% Soluble Powder (Me-rial); (OTC). Approved for use in calves (not veal calves). Slaughter withdrawal (when used as labeled) = 24 hours. A withdrawal period has not been established for pre-ruminating calves. There are also available medicated feeds (amprolium alone) and combination products (medicated feeds, feed additives) containing amprolium with other therapeutic agents. These products may be labeled for use in calves, chickens and/or turkeys. HUm AN­l Ab El ED PRODUCTS: None Amrinone Lactate — See Inamrinone Lactate Antacids, Oral — See Aluminum Hydroxide; or Magnesium Hydroxide Antivenin (crot Alid Ae) polyv Alent (equine origin) Antivenin (crot Alid Ae) polyv Alent immune f Ab (ovine origin) (an-tie-ven-nin) Pit Viper Antivenin; Cro Fab® antid Ote Note : The location of antivenins for rare species and the telephone num-bers for enveno mation experts are available from the Arizona Poison and Drug Information Center (800-222-1222). The National Animal Poison Control Center (888-426-4435) is another source for up-to-date snake-bite treatment recommendations. Prescriber Highlights May cause hypersensitivity reactions T T Treatment can be very expensive T T

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64 ANTIVENIN (CROTAl IDAE) Uses/Indications The equine-derived product is indicated for the treatment of en-venomation from most ven omous snake bites (pit vipers) in North America and those caused by several species found in Central and South America (fer-de-lance, Central and South American Rattlesnake). The ovine-derived product is indicated for North American Crotalid snake envenomation in humans, but has been used in dogs. There is a fair amount of controversy with regard to use of these products in domestic animals. The risks of adminis-tration (e. g., anaphy laxis—see below) may outweigh their potential benefits in certain circumstances. However, these agents can be life saving when given early in select situations. Many factors contribute to the poten tial for toxicity (victim's size and general health, bite site(s), number of bites, age, species and size of snake, etc. ). Pharmacology/Actions Antivenins act by neutralizing the venoms (complex proteins) in pa-tients via pas sive immunization of globulins obtained from horses immunized with the venom. Antivenin is very effective in reversing venom-related coagulation abnormalities, but Timber Rattlesnake venom-induced thrombocytopenia may be resistant to treatment. Contraindications/Precautions/Warnings Because there is a risk of anaphylaxis occurring sec ondary to equine-origin proteins, some recommend performing sensitivity testing be-fore administration, but evaluation of results may be difficult and a test-dose is not provided with the veterinary-labeled product. Up to 50% of the veterinary-labeled product contains equine albumin and other equine proteins. Adverse Effects The most significant adverse effect associated with the use of the equine origin product is anaphylaxis secondary to its equine serum source; an incidence rate of less than 2% has been reported. A 1:10 di-lution of the antivenin given intracutaneously at a dose of 0. 02-0. 03 m L has been suggested as a test for hypersensitivity. Wheal forma-tion and erythema indicate a positive reaction and are generally seen within 30 minutes of administration. However, a negative response does not insure that anaphylaxis will be avoided and slow intrave-nous administration is usually sufficient to identify animals that will react to the product. A pre-treatment dose of diphenhydramine is often recommended before administering antivenin primarily to se-date the patient and, theoretically, reduce any possible allergic reac-tions to the antivenin. Should an anaphylactoid reaction be detected (nausea, pruritus, hyperemia of the inner pinna), stopping the infu-sion, giving an additional dose of diphenhydramine and restarting the infusion 5 minutes later at a slower rate may allow the dose to be administered without further problems. One case of a dog developing antivenin-associated serum sick-ness has been reported after treatment using Crotilidae antivenin (Berdoulay, Schaer et al. 2005). Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Safety during nursing has not been established but it would un-likely pose much risk. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving antivenin and may be of significance in veterinary patients:ANAlg ESICS/SEDATIVEST! : Although reducing excessive movement and other supportive therapy are im portant parts of treating en-venomation, drugs that can mask the clinical signs associated with the venom (e. g., analgesics and sedatives) should initially be used with caution. ANTIHISTAm INEST! : It has been stated that an tihistamines may poten-tiate the venom; however, documentation of this interaction was not located and diphenhydramine is routinely used by many clini-cians treating snakebite in dogs. b ETAT!-bl OCKERS : May mask the early signs associated with anaphy-laxis CORTICOSTEROIDT! use has fallen out of favor in the treatment of snakebite envenomation and is usually considered contraindicat-ed. Corticosteroids may be useful to treat anaphylaxis, however. HEPARIN:T! Is reportedly not effective in treating the thrombin-like enzymes found in rattlesnake venom. Doses Note : The treatment of pit viper snakebite involves significant treat-ment (aggressive IV fluids, antibiotics) and monitoring beyond administration of antivenin. It is highly recommended to refer to specialized references e. g., (Peterson 2006b) or to contact an animal poison control center for guidance beyond what is listed below. DOg S/CATS:T! Crotilidae antivenin (equine origin):a) Dogs/Cats: Dose necessary is calculated relative to the amount of venom injected, body mass of patient and the bite site. Av-erage dose required for dogs or cats is 1-2 vials of antivenin. The earlier the antivenin is administered the more effective it is. Intravascular bites or bites to the torso or tongue are se-rious and require prompt, aggressive antivenin administra-tion. Smaller patients may require higher doses (as venom amount/kg body weight is higher), and multiple vials may be necessary. Initially, give one vial, by diluting to 100-250 m L of crystalloid fluids and initially administer by slow IV (if there are no problems, may increase rate and administer volume over 30 minutes). In smaller patients, adjust infusion volume to prevent fluid overload. (Peterson 2006b) b) Dogs: Administer 1-5 rehydrated vials (10-50 m L) IV de-pending on severity of symptoms, duration of time after the bite, snake size, patient size (the smaller the victim, the larger the dose). Additional doses may be given every 2 hours as re-quired. If unable to give IV, may administer IM as close to bite as practical. Give supportive therapy (e. g., corticosteroids, an-tibiotics, fluid therapy, blood products, and tetanus prophy-laxis) as re quired. (Package Insert; Antivenin®—Fort Dodge) HORSES:T! a) Crotilidae Antivenin: Use only if necessary to treat systemic effects, otherwise avoid use. Administer 1-2 vials slowly IV diluted in 250-500 m L saline or lactated Ringer's. Admin ister antihistamines; corticosteroids are contraindicated. (Bailey and Garland 1992) monitoring Signs associated with an allergic response to the antivenin (ana-T! phylaxis, anaphylactoid-reactions, serum sickness) CBC with platelets; coagulation parameters T! Biochem profile; hydration status T! ECGT!

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ANTIVENIN (CORAl SNAKE) 65 Client Information Clients must be made aware of the potential for anaphylaxis as T! well as the ex penses associated with treatment, monitoring and hospitalization. Chemistry Antivenin products are concentrated serum globulins obtained from horses immunized with the venoms of several types of snakes. They are provided as refined, lyophilized product with a suit able di-luent. Up to 50% of the proteins contained in the veterinary prod-uct may be equine-specific proteins. Storage/Stability/Compatibility Do not store above 98°F (37°C); avoid freezing and excessive heat. Reconstitute the vial with the diluent provided; gently swirl the vial (may require several minutes; do not shake) to prevent excessive foaming. Warming the vial to body temperature may speed up re-constitution. Once reconstituted the vial contents are often added to a crystalloid intravenous solution (D5W, normal saline often recommended) for infusion. Depending on dog size, one vial in 100-250 m L has been suggested for infusion (Peterson 2006b). The package insert for the veterinary-labeled product states that after rehydration the vial should be used immediately. One refer-ence (anon 2007a) states that the human-labeled equine origin product can be used within 4 hours of reconstitution if refrigerated, but another (anon 2007b) states that it can be used within 48 hours after reconstitution and within 12 hours after further dilution into IV fluids. The polyvalent immune fab (ovine) product should be stored in the refrigerator and used within 4 hours of reconstitution. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Antivenin (Crotalidae) Polyvalent Equine Origin single dose vial lyophilized; 10 m L vials with diluent. Antivenin® (Fort Dodge); (Rx). Approved for use in dogs. HUm AN­l Ab El ED PRODUCTS: Antivenin (Crotalidae) Polyvalent Powder for Injection (lyo-philized): combo packs with 1 m L vial of normal horse serum (for testing) and 10 m L Bacteriostatic water for injection USP; Antivenin (Crotalidae) Polyvalent® (Wyeth); (Rx) Antivenin (Crotalidae) Polyvalent Immune Fab (Ovine Origin) Powder for Injection (lyophilized): 1 g total protein per single use vial; Cro Fab® (Altana); (Rx)Antivenin ( micrurus fulvi As) e Astern And tex As cor Al sn Ake (an-tie-ven-nin) North American Coral Snake Antivenin antid Ote Note : The location of antivenins for rare species and the telephone num-bers for enveno mation experts are available from the Arizona Poison and Drug Information Center (800-222-1222). The National Animal Poison Control Center (888-426-4435) is another source for up-to-date snake-bite treatment recommendations. Prescriber Highlights May cause hypersensitivity reactions T T Treatment can be very expensive T T Uses/Indications This product is indicated for the treatment of envenomation from the Eastern coral snake (Micrurus fulvius fulvius) and the T exas cor-al snake (Micrurus fulvius tenere). It will not neutralize the venom form the Sonoran or Arizona coral snake (Micruroides euryxanthus) or the Brazilian giant coral snake (Micrurus frontalis). Coral snake envenomation is quite rare in the United States and approximately 60% of coral snake bites do not result in envenomation. Unlike pit viper venom, coral snake venom primarily causes neurotoxicity and clinical signs may be delayed. It has been recommended that ani-mals suspected of a coral snake envenomation be hospitalized with close observation for 24-48 hours post-bite. Pharmacology/Actions Antivenins act by neutralizing the venoms (complex proteins) in patients via pas sive immunization of globulins obtained from hors-es immunized with the venom. Each vial of antivenin will neutral-ize approximately 2 mg of M. fulvius fulvius venom. Contraindications/Precautions/Warnings The coral snake antivenin will not neutralize M. euryxanthus (Sonoran or Arizona Coral Snake) venom. Because there is a risk of anaphylaxis occurring sec ondary to the horse serum, many recom-mend performing sensitivity testing before administration. Adverse Effects The most significant adverse effect associated with the use of these products is anaphylaxis secondary to the equine serum source of this product. An incidence rate of less than 2% has been reported. A 1:10 dilution of the antivenin given intracutaneously at a dose of 0. 02-0. 03 m L may be useful as a test for hypersensitivity. Wheal for-mation and erythema indicate a positive reaction and are generally seen within 30 minutes of administration. A negative response does not insure that anaphylaxis will not occur, however. A pre-treatment dose of diphenhydramine is often recommended before administer-ing antivenin. Should an anaphylactoid reaction be detected, stop-ping the infusion, giving an additional dose of diphenhydramine and restarting the infusion 5 minutes later at a slower rate may allow the dose to be administered without further problems.

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66 ANTIVENIN (bl ACK WIDOW SPIDER) Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving antivenin and may be of significance in veterinary patients: ANAlg ESICS/SEDATIVEST! : Although reducing excessive movement and other supportive therapy are im portant parts of treating en-venomation, drugs that can mask the clinical signs associated with the venom (e. g., analgesics and sedatives) should initially be used with caution ANTIHISTAm INEST! : It has been stated that an tihistamines may poten-tiate the venom; however, documentation of this interaction was not located and diphenhydramine is routinely used by many clini-cians treating snakebite in dogs. b ETAT!-bl OCKERS : May mask the early signs associated with anaphylaxis. CORTICOSTEROIDT! use has fallen out of favor in the treatment of snakebite envenomation and is usually considered contraindicat-ed. Corticosteroids may be useful to treat anaphylaxis, however. Doses Note : The treatment of Coral snakebite involves significant treatment and monitoring beyond administration of antivenin. It is highly rec-ommended to refer to specialized references e. g., (Peterson 2006a) or to contact an animal poison control center for guidance beyond what is listed below. DOg S/CATS:T! a) Dogs: After testing for hypersensitivity give 1-2 vials initially, and more in 4-6 hours if necessary. Therapy is best started within 4 hours after envenomation. Supportive care includes broad-spectrum an tibiotics, fluid therapy and mechanical ventilation if necessary. Corticosteroids are not recommend-ed. (Marks, Mannella et al. 1990) Coral Snake antivenin (not Sonoran or Arizona variety):b) Dogs/Cats: Dose necessary is calculated relative to the amount of venom injected and the body mass of patient. Average dose required for dogs or cats is 1-2 vials of antivenin. The earlier the antivenin is administered the more effective it is. Smaller patients may require higher doses (as venom amount/kg body weight is higher), and multiple vials may be necessary. Initially give one vial, by diluting to 100-250 m L of crystalloid fluids and initially administering by slow IV). In smaller patients, adjust infusion volume to prevent fluid overload. Give addi-tional vials as indicated by the progression of the syndrome. (Peterson 2006b) HORSES:T! Coral Snake Antivenin:a) Use only if necessary to treat systemic effects, otherwise avoid use. Administer 1-2 vials slowly IV diluted in 250-500 m L saline or lactated Ringer's. Admin ister antihistamines; corti-costeroids are contraindicated. May be used with Crotilidae antivenin. (Bailey and Garland 1992) monitoring Signs associated with an allergic response to the antivenin (ana-T! phylaxis, anaphylactoid-reactions, serum sickness) Cardiorespiratory monitoring; mechanical ventilation may be T! necessary Pulse oximetry T!Client Information Clients must be made aware of the potential for anaphylaxis as T! well as the ex penses associated with treatment, monitoring and hospitalization. Chemistry These products are concentrated serum globulins obtained from horses immunized with the venoms of several types of snakes. They are provided as refined, lyophilized product with a suit able diluent. Storage/Stability/Compatibility Product should be stored in the refrigerator. Avoid freezing and ex-cessive heat. Reconstitute vial with 10 m L of the supplied diluent. Gentle agitation may be used to hasten dissolution of the lyophilized powder. Reconstituted vials should be used within 48 hours (keep refrigerated) and within 12 hours once added to IV solutions. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Antivenin (Micrurus fulvius) Powder for Injection lyophilized: in single-use vials with 1 vial diluent (10 m L water for injection); Antivenin (Micrurus ful vius); (Ayerst); (Rx) Note : The manufacturer has discontinued producing this product, but has enough antivenin on hand to satisfy demand for several years. Antivenin (l A trodectus m Act Ans) bl Ack Wido W spider (an-tie-ven-nin) Black Widow Spider Antivenin antid Ote Note : The location of antivenins for rare species and the telephone num-bers for enveno mation experts are available from the Arizona Poison and Drug Information Center (800-222-1222). The National Animal Poison Control Center (888-426-4435) is another source for up-to-date enveno-mation treatment recommendations. Prescriber Highlights May cause hypersensitivity reactions T T May be difficult for veterinarians to obtain T T Uses/Indications Black widow spider antivenin is used to treat envenomation caused by this spider. Cats, camels and horses are considered to be extreme-ly sensitive to the venom. Primary toxic signs are due to neurotoxins in the venom. Pharmacology/Actions Antivenins act by neutralizing the venoms (complex proteins) in pa-tients via pas sive immunization of globulins obtained from horses immunized with the venom. In humans, symptoms begin to subside in 1-2 hours after administration.

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APOm ORPHINE HCl 67 Contraindications/Precautions/Warnings Because there is a risk of anaphylaxis occurring sec ondary to the horse serum, many recommend performing sensitivity testing be-fore administration. Adverse Effects The most significant adverse effect associated with the use of the equine origin product is anaphylaxis secondary to its equine se-rum source; an incidence rate of less than 2% has been reported. A 1:10 dilution of the antivenin given intracutaneously at a dose of 0. 02-0. 03 m L has been suggested as a test for hypersensitivity. Wheal formation and erythema indicate a positive reaction and are generally seen within 30 minutes of administration. However, a negative response does not insure that anaphylaxis will be avoided and slow intravenous administration is usually sufficient to iden-tify animals that will react to the product. A pre-treatment dose of diphenhydramine is often recommended before administer-ing antivenin primarily to sedate the patient and, theoretically, to reduce any possible allergic reactions to the antivenin. Should an anaphylactoid reaction be detected (nausea, pruritus, hyperemia of the inner pinna), stopping the infusion, giving an additional dose of diphenhydramine and restarting the infusion 5 minutes later at a slower rate may allow the dose to be administered without further problems. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving black widow spider an-tivenin and may be of significance in veterinary patients: b ETA-bl OCKERS : May mask the early signs associated with anaphylaxis Doses DOg S/CATS:T! a) After reconstituting the antivenin, add to 100 m L of normal saline and administer via slow IV over 30 minutes. Pretreat-ment with 2-4 mg/kg of diphenhydramine SC may help calm the patient and may possibly protect against allergic reactions from the antivenin. Monitor inner pinna during infusion for signs of anaphylaxis (hyperemia). If hyperemia occurs, discontinue infusion and give a second dose of di-phenhydramine. If allergic reactions abate, may restart in-fusion at a slower rate; if they recur, stop infusion and seek consultation. Use care with administration of IV fluids as envenomation can cause significant hypertension. Benzodi-azepines may alleviate muscle cramping. (Peterson and Mc-Nalley 2006) b) Dissolve contents of one vial and add to 100-200 m L of warm 0. 9% Na Cl and infuse over 2-6 hours. Administer diphenhydramine at 0. 5-1 mg/kg prior to infusion. (Atkins 2006a) Client Information Clients must be made aware of the potential for anaphylaxis as T! well as the ex penses associated with treatment, monitoring and hospitalization. monitoring Signs associated with an allergic response to the antivenin (ana-T! phylaxis, anaphylactoid-reactions, serum sickness) Respiratory/cardiac rate T! Blood pressure T! Serum chemistry (blood glucose mandatory)T! CBCT! Urine output; urinalysis T! Chemistry This product is concentrated serum globulins obtained from horses immunized with the venom of the black widow spider. It is pro-vided as refined, lyophilized product with a suit able diluent. Storage/Stability/Compatibility Product should be stored in the refrigerator (2-8°C). It is recon-stituted by adding 2. 5 m L of the diluent provided; shake the vial to completely dissolve the contents. Do not freeze the reconstituted solution. For IV use, further dilute the solution in 10-100 m L of normal saline injection. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Antivenin (Latrodectus mactans) Powder for Injection: 6000 anti-venin units/vial in vials with 1 vial diluent (2. 5 m L vial of sterile water for injection) and l m L vial of normal horse serum (1:10 dilution) for sensitivity testing; Antivenin (Lactrodectus mactans); (Merck) (Rx) Note : It has been reported that veterinarians may have difficulty in obtaining this product directly from the manufacturer. Alternative sources include obtaining from a local hospital pharmacy or hav-ing a physician colleague obtain directly from the manufacturer for your practice. Apomorphine hcl (a-poe-mor-feen) Apokyn® emetic Prescriber Highlights Rapid acting, centrally-mediated emetic used in dogs & T T sometimes in cats Contraindicated in certain species (T T e. g., rodents, rabbits) & when vomiting may be deleterious (e. g., impending coma, aspiration) May cause protracted vomiting; naloxone should reverse T T CNS effects or cardio-respiratory depression, but not vomiting Availability & expense may be an issue T T Uses/Indications Apomorphine is used primarily as an emetic in dogs, and is consid-ered the emetic of choice for dogs by many clinicians. It is sometimes used in cats, but its use in this species is somewhat controversial. Pharmacology/Actions Apomorphine stimulates dopamine receptors in the chemorecep-tor trigger zone, thus inducing vomiting. It can cause both CNS

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68 APOm ORPHINE HCl depression and stimulation, but tends to cause more stimulatory ef-fects. Medullary centers can be depressed with resultant respiratory depression. Pharmacokinetics Apomorphine is slowly absorbed after oral administration and has unpre dictable efficacy when given by this route, therefore, it is usu-ally administered parenterally or topically to the eye. When given intravenously in dogs, emesis occurs very rapidly; after IM use, vom-iting occurs generally within 5 minutes but may be more prolonged. T opical administration to the conjunctival sac is usually effective but less so than either IV or IM administration. Apomorphine is primarily conjugated in the liver and then ex-creted in the urine. Contraindications/Precautions/Warnings Emetics can be an important aspect in the treatment of orally in-gested toxins, but must not be used injudiciously. Emetics should not be used in rodents or rabbits, because they are either unable to vomit or do not have stomach walls strong enough to tolerate the act of emesis. Emetics are also contraindicated in patients that are: hypoxic, dyspneic, in shock, lack normal pharyngeal reflexes, seizuring, comatose, severely CNS depressed or where CNS function is deteriorating, or extremely physically weak. Emetics should also be withheld in patients who have previously vomited repeatedly. Because of the risk for additional esophageal or gastric injury with emesis, emetics are contraindicated in patients who have ingested strong acids, alkalis, or other caustic agents. Because of the risks of aspiration, emetics are usually con traindicated after petroleum distillate ingestion, but may be employed when the risks of toxic-ity of the compound are greater than the risks of aspiration. Use of emetics after ingestion of strychnine or other CNS stimulants may precipitate seizures. Emetics generally do not remove more than 80% of the material in the stomach (usually 40-60%) and successful induction of em-esis does not signal the end of appropriate monitoring or therapy. In addition to the contraindications outlined in the general state-ment, apomorphine should not be used in cases of oral opiate or other CNS depressant (e. g., barbiturates) toxicity, or in patients hypersensi tive to morphine. The use of apomorphine in cats is controversial, and several clini-cians state that it should not be used in this species as it is much less effective than either xylazine or ipecac syrup and possibly, less safe. If vomiting does not occur within the expected time after apo-morphine administration, repeated doses are unlikely to induce em-esis and may cause clinical signs of toxicity. Adverse Effects At usual doses, the principal adverse effect that may be seen with apo-morphine is protracted vomiting. Protracted vomiting after ophthal-mic administration may be averted by washing the conjunctival sac with sterile saline or ophthalmic rinsing solution. Excite ment, rest-lessness, CNS depression or respiratory depression are usually only associated with over doses of the drug. Anecdotal reports of corneal ulcers have been noted after conjunctival administration. Reproductive/Nursing Safety The reproductive safety of this drug has not been established; weigh the risks of use versus the po tential benefits. Overdosage/Acute Toxicity Excessive doses of apomorphine may result in respiratory and/or cardiac depression, CNS stimulation (excitement, seizures) or de-pression and protracted vomiting. Naloxone may reverse the CNS and respiratory effects of the drug but cannot be expected to halt the vomiting. Atropine has been suggested to treat severe bradycardias. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving apomorphine and may be of significance in veterinary patients: ANTIDOPAm INERg IC DRUg S T! (e. g., phenothiazines ) may negate the emetic effects of apomorphine OT!PIATES or OTHER CNS or RESPIRATOR y DEPRESSANTS (e. g., barbitu­ rates ): Additive CNS, or respiratory depression may occur when apomorphine is used with these agents Doses DOg S:T! For induction of emesis:a) 0. 03 mg/kg IV or 0. 04 mg/kg IM (IV route preferred); al-ternatively a portion of tablet may be crushed in a syringe, dissolved with few drops of water and administered into the conjunctival sac. After sufficient vomiting occurs, rinse con-junctival sac free of unab sorbed apomorphine. (Beasley and Dorman 1990) b) 0. 04 mg/kg IV or 0. 08 mg/kg IM or SC (Bailey 1989), (Riviere 1985), (Mount 1989) c) 0. 04 mg/kg IV, 0. 07 mg/kg IM, or 0. 25 mg/kg into the con-junctival sac (Jenkins 1988) CATS:T! Note : Use of apomorphine in cats is controversial and many rec-ommend not using in this species. a) For induction of emesis: 0. 04 mg/kg IV or 0. 08 mg/kg IM or SC (Bailey 1989), (Reid and Oehme 1989) monitoring CNS, respiratory, and cardiac systems should be monitored T! Vomitus should be quantified, examined for contents and saved T! for possible later analysis Client Information This agent must be used in a professionally supervised setting T! only Chemistry/Synonyms A centrally-acting emetic, apomorphine occurs as a white powder or minute, white or grayish-white crystals and is sparingly soluble in water or alcohol. Apomorphine HCl may also be known as: apomorphini hydro-chloridum, APO-go®, APO-go Pen®, Apofin®, Apokinon®, Apokyn ®, Apomine®, Britaject®, Ixense®, Taluvian®, or Uprima®. Storage/Stability/Compatibility Apomorphine soluble tablets should be stored in tight containers at room temperature (15-30°C) and protected from light. Upon exposure to light and air, apomorphine gradually darkens in color. Discolored tablets or discolored solutions (green to tur-quoise) should not be used. Apomorphine solutions are more stable in acidic than in alkaline solutions. A 0. 3% solu tion of apomorphine has a p H of about 3-4. Solutions of apomorphine can be made by solubilizing tablets in at least 1-2 m L of either sterile water for injection or 0. 9% so-dium chloride for injection. After being sterilized by filtration, the so lution is stable for 2 days if protected from light and air and stored in the refrigerator. Do not use so lutions that are discolored or form a precipitate after filtering.

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APRAmy CIN SUl FATE 69 Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Pharmaceutical dosage forms of apomorphine have been occasion-ally difficult to obtain and compounding pharmacies may be re-quired to obtain the drug. One commercially prepared product (6 mg tablets) that may be available is produced by JK Levi Co. Some veterinary distributors (e. g., MWI) reportedly stock this product. The ARCI (Racing Commissioners International) has desig-nated this drug as a class 1 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Apomorphine HCl for Injection: 10 mg per m L in 2 m L amps and 3 m L cartridges; Apokyn ® (Mylan Bertek); (Rx) Apr Amycin sulf Ate (a-pra-mye-sin) Apralan® amin O glyc Oside antibi O tic Prescriber Highlights Orally administered aminocyclitol antibiotic for porcine T T E. coli bacillosis in swine (sometimes used in calves— not approved) Products no longer available in USAT T May be partially absorbed in neonates; potentially T T nephro-& ototoxic if absorbed sys temically Uses/Indications Apramycin is no longer commercially available in the USA, but it is used in some countries for the treatment of bacterial enteritis, colibacillosis, salmonellosis, etc. in pigs, calves and poultry. Pharmacology/Actions Apramycin is an aminoglycoside that is bactericidal against many gram-negative bacteria (E. coli, Pseu domonas, Salmonella, Klebsiella, Proteus, Pasturella, Treponema hyodysenteriae, Bordetella bron chiseptica), Staphylococcus and Mycoplasma. It prevents pro-tein synthesis by susceptible bacteria, presumably by binding to the 30S ribosomal subunit. Pharmacokinetics After oral administration, apramycin is partially absorbed, particu-larly in neonates. Absorption is dose related and decreases substan-tially with the age of the animal. Ab sorbed drug is eliminated via the kidneys unchanged. Contraindications/Precautions/Warnings Do not use in known cases of apramycin hypersensitivity. The drug apparently has a wide margin of safety when used orally and is safe to use in breeding swine. Apramycin is contraindicated in cats and in patients with myasthenia gravis. Adverse Effects When used as labeled, the manufacturer does not list any adverse re actions. Should substantial amounts of the drug be absorbed, both ototoxicity and nephrotoxicity are a distinct possibility. Drug Interactions/laboratory Considerations None were noted. May have similar interaction po tential as neomy-cin; refer to that monograph for more information. Doses SWINE:T! For bacterial enteritis caused by susceptible organisms:a) Treated pigs should consume enough water to receive 12. 5 mg/kg body weight per day for 7 days. Add to drinking water at a rate of 375 mg per gallon. After adding to water, stir and allow to stand for 15 minutes, then stir again. (Label direc-tions; Apralan® Solu ble Powder—SKB) b) 20-40 mg/kg PO daily in drinking water (Huber 1988a) c) Pigs: T o be administered via the drinking water. Add 1 small measure (4. 4 m L) or 1 sachet of soluble powder per 20 L of drinking water. (Label information; Apralan Soluble Powder ®—Elanco U. K. ) CATTl E:T! a) For bacterial enteritis caused by susceptible organisms: 20-40 mg/kg PO daily in drinking water (Huber 1988a) b) Calves: For the treatment of colibacillosis or salmonellosis: 1-2 sachets to be administered in the drinking water, milk, or milk replacer to provide 20-40 mg of apramycin activity per kg of bodyweight daily according to the severity of the disease. Continue treatment for 5 days. (Label information; Apralan Soluble Powder®—Elanco U. K. ) POUl TRy:T! a) For bacterial enteritis caused by susceptible organisms: T o be administered via drinking water to provide 250-500 mg of apramycin activity per liter for 5 days. This may be achieved by adding 50 g apramycin per 100-200 liters of water. (Label information; Apralan Soluble Powder®—Elanco U. K. ) monitoring Clinical efficacy T! Chemistry/Synonyms Apramycin is an aminocyclitol antibiotic produced from Streptomyces tenebrarius; it is soluble in water. Apramycin may also be known as nebramycin factor 2, ne-bramcyin II, apramycine, apramicina, AIDS166733, Apralan® or Abylan®. Storage/Stability/Compatibility Apramycin powder should be stored in a cool dry place, in tightly closed containers, protected from moisture. Store at temperatures less than 25°C. If exposed to rust, as in a rusty waterer, the drug can be inactivated. The manufacturer recommends preparing fresh water daily. Shelf life of the powder is 24 months. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None at present in the USA. A swine product: Apramycin Sul-fate Soluble Powder 37. 5 & 48 g (base) bottle; Apralan® (Elanco); (OTC), was formerly marketed in the USA and is still available in several countries. In the UK: Apramycin Soluble Powder: 1 gram sachets and 50 g (apramycin activity) in 220 m L; Apralan Soluble Powder® (Elanco); (POM-V). In the UK when used as labeled: Slaughter withdrawal: Pigs = 14 days, Calves = 28 days, Poultry = 7 days. Not for use in laying hens where eggs are for human consumption. HUm AN­l Ab El ED PRODUCTS: None ASA — see Aspirin

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70 ASCORb IC ACID Ascorbic Acid vit Amin c (a-skor-bik) Prescriber Highlights Prevention/treatment of scurvy in Guinea pigs most ac-T T cepted use At usual dosages, little downside to use; may exacerbate T T liver injury in copper toxicosis Some drug interactions, primarily due to its urinary acidi-T T fication qualities May alter some lab results (urine glucose, occult blood in T T stool, serum bilirubin) Uses/Indications Ascorbic acid is used to prevent and treat scurvy in guinea pigs. It has been used as a urinary acidifier in small animals, but its efficacy is in question. Sodium ascorbate does not acidify the urine. In the past, it was used to treat copper-induced hepatopathy in dogs but this use has fallen into disfavor (see Contraindications below). Pharmacology/Actions Exogenously supplied ascorbic acid is a dietary requirement in some exotic species (including rainbow trout, Coho salmon), guinea pigs, and in primates. The other domestic species are able to synthesize in vivo enough Vitamin C to meet their nutritional needs. Vitamin C is used for tissue repair and collagen formation. It may be involved with some oxidation-reduction reac tions, and with the metabolism of many substances (iron, folic acid, norepinephrine, his tamine, phenylalanine, tyrosine, some drug enzyme systems). Vitamin C is believed to play a role in protein, lipid and carnitine synthesis, main-taining blood vessel integrity and immune function. Pharmacokinetics Vitamin C is generally well absorbed in the jejunum (human data) after oral administration, but absorption may be reduced with high doses as an active process is involved with absorption. Ascorbic acid is widely distributed and only about 25% is bound to plasma pro-teins. Vi tamin C is biotransformed in the liver. When the body is saturated with vitamin C and blood con centrations exceed the re-nal threshold, the drug is more readily excreted unchanged into the urine. Contraindications/Precautions/Warnings Vitamin C (high doses) should be used with caution in patients with diabetes mellitus due to the laboratory interactions (see below), or in patients susceptible to urolithiasis. Because there is some evidence that it may increase copper's oxi-dative damage to the liver, avoid vitamin C's use in animals with copper-associated hepatopathy. Adverse Effects At usual doses vitamin C has minimal adverse effects. Occasionally GI disturbances have been noted in humans. At higher dosages there is an increased potential for urate, oxalate or cystine stone forma-tion, particularly in susceptible patients. Reproductive/Nursing Safety The reproductive safety of vitamin C has not been studied, but it is gen erally considered safe at moderate dosages. In humans, the FDA categorizes this drug as category A for use during pregnancy (Adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) But in dosages greater than the RDA, the FDA categorizes vitamin C as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Very large doses may result in diarrhea and potentially urolithiasis. Generally, treatment should consist of monitoring and keeping the patient well hydrated. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ascorbic acid (high dos-ages) and may be of significance in veterinary patients: Am INOgly COSIDEST! : (e. g., gentamicin ) and ERy THROmy CIN : Are more effective in an alkaline medium; urine acidification may diminish these drugs' effectiveness in treating bacterial urinary tract infec-tions QUINIDINET! : Urine acidification may increase renal excretion DEFEROx Am INET! : While vitamin C may be synergistic with deferox-amine in re moving iron, it may lead to increased iron tissue toxic-ity, especially in cardiac muscle. It should be used with caution, particularly in patients with preexisting cardiac disease. laboratory Considerations URINE gl UCOSE:T! Large doses of vitamin C may cause false-negative values STOOl OCCUl T bl OOD: T! False-negative results may occur if vitamin C is administered within 48-72 hours of an amine-dependent test b Il IRUb IN, SERUm:T! Vitamin C may decrease concentrations Doses CATS:T! a) For adjunctive treatment of FIP: 125 mg PO q12h (Weiss 1994) b) For adjunctive treatment of toxic (e. g., acetaminophen) meth-emoglobinemia (with oxygen, acetylcysteine): 30 mg/kg PO q6h (Macintire 2006b) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: For soft stools (may reduce cecal absorption of clostridial endotoxins): 100 mg/kg PO q12h (Ivey and Mor-risey 2000) g UINEA PIg S:T! For treatment of scurvy: a) During pregnancy: 30 mg/kg either parenterally or PO (in feed or water) (Fish and Besch-Williford 1992) b) 25-50 mg (total dose) parenterally once daily until improve-ment is noted, then give oral supplemental vitamin C (daily requirement is 15 mg/day) (Wilson 2005) c) 10 mg/kg daily, by injection if necessary, plus supportive care. Re covery is relatively rapid, usually within a week. Prevention is adequate daily intake of vitamin C. (Burke 1999) d) 50 mg/kg PO, IM or SC (Adamcak and Otten 2000) For prevention of scurvy: a) Add 200 mg vitamin C to one liter of dechlorinated water and add to water bottle. 10-30 mg/kg PO, SC or IM (Adamcak and Otten 2000)

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ASPARAg INASE 71 HORSES:T! a) For replacement therapy after stress (e. g., strenuous exercise): 20 grams PO daily (Ferrante and Kronfeld 1992) b) For adjunctive treatment of erythrocyte oxidative injury (e. g., red maple toxicity): 10-20 grams PO once daily (Davis and Wilkerson 2003) c) As a urinary acidifier: 1-2 g/kg PO daily (Jose-Cunilleras and Hinchcliff 1999) d) As adjunctive therapy for perinatal asphyxia syndrome in foals: 100 mg/kg per day IV (Slovis 2003b) CATTl E:T! a) For vitamin C-responsive dermatitis in calves: 3 grams SC once or twice (Miller 1993) Chemistry/Synonyms A water-soluble vitamin, ascorbic acid occurs as white to slightly yellow crystal or powder. It is freely soluble in water and sparingly soluble in alcohol. The parenteral solution has a p H of 5. 5-7. Ascorbic acid may also be known as: acidum ascorbicum, L-ascorbic acid, cevitamic acid, E300, or vitamin C; many trade names are available. Storage/Stability/Compatibility Protect from air and light. Ascorbic acid will slowly darken upon light exposure; slight discoloration does not affect potency. Because with time ascorbic acid will de compose with the production of CO2, open ampules and multidose vials carefully. T o reduce the po-tential for excessive pressure within ampules, store in refrigerator and open while still cold. Ascorbic acid for injection is compatible with most commonly used IV solutions, but is incompat ible with many drugs when mixed in syringes or IV bags. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized refer ences or a hospital pharmacist for more specific informa tion. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Parenteral Injection: 250 mg/m L (as sodium ascorbate) in 100 and 250 m L vials; generic; (Rx or OTC depending on label ing) Ascorbic Acid Powder: 442. 25 g/lb Vita-Flex Pure C® (Vita-Flex); 50 grams/lb Mega-C Powder® (AHC); 146 g/pack Stabilized C® (Alpharma); (OTC) HUm AN­l Ab El ED PRODUCTS: As ascorbic acid or sodium ascorbate—Tablets & Capsules: 250 mg, 500 mg, 1000 mg & 1500 mg; Cevi-Bid® (Lee); generic; (OTC); Oral Extended-release Tablets: 500 mg & 1000 mg; generic; (OTC)Crystals: 1000 mg per G tsp. in 120g and 1 lb; Vita-C® (Freeda); (OTC) Powder: 1060 mg per G tsp. in 120 g and 1 lb; 60 mg per G tsp. in 454 g; Dull-C® (Freeda); Ascorbic Acid (Humco); (OTC)Liquid/Solution: 100 mg/m L in 50 m L and 500 mg/5 m L in 120 m L and 480 m L; Cecon® (Abbott); generic; (OTC) Parenteral Injection: 500 mg/m L in 50 m L vials; Ascor L 500® (Mc Guff); generic; (Rx)Asp Ar Agin Ase (a-spar-a-gin-ase) L-Asparaginase, Elspar® antine Oplastic Prescriber Highlights Antineoplastic useful in treating lymphoid malignancies T T in dogs/cats Two primary adverse effects: hypersensitivity & effects T T on protein synthesis (usually manifested by: GI effects, hemorrhagic pancreatitis, hepatotoxicity or coagulation disor ders); bone marrow suppression is more rare Uses/Indications Asparaginase has been useful in combination with other agents in the treatment of lymphoid malignancies. The drug is most useful in inducing remission of disease but is occasion ally used in mainte-nance or rescue protocols. Use of asparaginase as part of an initial treatment lymphosar-coma protocol is now somewhat controversial, as one study (Mac Donald, Thamm et al. 2005) in dogs showed no statistical difference for response rates, remission or survival rate, remission or survival duration, or prevalence of toxicity and treatment delay in dogs treated with or without asparaginase as part of a standard CHOP protocol. Pharmacology/Actions Some malignant cells are unable to synthesize asparagine and are dependent on ex ogenous asparagine for DNA and protein synthe-sis. Asparaginase catalyzes asparagine into ammonia and aspartic acid. The antineoplastic activity of asparaginase is greatest during the post mitotic (G 1) cell phase. While normal cells are able to syn-thesize asparagine intracellularly, some normal cells having a high rate of protein synthesis, require some exogenous asparagine and may be adversely af fected by asparaginase. Resistance to asparaginase can develop rapidly, but apparently, there is no cross-resistance between asparaginase and other antine-oplastic agents. Asparaginase possesses antiviral activity, but its toxicity prevents it from being clinically useful in this regard. Pharmacokinetics Asparaginase is not absorbed from the GI tract and must be given either IV or IM. After IM injection, serum levels of asparaginase are approximately H of those after IV injec tion. Because of its high molecular weight, asparaginase does not diffuse readily out of the capillar ies and about 80% of the drug remains within the intravas-cular space. In humans after IV dosing, serum levels of asparagine fall al-most immediately to zero and remain that way as long as therapy continues. Once therapy is halted, serum levels of asparagine do not re cover for at least 23 days. The metabolic fate of asparaginase is not known. In humans, the plasma half-life is highly variable and ranges from 8-30 hours. Contraindications/Precautions/Warnings Asparaginase is contraindicated in patients who have exhibited anaphylaxis to it, or those with pancreatitis or a history of pan-creatitis. As paraginase should be used with caution in patients with preexisting hepatic, renal, hematologic, gas trointestinal, or CNS dysfunction.

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72 ASPARAg INASE No special precautions are required for handling asparaginase, but any inadvertent skin contact should be washed off, as the drug can be a contact irritant. Adverse Effects Asparaginase adverse reactions are classified in two main cat-egories, hypersensitivity reactions and effects on protein synthesis. Hypersensitivity reactions can occur with clinical signs of vomit-ing, diarrhea, urticaria, pruritus, dyspnea, restlessness, hypotension and col lapse. The likelihood of hypersensitivity reactions occurring increases with subsequent doses and in travenous administration. Some clinicians recommend giving a test dose before the full dose to test for local hypersensitivity. Most oncologists now recommend administering antihistamines (e. g., diphenhydramine (at 2 mg/kg in dogs and 1 mg/kg in cats SC 30 minutes prior to administration) prior to dosing. If a hypersensitivity reaction occurs, diphenhy-dramine (0. 2-0. 5 mg/kg slow IV), dexamethasone sodium phos-phate (1-2 mg/kg IV), intravenous fluids and, if severe, epinephrine (0. 1-0. 3 m L of a 1:1000 solution IV) have been suggested (O'Keefe and Harris 1990). The other broad category of toxicity is associated with aspara-ginase's effects on protein synthesis. Hemorrhagic pancreatitis or other gastrointestinal disturbances, hepatotoxicity and coagulation de fects may be noted. Large doses may be associated with hyper-glycemia secondary to altered insulin synthesis. Bone marrow de-pression is an uncommon consequence of asparaginase therapy, but leukopenia has been reported. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Little information was located regarding overdosages with this agent. It would be expected that toxicity secondary to the protein synthesis altering effects of the drug would be encountered. In dogs, it has been reported that the maximally tolerated dose of asparaginase is 10,000 IU/kg and the lethal dose is 50,000 IU/kg. It is recommended to treat supportively if an overdose occurs. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving asparaginase and may be of significance in veterinary patients: m ETHOTREx ATET! : Asparaginase may reduce methotrexate effective-ness against tumor cells until serum asparagine levels return to normal PREDNISONET! : Use with asparaginase may increase risk for hyper-glycemia; in humans, asparaginase is usually administered after prednisone VINCRISTINET! : In humans, increased toxicity (neuropathy and erythropoiesis disruption) may occur when asparaginase (IV) is given concurrently with or be fore vincristine. Myelosuppression reportedly occurs in a minority of dogs treated with vincristine/ asparaginase; some veterinary oncologists separate the dosing by a few days to a week, but others do not feel this is beneficial. laboratory Considerations SERUm Amm ONIA AND UREA NITROg EN: T! levels may be increased by the action of the drug THy ROx INE­b INDINg gl Ob Ul IN:T! Asparaginase may cause rapid (with-in 2 days) and profound decreases in circulating TBG, which may alter interpretation of thyroid function studies; values may return to normal after approximately 4 weeks Doses For more information, refer to the protocols found in the appendix or other dosages/protocols found in numerous references, includ-ing: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). Note : Many oncologists recommend administering antihistamines such as diphenhydramine at 2 mg/kg for dogs and 1 mg/kg for cats SC 30 minutes prior to administration. DOg S:T! For lymphoid malignancies (Usually used in combination proto-cols with other drugs; rarely used alone):a) For induction therapy (as part of a protocol): 10,000 Units/m2 SC or IM (Kitchell and Dhaliwal 2000) For evaluation of hypercalcemia of undetermined etiology to rule out occult lymphoma: a) Pre-treat with an antihistamine, then asparaginase at 20,000 IU/m2 IV. Measure serum calcium prior to therapy and ev-ery 12 hours after administration, for as long as 72 hours. A decline in serum calcium, usually into the normal range, is strongly suggestive of occult lymphoma. (Nelson 2002a) For relapsed or refractory canine lymphoma (LSA) with lomus-tine and prednisone: a) Lomustine at 70 mg/m2 (for dogs weighing 15 kg or more (60 mg/m2 (for dogs weighing less than 15 kg) PO every three weeks for a total of 5 doses or until disease progression. In dogs with neutrophil counts less than 500 cells/microliter 1 week after lomustine treatment, doses are decreased by 10 mg/m2 for subsequent doses. As lomustine comes in 10 mg, 40 mg, & 100 mg capsules, round lomustine doses down if necessary. Asparaginase at 400 Units/kg SC concurrently with the first two lomustine treatments and then discontinued. Prednisone started at 2 mg/kg PO once daily and then tapered over the protocol duration to 1 mg/kg PO every other day. (Saba, Thamm et al. 2007) CATS:T! For lymphoid malignancies (usually used in combination proto-cols with other drugs; rarely used alone):a) 10,000 Units/m2 SC, intraperitoneally, or IM every 1-3 weeks (Couto 1989b) b) 400 Units/kg SC or IM (as part of a protocol) (Kitchell and Dhaliwal 2000) For evaluation of hypercalcemia of undetermined etiology to rule out occult lymphoma: a) Pre-treat with an antihistamine, then asparaginase at 20,000 IU/m2 IV. Measure serum calcium prior to therapy and ev-ery 12 hours after administration, for as long as 72 hours. A decline in serum calcium, usually into the normal range, is strongly suggestive of occult lymphoma. (Nelson 2002a) monitoring Animals should have hepatic, renal, pancreatic (blood glucose, T! amylase) and hematopoietic function determined prior to initiat-ing therapy and regularly monitored during ther apy. Client Information Clients must be briefed on the possibilities of severe toxicity de-T! veloping from this drug, including drug-related mortality

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ASPIRIN 73 Clients should contact the veterinarian if the patient ex hibits any T! symptoms of profound depression, severe diarrhea, abnormal bleeding (including bloody diarrhea) and/or bruising Chemistry/Synonyms Asparaginase is an enzyme derived from E. coli and occurs as a white or almost white, slightly hygroscopic powder that is soluble in wa-ter. The commercially available product is a lyophilized powder that also contains mannitol that after reconstituting has a p H of about 7. 4. Ac tivity of asparaginase is expressed in terms of International Units (I. U. ). Asparaginase may also be known as: coloaspase, A-ase, ASN-ase, L-asparaginase, L-asparagine amidohydrolase, MK-965 NSC-109229, Re-82-TAD-15, Crasnitin®, Crasnitine®, Elspar®, Erwinase®, Kidrolase®, L-Asp ®, Laspar®, Leucogen®, Leunase®, Paronal®, or Serasa®. Storage/Stability/Compatibility Asparaginase powder for injection should be stored at tempera-tures less than 8°C, but it is stable for at least 48 hours at room temperature. After reconstituting, the manufacturer states that the drug is stable when refrigerated for up to 8 hours, but other sources state that it is stable for up to 14 days. Solutions should be used only if clear; turbid solutions should be discarded. Upon standing, gelati nous fibers may be noted in the solution occasionally. These may be removed without loss of po-tency with a 5 micron filter. Some loss of potency may occur if a 0. 2 micron filter is used. The solution may be shaken while reconstituting, but vigorous shaking should be avoided as the solution may become foamy and difficult to withdraw from the vial and some loss of potency can oc-cur. Recommended intravenous diluents for asparaginase include D5W and sodium chloride 0. 9%. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Asparaginase Powder for Injection: 10,000 IU in 10 m L vials (with 80 mg mannitol, preservative-free); Reconsti tute vial with 5 m L So-dium Chloride Injection or Sterile Water for Injection for IV use. For IM use, add 2 m L Sodium Chloride Injection. See Storage/Sta-bility section for more information. Elspar® (Merck); (Rx) Aspirin (ass-pir-in) ASA, Acetylsalicylic Acid analgesic; antipyretic; platelet aggre-gati On reducer; antiinflammat Ory Prescriber Highlights NSAID used for analgesic, antiinflammatory & antiplate-T T let effects in a variety of species Contraindicated in patients hypersensitive to it or with T T active GI bleeds; Relatively contraindi cated in patients with bleeding disorders, asthma, or renal insufficiency (but has been used to treat glomerular disease) Cats relatively sensitive to salicylates (dose carefully); T T dogs relatively sensitive to GI effects (bleeding)Low grade teratogen & may delay labor; avoid use in T T pregnancy Many drug & lab interactions T TUses/Indications Aspirin is used in all species for its analgesic and antipyretic effects. It is one of the few nonsteroidal antiinflammatory agents that is relatively safe to use in both dogs and cats, although it can cause sig-nificant GI bleeding in dogs. Besides its analgesic, antiinflammatory and antipyretic effects, aspirin is used therapeutically for its effects on platelet aggregation in the treatment of DIC and pulmonary ar-tery disease secondary to heartworm infestation in dogs. It is also used in cats with cardiomyopathy. Aspirin (at low doses) may be of benefit in the adjunctive treatment of glomerular disease due to its antiplatelet and antiinflammatory activity. Pharmacology/Actions Aspirin inhibits cyclooxygenase (prostaglandin synthetase) thereby reducing the synthesis of prostaglandins and thromboxanes. These effects are thought to be how aspirin produces analgesia, antipyrex-ia, and reduces platelet aggregation and inflammation. Most cells can synthesize new cyclooxygenase, but platelets cannot. Therefore, aspirin causes an irreversible effect on platelet aggregation. Aspirin has been shown to decrease the clinical signs of experimentally in-duced anaphylaxis in calves and ponies. Pharmacokinetics Aspirin is rapidly absorbed from the stomach and proximal small intestine in monogastric animals. The rate of absorption is depen-dent upon factors as stomach content, gastric emptying times, tab-let disintegration rates and gastric p H. Absorption is slow from the GI tract in cattle, but approximately 70% of an oral dose will be absorbed. During absorption, aspirin is partially hydrolyzed to salicylic acid where it is distributed widely throughout the body. Highest levels may be found in the liver, heart, lungs, renal cortex, and plasma. The amount of plasma protein binding is variable depending on species, serum salicylate and albu min concentrations. At lower sali-cylate concentrations it is 90% protein bound, but only 70% pro-tein bound at higher concentrations. Salicylate is excreted into milk but levels appear to be very low. Salicylate will cross the placenta and fetal levels may actually exceed those found in the mother. Salicylate is metabolized in the liver primarily by conjugation with glycine and glucuronic acid via glucuronyl transferase. Because cats are deficient in this enzymatic pathway, they have prolonged half-lives and are susceptible to accumulating the drug. Minor me-tabolites formed include gentisic acid, 2,3-dihydroxybenzoic acid, and 2,3,5-trihydroxybenzoic acid. Gentisic acid appears to be the only active metabolite, but because of its low concentrations ap-pears to play an insignificant role therapeutically. The rate of me-tabolism is determined by both first order kinetics and dose-de-pendent kinetics depending on which metabolic pathway is looked at. Generally, steady-state serum levels will increase to levels higher (proportionally) than expected with dosage increases. These ef fects have not been well studied in domestic animals, however. Salicylate and its metabolites are rapidly excreted by the kidneys by both filtration and renal tubular secretion. Significant tubular reabsorption occurs which is highly p H dependent. Salicylate ex-cretion can be significantly increased by raising urine p H to 5-8. Salicylate and metabolites may be removed using peritoneal dialysis or more rapidly using hemodialysis. Contraindications/Precautions/Warnings Aspirin is contraindicated in patients demonstrating previous hy-persensitivity reactions to it or in patients with bleeding ulcers. It is relatively contraindicated in patients with hemorrhagic disorders, asthma, or renal insufficiency. Because aspirin is highly protein bound to plasma albumin, patients with hypoalbuminemia may require lower dosages to

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74 ASPIRIN prevent clinical signs of toxicity. Aspirin should be used cautiously with en hanced monitoring in patients with severe hepatic failure or diminished renal function. Because of its effects on platelets, aspi-rin therapy should be halted, if possible, one week prior to surgical proce dures. Aspirin must be used cautiously in cats because of their inability to rapidly metabolize and excrete salicylates. Clinical signs of toxic-ity may occur if dosed recklessly or without stringent monitoring. As pirin should be used cautiously in neonatal animals; adult doses may lead to toxicity. Adverse Effects The most common adverse effect of aspirin at therapeutic doses is gastric or intestinal irritation with varying degrees of occult GI blood loss occurring. The resultant irritation may result in vomiting and/or anorexia. Severe blood loss may result in a secondary anemia or hypoproteinemia. In dogs, plain uncoated aspirin may be more irritating to the gastric mucosa than either buffered aspirin or en-teric-coated tablets. Hypersensitivity reactions have been reported in dogs although they are thought to occur rarely. Cats may develop acidosis from aspirin therapy. Reproductive/Nursing Safety Salicylates are possible teratogens and have been shown to delay par-turition; their use should be avoided during pregnancy, particularly during the later stages. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) In a separate sys-tem evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the benefit of therapy clearly outweighs the risks. ) Overdosage/Acute Toxicity Clinical signs of acute overdosage in dogs and cats include: depres-sion, vomiting (may be blood tinged), anorexia, hyperthermia, and increased respiratory rate. Initially, a respiratory alka losis occurs with a compensatory hyperventilation response. A profound meta-bolic acidosis follows. If treatment is not provided, muscular weak-ness, pulmonary and cerebral edema, hypernatremia, hy pokalemia, ataxia, and seizures may all develop with eventual coma and death. There were 899 exposures to aspirin reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 754 were dogs with 114 showing clinical signs and the remaining 132 cases were cats with 9 showing clinical signs. The remaining 12 cases were made up of 5 birds, 3 equine, 2 lagomorphs and 2 rodents that showed no clinical signs. Common findings in dogs recorded in decreasing frequency included: anorex-ia, vomiting, lethargy, bloody vomitus, diarrhea and hyperthermia. Common findings in cats recorded in decreasing frequency includ-ed vomiting, dyspnea, cyanosis and abnormal mucous membrane color. Treatment of acute overdosage initially consists of emptying the gut if ingestion has occurred within 12 hours, giving activated char-coal and an oral cathartic, placing an intravenous line, begin ning fluids and drawing appropriate lab work (e. g., blood gases). Some clinicians suggest performing gastric lavage with a 3-5% solution of sodium bicarbonate to delay the absorption of aspirin. A rea-sonable choice for an intravenous solution to correct dehydration would be dextrose 5% in water. Acidosis treatment and forced al-kaline diuresis with sodium bicarbonate should be performed for serious ingestions, but should only be attempted if acid-base status can be monitored. Diuresis may be enhanced by the administration of mannitol (1-2 gm/kg/hr). GI protectant medications should also be administered. Seizures may be controlled with IV diazepam. Treatment of hypoprothrombinemia may be attempted by using phytonadione (2. 5 mg/kg divided q8-12h) and ascorbic acid (25 mg parenterally) but ascorbic acid may negate some of the urinary alkalinization effects of bicarbonate. Peritoneal dialy sis or exchange transfusions may be attempted in very severe ingestions when heroic measures are desired. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aspirin and may be of significance in veterinary patients: DRUg S THAT Al KAl INIz E THE URINE T! (e. g., acetazolamide, sodium bicar­ bonate ) significantly increase the renal excretion of salicylates; be-cause carbonic anhydrase inhibitors (e. g., acetazolamide, dichlo-rphenamide) may cause systemic acidosis and increase CNS levels of salicy lates, toxicity may occur Am INOgly COSIDEST! : Some clinicians feel that aspirin should not be given concomitantly with aminoglycoside antibi otics because of an increased likelihood of nephrotoxicity developing. The actual clinical signifi cance of this interaction is not clear, and the risk versus benefits should be weighed when contemplating therapy CORTICOSTEROIDST! : May increase the clearance of salicylates and de-crease serum levels and increase the risks for GI bleeding DIg Ox INT! : In dogs, aspirin has been demonstrated to increase plas-ma levels of digoxin by decreasing the clearance of the drug FUROSEm IDET! : May compete with the renal excretion of aspirin and delay its excretion; this may cause clinical signs of toxicity in ani-mals receiving high aspirin doses HEPARIN T! or ORAl ANTICOAg Ul ANTS : Aspirin may increase the risks for bleeding m ETHOTREx ATET! : Aspirin may displace MTX from plasma proteins increasing the risk for toxicity NSAIDST! : Increased chances of developing GI ulceration exist PHENOb ARb ITAl T! : May increase the rate of metabolism of aspirin by inducing hepatic enzymes PROb ENECID, SUl FINPy RAz ONET! : At usual doses, aspirin may antago-nize the uricosuric effects of probenicid or sulfinpyrazone SPIRONOl ACTONET! : Aspirin may inhibit the diuretic activity of spironolactone TETRACy Cl INET! : The antacids in buffered aspirin may chelate tetra-cycline products if given simultaneously; space doses apart by at least one hour URINAR y ACIDIFy INg DRUg S T! (methionine, ammonium chloride, ascorbic acid): Can decrease the uri nary excretion of salicylates laboratory Considerations At high doses, aspirin may cause false-positive results for T! urinary glucose if using the cupric sulfate method (Clinitest®, Benedict's solution) and false-negative re sults if using the glucose oxidase method (Clinistix® or Tes-Tape®). Urinary ketones T! measured by the ferric chloride method (Ger-hardt) may be affected if salicylates are in the urine (reddish-color produced). 5­HIAA determinations by fluorescent methods may be interfered by salicylates in the urine. Falsely elevated Vm A (vanilly-lmandelic acid) may be seen with most methods used if salicylates are in the urine. Falsely lowered Vm A levels may be seen if using the Pisano method.

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ASPIRIN 75 Urinary excretion of T! xylose may be decreased if aspirin is given concurrently. Falsely elevated serum uric acid values may be mea-sured if using colorimetric methods. Aspirin can decrease serum concentrations of T! T3, T4 and free T4 in dogs. Doses DOg S:T! Note : Recommend using buffered varieties of aspirin in dogs For analgesia: a) 10-25 mg/kg PO q8-12h (Morgan 1988); (Mc Laughlin 2000) b) 10-20 mg/kg PO q12h (Jenkins 1987), (Holland and Chastain 1995) c) 10-25 mg/kg PO q12h in food (Hardie 2000) d) 10 mg/kg PO q12h (Lascelles 2003) As an antiinflammatory/antirheumatic: a) 25 mg/kg PO q8h (Holland and Chastain 1995) For antipyrexia: a) 10 mg/kg PO twice daily (Morgan 1988); (Holland and Chastain 1995) Post-Adulticide therapy for heartworm disease: a) 7-10 mg/kg PO once a day (Calvert 1987) T o decrease platelet aggregation; as an antithrombotic: a) 0. 5 mg/kg PO twice daily (Rackear et al. 1988); (Holland and Chastain 1995) b) For adjunctive therapy of glomerular disease: 0. 5 mg/kg PO q12-24h (Grauer and Di Bartola 2000) c) For adjunctive therapy of glomerular disease: 0. 5 mg/kg PO q24h (Di Bartola and Chew 2006b) d) For adjunctive therapy with azathioprine and glucocorti-coids for immune-mediated hemolytic anemia: 0. 5 mg/kg PO once daily (Weinkle, Center et al. 2004) For Disseminated Intravascular Coagulation (DIC): a) 150-300 mg/20kg animal PO once a day to once every other day for 10 days (Morgan 1988) As an analgesic/antiinflammatory prior to elective intraocular surgery: a) 6. 5 mg/kg two to three times daily (Wyman 1986) CATS:T! For analgesia: a) 10 mg/kg PO every other day (Jenkins 1987); (Holland and Chastain 1995) b) 10 mg/kg PO q48-72h in food (Hardie 2000) c) 11-22 mg/kg PO q48h (every other day) (Kelly 1995 For the treatment of arthritis as an antirheumatic/anti- inflammatory: a) 10-20 mg/kg PO every other day (q48h) (Hardie 1997) b) 25 mg/kg PO once daily (Chastain 1987); (Holland and Chastain 1995) For antipyrexia: a) 10 mg/kg PO q48h (every other day) (Holland and Chastain 1995) As an antithrombotic agent:a) For adjunctive treatment of hypertrophic feline cardiomyo-pathy or intermediate (restrictive) fe line cardiomyopathy (as an anti-thrombogenic agent): 5 mg per cat PO q72h (every 3 days) (T obias 2000) b) For prophylaxis of arterial thromboembolism (ATE): 5 mg (total dose) per cat PO q72hours (every 3rd day) (Smith, T o-bias et al. 2003)c) For prophylaxis of arterial thromboembolism: 81 mg (total dose; one “baby” aspirin) q72hours (every 3 rd day). Likely a weaker, but less expensive option than clopidogrel/LMWH. Generally, aspirin therapy is recommended in all cats with atrial enlargement and cardiomyopathy. (Meurs 2006d) d) 25 mg/kg PO q56-84h (Holland and Chastain 1995) As an analgesic/antiinflammatory prior to elective intraocular surgery: a) 6. 5 mg/kg two to three times daily (Wyman 1986) T o inhibit platelet function: a) 25 mg/kg, (or G of a 325 mg tablet) PO every 48-72 hours. Will inhibit platelet function for 3-5 days. (Fox 2000) FERRETS:T! a) 10-20 mg/kg PO once daily (has short duration of activity) (Williams 2000) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: 5-20 mg/kg PO once daily for low grade analgesia (Ivey and Morrisey 2000) b) Mice, Rats, Gerbils, Hamsters: 100-150 mg/kg PO q4h. Guinea pigs: 87 mg/kg PO (Adamcak and Otten 2000) CATTl E:T! For analgesia/antipyrexia: a) 100 mg/kg PO q12h (Walz 2006b) b) Mature Cattle: two to four 240 grain boluses PO; Calves: one to two 240 grain boluses, allow animals to drink water after administration (Label directions; Vedco Brand) HORSES: (T! Note : ARCI UCGFS Class 4 Drug) For analgesia: a) Mature Horses: two to four 240 grain boluses PO b) Foals: one to two 240 grain boluses; allow animals to drink water after administration (Label directions-Vedco Brand) c) 25 mg/kg PO q12h initially, then 10 mg/kg once daily (Jen-kins 1987) d) 15- 100 mg/kg PO onc e daily (Robinson 1987) For anti-platelet activity as an adjunctive treatment of laminitis: a) 5-10 mg/kg PO q24-48 hours or 20 mg/kg PO every 4-5 days (Brumbaugh, Lopez et al. ) SWINE:T! For analgesia: a) 10 mg/kg q4h PO (Jenkins 1987), (Koritz 1986) b) 10 mg/kg q6h PO (Davis 1979) AVIAN:T! a) 5 grams in 250 m L of water as sole water source (Clubb 1986) Note: Because of the significant hydrolysis that will occur, this solution should be freshly prepared every 12 hours if stored at room temperature or every 4 days if kept refrigerated at 5° C. monitoring Analgesic effect &/or antipyretic effect T! Bleeding times if indicated T! PCV and stool guaiac tests if indicated T! Client Information Contact veterinarian if symptoms of GI bleeding or distress oc-T! cur (black, tarry feces; anorexia or vomiting, etc. ). Because aspirin is a very old drug, formal approvals from the T! FDA for its use in animals have not been required. There is no listed meat or milk withdrawal times listed for food-producing animals but because there are salicylate-sensitive people, in the interest of public health, this author suggests a minimum of 1 day withdrawal time for either milk or meat.

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76 ASPIRIN Chemistry/Synonyms Aspirin, sometimes known as acetylsalicylic acid or ASA, is the sali-cylate ester of acetic acid. The compound occurs as a white, crystal-line powder or tabular or needle-like crystals. It is a weak acid with a p K a of 3. 5. Aspirin is slightly soluble in water and is freely soluble in alcohol. Each gram of aspirin contains approximately 760 mg of salicylate. Aspirin may also be known as: ASA, acetylsal acid, acetylsalicylic acid, acidum acetylsalicylicum, polopiryna, or salicylic acid acetate; many trade names are available. Storage/Stability/Compatibility Aspirin tablets should be stored in tight, moisture resistant con-tainers. Do not use products past the expiration date or if a strong vinegar-like odor is noted emitting from the bottle. Aspirin is stable in dry air, but readily hydrolyzes to acetate and salicylate when exposed to water or moist air; it will then exude a strong vinegar-like odor. The addition of heat will speed the rate of hydrolysis. In aqueous solutions, aspirin is most stable at p H's of 2-3 and least stable at p H's below 2 or greater than 8. Should an aqueous solution be desirable as a dosage form, the commercial prod uct Alka-Seltzer® will remain stable for 10 hours at room tem-perature in solution. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Aspirin Tablets (Enteric-Coated): 81 mg; (Hartz); (OTC) Labeled for use in dogs. Aspirin Tablets (Buffered, Microencapsulated, Chewable for dogs): 150 mg & 450 mg; Canine Aspirin Chewable Tablets for Small & Me-dium (150 mg) or Large Dogs® (450 mg) (Pala-T ech); (OTC) La-beled for use in dogs. Aspirin Tablets 60 grain (3. 9 g): Aspirin 60 Grain (Butler); (OTC) and (Vedco); (Rx); Rx is labeled for use in horses, cattle, sheep and swine; not for use in horses intended for food or in lactating dairy ani mals. Aspirin Boluses 240 grain (15. 6 g): Labeled for use in horses, foals, cattle and calves; not for use in lactat ing animals. Aspirin 240 Grain Boluses, Aspirin Bolus (various); (OTC) Aspirin Boluses 480 grain (31. 2 g). Labeled for use in mature horses, & cattle. Aspirin 480 Grain Boluses (various); (OTC) Oral Aspirin Gel: 250 mg/m L in 30 m L: Aspir-Flex® Aspirin Gel for Small and Medium Dogs (Durvet); 500 mg/1 m L in 30 m L: Aspir-Flex® Aspirin Gel for Large Dogs (Durvet); (OTC) Labeled for use in dogs. Aspirin Powder: l lb. (various); (OTC); Aspirin Powder Molasses-Flavored 50% acetylsalicylic acid in base (Butler); Aspirin USP 204 g/lb (apple flavored) (Neogen); Acetylsalicylic acid; (OTC) Aspirin Granules: 2. 5 gram per 39 m L scoop (apple and molasses flavor); Arthri-Eze Aspirin Granules® (Durvet); (OTC); Labeled for use in horses Aspirin Liquid Concentrate (equiv to 12% aspirin) for Dilution in Drinking Water in 32 oz btls. (Agri Pharm, First Priority); (OTC); Labeled for addition to drinking water for swine, poultry, beef and dairy cattle There are no listed meat or milk withdrawal times listed for food-producing animals, but because there are salicylate-sensitive peo-ple, in the interest of public health, this author suggests a mini-mum of 1 day withdrawal time for either milk or meat. For further guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for con-tact information). The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS:T! Note : Many dosage forms and brand names are commercially avail-able; the following is an abbre viated list of some products that have been used for veterinary indications: Aspirin, Chewable Tablets: 81 mg (1. 25 grains); Bayer ® Children's As-pirin (Bayer); St. Joseph® Adult Chewable Aspirin (Schering-Plough); (OTC)Aspirin, Tablets; plain uncoated; 325 mg (5 grain), & 500 mg (7. 8 grain); Genuine and Maximum Bayer® Aspirin Tablets and Caplets (Bayer); Empirin® (Glaxo Wellcome); Arthritis Foundation® Pain Reliever (Mc Neil-CPC); Norwich® Regular Strength (Lee); Norwich Extra-Strength® (Procter & Gamble); generic; (OTC) Aspirin Tablets, enteric coated: 81 mg, 165 mg, 325 mg, 500 mg, 650 mg, & 800 mg; Ecotrin ® Adult Low Strength (Glaxo Smith Kline Consumer Healthcare); Halfprin 81® and H Halfprin® (Kramer), Heartline® (BDI), Ecotrin ® Tablets & Caplets and Ecotrin ® Maximum Strength Caplets (Smith Kline Beecham); Extra Strength Bayer® En-teric 500 Aspirin (Bayer); generic; (OTC) Aspirin Extended-controlled Release Tablets: 81 mg, 650 mg, 800 mg & 975 mg; Extended Release Bayer® 8-hour Caplets (Bayer); (OTC), ZORprin® (PAR); (Rx), Bayer ® Low Adult Strength (Bayer); generic; (OTC) Aspirin, Tablets; buffered uncoated; 325 mg (5 grain), with alumi-num &/or magnesium salts; Tri-Buffered Bufferin Tablets and Ca-plets® (Bristol-Myers Squibb); Bayer ® Buffered Aspirin (Bayer); Asp-rimox® and Asprimox® Extra Protection for Arthri tis (Invamed); 500 mg with calcium carbonate, magnesium carbonate, & magnesium oxide; Extra Strength Bayer® Plus Caplets (Bayer); Bufferin® (Bristol-Myers); 500 mg with 237 mg calcium carbonate, 33 mg magne-sium hydroxide, 33 mg aluminum hydroxide; Ascriptin® Maximum Strength (Novartis); 500 mg with 100 mg magnesium hydroxide and 27 mg aluminum hydroxide; Arthritis Pain Formula® (Whitehall); 325 mg with 75 mg aluminum hydroxide, 75 mg magnesium hy-droxide and calcium carbonate; Asprimox Extra Protection for Ar-thritis Pain® (Invamed); generic; (OTC) Aspirin Tablets: buffered coated: 325 mg & 500 mg. Adprin-B® (Pfe-iffer); Asprimox® (Invamed); Magnaprin® and Magnaprin® Arthritis Strength Captabs® (Rugby); Ascriptin® and Ascriptin® Extra Strength (Rhone-Poulenc Rorer), Bufferin® (Bristol Myers); generic; (OTC) Rectal suppositories, chewing gum and effervescent oral dosage forms are also available commercially for human use.

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ATENOl Ol 77 Atenolol (a-ten-oh-lol) Tenormin® beta-adrenergic bl Ocker Prescriber Highlights Beta-blocker that is used primarily for hypertension & T T tachyarrhythmias in small ani mals Has minimal beta-2 activity at usual doses; compara-T T tively safe to use in asthmatic patients Contraindicated in patients with bradycardic arrhythmias, T T or hypersensitivity to it Negative inotrope so must be used with caution in pa-T T tients with CHF; use with caution in renal fail ure patients & those with sinus node dysfunction Higher dosages may mask clinical signs of hyper-T T thyroidism or hypoglycemia; may cause hyper-or hypoglycemia—use with caution in brittle diabetics Primary adverse effects are lethargy, hypotension, or T T diarrhea If discontinuing, recommend withdrawing gradually T T Uses/Indications Atenolol may be useful in the treatment of supraventricular tach-yarrhythmias, premature ventricular contractions (PVC's, VPC's), systemic hypertension and in treating cats with hypertrophic car-diomyopathy. Atenolol is relatively safe to use in animals with bron-chospastic disease. Pharmacology/Actions Atenolol is a relatively specific Beta 1-blocker. At higher dosages, this specificity may be lost and Beta 2 blockade can occur. Atenolol does not possess any intrinsic sympathomimetic activity like pindolol nor does it possess membrane-stabilizing activity like pindolol or propranolol. Cardiovascular effects secondary to atenolol's nega-tive inotropic and chronotropic actions include: decreased sinus heart rate, slowed A V conduction, diminished cardiac output at rest and during exer cise, decreased myocardial oxygen demand, reduced blood pressure, and inhibition of isoproterenol-induced tachycardia. Pharmacokinetics Only about 50-60% of an oral dose is absorbed in humans, but is absorbed rapidly. In cats, it is reported to have a bioavailability of approximately 90%. The drug has very low protein binding charac-teristics (5-15%) and is distributed well into most tissues. Atenolol has low lipid solubility and unlike propranolol, only small amounts of atenolol are distributed into the CNS. Atenolol crosses the placen-ta and levels in milk are higher than those found in plasma. Atenolol is minimally biotransformed in the liver; 40-50% is excreted un-changed in the urine and the bulk of the remainder is excreted in the feces unchanged (unabsorbed drug). Reported half-lives: dogs = 3. 2 hours; cats = 3. 7 hours; humans = 6-7 hours. Duration of beta blockade effect in cats persists for about 12 hours. Contraindications/Precautions/Warnings Atenolol is contraindicated in patients with overt heart failure, hypersensitivity to this class of agents, greater than first-degree heart block, or si nus bradycardia. Non-specific beta-blockers are generally contraindicated in patients with CHF un less secondary to a tachyarrhythmia responsive to beta-blocker therapy. They are also relatively contraindicated in patients with bronchospastic lung disease. Atenolol should be used cautiously in patients with significant renal insufficiency or sinus node dysfunction. Atenolol (at high dosages) can mask the clinical signs associ-ated with hypoglycemia. It can also cause hypoglycemia or hyperg-lycemia and, therefore, should be used cautiously in labile diabetic patients. Atenolol can mask the clinical signs associated with thyrotoxi-cosis, however, it may be used clinically to treat the clinical signs associated with this condition. Adverse Effects It is reported that adverse effects most commonly occur in geriat-ric animals or those that have acute decompensating heart disease. Adverse effects considered clin ically relevant include: bradycardia, inappetance, lethargy and depression, impaired A V conduction, CHF or worsening of heart failure, hypotension, hypoglycemia, and bronchoconstriction (less so with Beta 1 specific drugs like atenolol). Syncope and diarrhea have also been reported in canine patients with beta-blockers. Lethargy and hypotension may be noted within 1 hour of administration. Exacerbation of symptoms has been reported following abrupt cessation of beta-blockers in hu mans. It is recommended to with-draw therapy gradually in patients who have been receiving the drug chronically. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity There were 208 exposures to atenolol reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 145 were dogs with 11 showing clini-cal signs, 62 cases were cats with 4 showing clinical signs and the remaining reported case was a bird that showed no clinical signs. Common findings in dogs recorded in decreasing frequency in-cluded bradycardia, lethargy and arrhythmia. Common findings in cats recorded in decreasing frequency included: coma, lethargy, protrusion of the third eyelid, subdued, and vomiting. Humans have appar ently survived dosages of up to 5 grams. The most predominant clinical signs expected would be ex tensions of the drug's pharmacologic effects: hypotension, bradycardia, bron-chospasm, cardiac fail ure and hypoglycemia. If overdose is secondary to a recent oral ingestion, emptying the gut and charcoal administration may be considered. Monitor: ECG, blood glucose, potassium and, if possible, blood pressure. Treat ment of the cardiovascular effects is symptomatic. Use fluids and pressor agents to treat hypoten sion. Bradycardia may be treated with atropine. If atropine fails, isoproterenol given cautiously has been recommended. Use of a transvenous pacemaker may be neces-sary. Cardiac failure can be treated with a digitalis glycoside, diuret-ics and oxygen. Glucagon (5-10 mg IV; human dose) may increase heart rate and blood pressure and reduce the cardiodepressant ef-fects of atenolol. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atenolol and may be of significance in veterinary patients:

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78 ATENOl Ol ANESTHETICST! (myocardial depressant ): Additive myocardial depres-sion may occur with the concurrent use of atenolol and myocar-dial depressant anesthetic agents CAl CIUm­CHANNEl bl OCKERS T! (e. g., diltiazem, verapamil, amlodipine ): Concurrent use of beta-blockers with calcium channel blockers (or other negative inotropics) should be done with caution, par-ticularly in patients with preexisting cardiomy opathy or CHF Cl ONIDINET! : Atenolol may exacerbate rebound hypertension after stopping clonidine therapy FUROSEm IDE,T! Hy DRAl Az INE OR OTHER Hy POTENSIVE PRODUCINg DRUg S : May increase the hypotensive effects of atenolol PHENOTHIAz INEST! : With atenolol may ex hibit enhanced hypotensive effects RESERPINET! : Potential for additive effects (hypotension, bradycardia) Sym PATHOm Im ETICST! (metaproterenol, terbutaline, beta­effects of epi­ nephrine, phenylpropanolamine, etc. ): May have their actions blocked by atenolol and they may, in turn, reduce the efficacy of atenolol Doses DOg S:T! For indications where beta-blockade may be indicated (cardiac arrhythmias, obstructive heart disease, hypertension, myocardial infarction, etc. ):a) 0. 2-1 mg/kg PO q12-24h (Ware 2000) b) 0. 25-1 mg/kg PO q12-24h (Hogan 2004) c) 6. 25-25 mg (total dose) PO q12h (Muir and Bonagura 1994); (Fuentes 1999) d) For moderate to severe sub-valvular aortic stenosis (SAS): 0. 5-1 mg/kg PO twice a day (Meurs 2006c) e) T o attempt to decrease syncopal episodes associated with pul-monic stenosis: 0. 25-1 mg/kg PO twice a day (Meurs 2006c) For treatment of hypertension:a) 0. 25-1 mg/kg PO q12h (Stepian 2006b) b) For hypertension: 0. 5 mg/kg initially PO q12-24h; may com-bine with vasodilators and/or diuretics (Brown and Henik 2000) c) 0. 25-1 mg/kg PO q12-24h (Snyder and Cooke 2005) CATS:T! For treatment of hypertension: a) 2 mg/kg once daily; hyperthyroid cats being started on methi-mazole are treated usually for 2 weeks with atenolol. It is im-portant to closely monitor geriatric cats as renal disease may be a concurrent problem with hyperthyroidism or hyperten-sion. (Littman 1992) b) 6. 25-12. 5 mg per cat per day. Starting dose should be low and titrate to effect. Do not start treatment immediately prior to anesthesia or surgery without a suitable period of dosage titration. (Mooney and Thoday 2000) c) 0. 5 mg/kg initially PO q12-24h; may combine with vasodila-tors and/or diuretics (Brown and Henik 2000) d) 2 mg/kg PO q12-24h (Snyder and Cooke 2005) e) 6. 25-12. 5 mg (total dose) PO q12-24h. Treatment of choice for hyperthyroid, hypertensive cats. Beta-blockers are rarely sufficient alone to treat hypertension due to other causes. (Waddell 2005) f) 3 mg/kg PO q12h (or 6. 25-12. 5 mg total dose) PO q12h (Ste-pian 2006b)For indications where beta blockade may be indicated (cardiac arrhythmias, obstructive heart disease, hypertension, myocardial infarction, etc. ): a) 6. 25-12. 5 mg (total dose) PO q12-24h (Ware and Keene 2000); (Fox 2000) FERRETS:T! For hypertrophic cardiomyopathy: a) 6. 25 mg (total dose) PO once daily (Williams 2000) b) 3. 13-6. 25 mg (total dose) PO once daily (Johnson-Delaney 2005c) monitoring Cardiac function, pulse rate, ECG if necessary, BP if indicated T! T oxicity (see Adverse Ef fects/Overdosage) T! Client Information T o be effective, the animal must receive all doses as prescribed. T! Notify veteri narian if animal becomes lethargic or becomes exer-cise intolerant; develops shortness of breath or cough; or develops a change in behavior or attitude. Do not stop therapy without first conferring with veterinarian. Chemistry/Synonyms A beta 1-adrenergic blocking agent, atenolol occurs as a white, crys-talline powder. At 37°C, 26. 5 mg are soluble in 1 m L of water. The p H of the commercially available injection is ad justed to 5. 5-6. 5. Atenolol may also be known as atenololum, or ICI-66082; many trade names are available. Storage/Stability/Compatibility Tablets should be stored at room temperature and protected from heat, light and moisture. The injection solution should be stored at room temperature and protected from light. Atenolol injection is reported to be physically compatible with morphine sulfate injection and meperidine HCl for at least 4 hours. Dextrose injections, sodium chloride injections and combina-tions of the two are recommended for use as diluents when given parenterally. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more informa-tion. HUm AN­l Ab El ED PRODUCTS: Atenolol Tablets: 25, 50, & 100 mg; Tenormin® (Astra Zeneca); ge-neric; (Rx) Atenolol Injection: 5 mg/m L in 10 m L amps; Tenormin® (Astra Zen-eca); (Rx)Also available in an oral fixed dose combination product with chlo-rthalidone.

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ATIPAm Ez Ol E HCl 79 Atip Amezole hcl (at-i-pam-a-zole) Antisedan® alpha-2 adrenergic antag Onist Prescriber Highlights Alpha T T 2 adrenergic antagonist; antagonizes agonists such as medetomidine or xylazine No safety data on use in pregnant or lactating animals T T May reverse effects rapidly, including analgesia; animals T T should be observed & pro tected from self-harm or caus-ing harm to others Adverse Effects may include vomiting, diarrhea, hyper-T T salivation, tremors, or excitation Uses/Indications Atipamezole is labeled for use as a reversal agent for medetomidine and dexmedetomidine. It poten tially could be useful for reversal of other alpha 2-adrenergic agonists as well (e. g., amitraz, xy lazine, clonidine, tizanidine, brimonidine). Pharmacology/Actions Atipamezole competitively inhibits alpha 2-adrenergic receptors, thereby acting as a reversal agent for alpha 2-adrenergic agonists (e. g., medetomidine). Net pharmacologic effects are to reduce seda-tion, decrease blood pressure, increase heart and respiratory rates, and reduce the anal gesic effects of alpha 2-adrenergic agonists. Pharmacokinetics After IM administration in the dog, peak plasma levels occur in about 10 min utes. Atipamezole is apparently metabolized in the liver to compounds that are eliminated in the urine. The drug has an average plasma elimination half-life of about 2-3 hours. Contraindications/Precautions/Warnings While the manufacturer lists no absolute contraindications to the use of atipamezole, the drug is not recommended in pregnant or lactating animals due to the lack of data establishing safety. Caution should be used in administration of anesthetic agents to elderly or debilitated animals. When used as a reversal agent (antidote) for alpha 2-agonist tox-icity, atipamezole's effects may subside before non-toxic levels of the offending agent are reached; repeat dosing may be necessary. Adverse Effects Potential adverse effects include occasional vomiting, diarrhea, hyper salivation, tremors, and brief excitation or apprehensiveness. Because reversal can occur rapidly, care should be exercised as animals emerging from sedation and analgesia may exhibit ap-prehensive or aggressive behaviors. After reversal, animals should be protected from falling. Additional analgesia (e. g., butorphanol) should be considered, particularly after painful procedures. Reproductive/Nursing Safety The manufacturer states that the drug is not recommended in preg-nant or lactating animals, or in animals intended for breeding due to lack of data establishing safety in these animals. No other data was noted. Overdosage/Acute Toxicity Dogs receiving up to 10X the listed dosage apparently tolerated the drug without ma jor effects. When overdosed, dose related effects seen included panting, excitement, trembling, vomiting, soft or liq-uid feces, vasodilatation of sclera and some muscle injury at the IM injection site. Specific overdose therapy should generally not be necessary. Drug Interactions The manufacturer states that information on the use of atipam-ezole with other drugs is lacking, therefore, caution should be taken when using with other drugs (other than medetomidine). The fol-lowing drug interactions have either been reported or are theoreti-cal in humans or animals receiving atipamezole and may be of sig-nificance in veterinary patients: Al PHA1­ADRENERg IC bl OCKERS T! (e. g., prazosin ): Atipamezole is a relatively specific alpha-2 blocker it can also partially block al-pha1 receptors and reduce the effects of prazosin Al PHA2­ADRENERg ICS Ag ONISTS T! (e. g., detomidine, clonidine, brimo­ nidine, xylazine, amitraz, etc. ): Atipamezole can reduce the effects (toxic or therapeutic) of these agents Doses DOg S:T! For reversal of medetomidine:a) Give IM an equal volume of Antisedan® and Domitor® is ad-ministered (m L per m L). The actual concentration of Anti-sedan® will be 5X that of Domitor®, as Antisedan® is 5 mg/m L versus Domitor®'s 1 mg/m L. (Package Insert; Antisedan®— Pfizer) b) As above, but may give IV as well as IM. If it has been at least 45 minutes since medeto midine was given, may give atipa-mezole at half the volume of medetomidine if adminis tered IV. If after 10-15 minutes an IM dose of atipamezole has not seemed to reverse the effects of medetomidine, an additional dose of atipamezole at H the volume of the medetomidine dose may be given. (Mc Grath and Ko 1997) For treatment of amitraz toxicity: a) 50 mcg/kg IM (Hugnet, Buronrosse et al. 1996) CATS:T! For reversal of medetomidine as part of a medetomidine/ bu-torphanol or buprenorphine/ketamine/carprofen or meloxicam anesthesia/analgesia injectable combination: a) Use an equal volume IM of atipamezole as medetomidine was used in the combination. (Ko 2005) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: For medetomidine reversal: 1 mcg/kg SC, IV or IP. Will reverse analgesia as well. (Ivey and Morrisey 2000) b) Mice, Rats, Gerbils, Hamsters, Guinea pigs: T o reverse xyla-zine or medetomidine: 0. 1-1 mg/kg IM, IP, IV or SC (Adam-cak and Otten 2000) RUm INANTS:T! a) For reversal of alpha 2-adrenergic agonists in bovine, new world camelids, ovine and caprine species: 0. 02-0. 1 mg/kg IV to effect (Haskell 2005b) b IRDS:T! a) As a reversal agent for alpha 2-adrenergic agonists (e. g., xyla-zine, detomidine, etc. ): 0. 5 mg/kg IM (Clyde and Paul-Mur-phy 2000)

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80 ATOVAQUONE REPTIl ES:T! a) Reversal of all dosages ketamine/medetomidine combination (see ketamine or medeto midine monographs) with atipam-ezole is 4-5 times the medetomidine dose (Heard 1999) monitoring Level of sedation and analgesia T! Heart rate T! Body temperature T! Client Information Atipamezole should be administered by veterinary professionals T! only. Clients should be informed that occasionally vomiting, diar-rhea, hypersalivation, excitation and tremors may be seen after atipamezole administration. Should these be severe or persist af-ter leaving the clinic, clients should contact the veterinarian. Chemistry/Synonyms Atipamezole is an imidazole alpha 2-adrenergic antagonist. The in-jection is a clear, colorless solution. Atipamezole HCl may also be known as MPV-1248 or Antisedan®. Storage/Stability/Compatibility Atipamezole HCl injection should be stored at room temperature (15°-30°C) and protected from light. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Atipamezole HCl for Injection: 5 mg/m L in 10 m L multidose vials; Antisedan® (Pfizer); (Rx). Ap proved for use in dogs. HUm AN­l Ab El ED PRODUCTS: None Atov Aquone (ah-toe-va-kwone) Mepron® Oral antipr Ot Oz Oal agent Prescriber Highlights Atovaquone (with azithromycin) appears effective in T T treating dogs with Babesia gibsoni infections. Alone, it is a second-line agent (after trimethoprim/sulfa) for pneu-mocystosis in dogs. Limited use thus far; appears well-tolerated by dogs T T Treatment may be quite expensive T T Uses/Indications Atovaquone (with azithromycin) appears effective in treating dogs with Babesia gibsoni (Asian genotype) infections, particularly in dogs not immunosuppressed or splenectomized. Atovaquone may be of benefit for treating pneumocystosis in dogs, but it is consid-ered second line therapy after potentiated sulfonamides. Atovaquone (with azithromycin) may be of benefit in treating Cytauxzoon felis infections in cats (research is in progress at the time of writing). Pharmacology/Actions Atovaquone's antiprotozoal mechanism of action is not complete-ly understood. It is believed that the hydroxynaphthoquinones, like atovaquone, selectively inhibit protozoan mitochondrial elec-tron transport causing inhibition of de novo pyrimidine synthesis. Unlike mammalian cells, certain protozoa cannot salvage preformed pyrimidines. Pharmacokinetics Pharmacokinetic data for dogs was not located. In humans after oral administration, bioavailability ranges from 23-47%. The presence of food, particularly high in fat, can increase bioavailability sig-nificantly (2+ fold over fasted administration). The drug is highly bound to human plasma proteins (99. 9%) and levels in the CSF are approximately 1% of those found in plasma. Elimination half-life in people is about 70 hours presumably due to enterohepatic recycling. There may be limited hepatic metabolism, but the bulk of absorbed drug is eventually eliminated unchanged in the feces. Contraindications/Precautions/Warnings No absolute contraindications for using atovaquone in dogs have been documented. Dogs with malabsorption syndromes or that cannot take the drug with food should have alternate therapies con-sidered. The drug is contraindicated in human patients that develop or have a prior history of hypersensitivity reactions to the drug. Reproductive/Nursing Safety Studies in pregnant rats with atovaquone plasma levels approxi-mately 2-3 times those found in humans receiving therapeutic dos-ages revealed no increase in teratogenicity. Similar studies in rabbits showed increased maternal and fetal toxicity (decreased fetal growth and increased early fetal resorption). In humans, the FDA catego-rizes atovaquone as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Little information is available on the safety of this drug during lactation. In rats, milk levels were approximately N those found in maternal plasma. It is unlikely atovaquone in milk poses much risk to nursing puppies. Adverse Effects Atovaquone use in dogs has been limited and the adverse effect pro-file is not well known. One study (Birkenheuer, Levy et al. 2004) using atovaquone and azithromycin for treating Babesia gibsoni infections in 10 dogs reported that no adverse effects were noted. The combi-nation product containing atovaquone and proguanil (Malarone®) reportedly causes severe gastrointestinal effects in dogs. In humans treated with atovaquone, rashes (up to 39% of treated patients) and gastrointestinal effects (nausea, vomiting, diarrhea) are the most frequently reported adverse effects. Rashes or diarrhea may necessitate discontinuation of therapy. Other adverse effects re-ported in humans include hypersensitivity reactions, increased liver enzymes, CNS effects (headache, dizziness, insomnia), hyperglyce-mia, hyponatremia, fever, neutropenia, and anemia. Overdosage/Acute Toxicity Limited information is available for any species. Minimum toxic doses have not been established; laboratory animals have tolerated doses up to 31. 5 grams. The current recommendation for treating overdoses is basically symptomatic and supportive. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atovaquone and may be of significance in veterinary patients: m ETOCl OPRAm IDET! : Can decrease atovaquone plasma concentrations TETRACy Cl INET! : Can decrease atovaquone plasma concentrations RIFAm PINT! : Can decrease atovaquone plasma concentrations

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ATRACURIUm b ESyl ATE 81 laboratory Considerations No specific issues; see Monitoring for recommendations for testing for efficacy Doses DOg S:T! For susceptible infections:a) For Babesia gibsoni (Asian genotype) infections: Atovaquone 13. 3 mg/kg PO q8h and Azithromycin 10 mg/kg PO once daily. Give both drugs for 10 days. Reserve immunosuppres-sive therapy for cases that are not rapidly responding (3-5 days) to anti-protozoal therapy. (Birkenheuer, Levy et al. 2004), (Birkenheuer 2006) b) For Pneumocystosis: 15 mg/kg PO once daily for 3 weeks. (Greene, Chandler et al. 2006) monitoring Monitoring for therapy for T! Babesia gibsoni in dogs should include surveillance for potential adverse effects and signs for clinical ef-ficacy, including monitoring serial CBCs Severe cases may have elevated BUN or liver enzymes, and hy-T! pokalemia Current recommendation for determining “clearing” of the or-T! ganism is to perform a PCR test at 60 days and 90 days post-therapy Client Information Store medication at room temperature and away from bright T! light Before using, shake bottle gently T! T o increase the absorption from the GI tract, give with food high T! in fat (e. g., ice cream, tuna oil, butter, meat fat)Adverse effect profile in dogs for this medication is not well T! known Report any significant effects such as rash, or severe or persistent T! vomiting or diarrhea, to the veterinarian Chemistry/Synonyms Atovaquone is a synthetic, hydroxy-1,4-naphthoquinone antiproto-zoal agent. It occurs as a yellow powder that is highly lipid soluble, insoluble in water and slightly soluble in alcohol. Atovaquone may also be known as: BW-556C, Atovacuona, Atovakvon, Atovakvoni, Atovaquonnum, Malanil®, Mepron ®, or Wellvone®. Storage/Stability The commercially available oral suspension should be stored at room temperature (15-25°C) in tight containers and protected from bright light; do not freeze. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Atovaquone Oral Suspension: 150 mg/m L in 210 m L bottles; citrus flavor; Mepron ® (Glaxo Wellcome); (Rx) A tablet dosage form was previously available, but was discontinued when the oral suspension was approved; the suspension has much better oral bioavailability in humans. A combination tablet product containing atovaquone and proguanil HCl (Malarone®) is available that has labeled indications (human) for malaria prophylaxis and treatment. This combination has reportedly caused significant GI adverse effects in dogs. Atr Acurium besyl A te (a-tra-cure-ee-um) Tracrium® n Ondep Olarizing neur Omuscular bl Ocker Prescriber Highlights Non-depolarizing neuromuscular blocking agent; minimal T T cardiovascular effects More potent in horses than other species T T Relatively contraindicated in patients with myasthenia T T gravis, hypersensitivity to it Less incidence of histamine release than tubocurarine or T T metocurine Potential drug interactions T T Uses/Indications Atracurium is indicated as an adjunct to general anesthesia to produce muscle relaxation during surgical procedures or me-chanical ventilation and also to facilitate endotracheal intubation. Atracurium can be used in patients with significant renal or hepatic disease. Pharmacology/Actions Atracurium is a nondepolarizing neuromuscular blocking agent and acts by com petitively binding at cholinergic receptor sites at the motor end-plate thereby inhibiting the effects of acetylcholine. Atracurium is considered G to N as potent as pancuronium. In horses, atracurium is more potent than in other species tested and more potent than other nondepolarizing muscle relaxants studied. At usual doses, atracurium exhibits minimal cardiovascular ef-fects, unlike most other nondepolariz ing neuromuscular blockers. While atracurium can stimulate histamine release, it is considered to cause less histamine release than either tubocurarine or meto-curine. In humans, less than one percent of patients receiving atra-curium exhibit clinically significant adverse reactions or histamine release. Pharmacokinetics After IV injection, maximal neuromuscular blockade generally oc-curs within 3-5 minutes. The duration of maximal blockade in-creases as the dosage increases. Systemic alkalosis may diminish the degree and duration of blockade; acidosis potentiates it. In con-junction with bal anced anesthesia, the duration of blockade gener-ally persists for 20-35 minutes. Recovery times do not change after giving maintenance doses, so predictable blocking effects can be at-tained when the drug is administered at regular intervals. Atracurium is metabolized by ester hydrolysis and Hofmann elimination that occur indepen dently of renal or hepatic function. Contraindications/Precautions/Warnings Atracurium is contraindicated in patients who are hypersensitive to it. Because it may rarely cause significant release of histamine, it should be used with caution in patients where this would be haz-ardous (severe cardiovascular disease, asthma, etc. ). Atracurium has minimal cardiac effects and will not counteract the bradycardia or vagal stimulation induced by other agents. Use of neuromuscu-lar blocking agents must be done with extreme caution, or not at all, in patients suffering from myasthenia gravis. Atracurium has no analgesic or sedative/anesthetic ac tions.

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82 ATRACURIUm b ESyl ATE It is not known whether this drug is excreted in milk. Safety for use in the nursing mother has not been established. Adverse Effects Clinically significant adverse effects are apparently quite rare in pa tients (<1% in humans) receiving recommended doses of atra-curium and usually are secondary to histamine release. They can include: allergic reactions, inadequate or prolonged block, hypoten-sion vasodilatation, bradycardia, tachycardia, dyspnea, broncho-, laryngo-spasm, rash, urticaria, and a reaction at the injection site. Patients developing hypotension usually have preexisting severe car-diovascular disease. Overdosage/Acute Toxicity Overdosage possibilities can be minimized by monitoring muscle twitch responses to peripheral nerve stimulation. Increased risks of hypotension and histamine release occur with over doses, as well as prolonged duration of muscle blockade. Besides treating conservatively (mechanical ventilation, O 2, flu-ids, etc. ), reversal of blockade may be accomplished by administer-ing an anticholinesterase agent (edrophonium, physostigmine, or neostigmine) with an anticholinergic (atropine or glycopyrrolate). Reversal is usually attempted (in humans) approximately 20-35 minutes after the initial dose, or 10-30 minutes after the last mainte-nance dose. Reversal is usually complete within 8-10 minutes. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atracurium and may be of significance in veterinary patients: The following agents may enhance the neuromuscular blocking activity of atracurium: Am INOgly COSIDE ANTIb IOTICST! (gentamicin, etc. ) ANESTHETICS, g ENERAl T! (enflurane, isoflurane, halothane ) b ACITRACIN, POlymyx IN b T! (systemic ) PROCAINAm IDET! QUINIDINE T! l ITHIUm T! m Ag NESIUm SAl TS T! ANTICONVUl SANTST! (phenytoin, carbamazepine ): Have been reported to both decrease the effects and duration of neuromuscular block-ade OTHER m USCl E REl Ax ANT DRUg S: T! May cause a synergistic or antago-nistic effect SUCCINyl CHOl INE:T! May speed the onset of action and enhance the neuromuscular blocking actions of atracurium. Do not give atra-curium until succinylcholine effects have diminished. Doses DOg S:T! a) Induction dose: 0. 22 mg/kg IV, give 1/10th to 1/6th of this dose initially as a “priming” dose, followed 4-6 minutes later with the remainder and a sedative/hypnotic agent. Intraoperative dose: 0. 11 mg/kg IV (Mandsager 1988) b) After acepromazine and/or meperidine premedication, give 0. 5 mg/kg IV initially. Induce anesthesia with thiopental or methohexital; after intratracheal intubation maintain anes-thesia with nitrous oxide:oxygen (2:1) and halothane (0. 5%) using controlled ventilation. Additional doses of atracurium may be administered at 0. 2 mg/kg IV. (Jones 1985b) c) For neuromuscular blockade augmentation during corneal surgery: 0. 15 mg/kg IV (Nasisse 2004) d) As a muscle relaxant to facilitate intubation in patients with severe blunt trauma: IV started and acepromazine 0. 01 mg/kg plus butorphanol 0. 1 mg/kg plus ketamine 1 mg/kg is infused. If patient requires intubation, give atracurium at 0. 25 mg/kg IV push. (Crowe 2004) e) For induction of respiratory muscle paralysis during me-chanical ventilation: Loading dose: 0. 2-0. 5 mg/kg IV, then a constant rate infusion 5 minutes later of 3-9 mcg/kg/min. Use D5W or 0. 9% sodium chloride for diluent; do not mix with other drugs. Respiratory and cardiovascular monitoring should be provided. (Dhupa 2005) CATS:T! a) Induction dose: 0. 22 mg/kg IV, give 1/10th to 1/6th of this dose initially as a “priming” dose, followed 4-6 minutes later with the remainder and a sedative/hypnotic agent. Intraoperative dose: 0. 11 mg/kg IV (Mandsager 1988) b) For induction of respiratory muscle paralysis during me-chanical ventilation: Loading dose: 0. 2-0. 5 mg/kg IV, then a constant rate infusion 5 minutes later of 0. 37 mcg/kg/min. Use D5W or 0. 9% sodium chloride for diluent; do not mix with other drugs. Respiratory and cardiovascular monitoring should be provided. (Dhupa 2005) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: For paralysis for periophthalmic surgery: 0. 1 mg/kg (Ivey and Morrisey 2000) HORSES: T! (Note : ARCI UCGFS Class 2 Drug) a) Intraoperative dose: 0. 055 mg/kg IV (Mandsager 1988) monitoring Level of neuromuscular blockade T! Cardiac rate T! Client Information This drug should only be used by professionals familiar with its T! use. Chemistry/Synonyms A synthetic, non-depolarizing neuromuscular blocking agent, atra-curium, is a bisqua ternary, non-choline diester structurally similar to metocurine and tubocurarine. It occurs as white to pale yellow powder; 50 mg are soluble in 1 m L of water, 200 mg are soluble in 1 m L of alcohol, and 35 mg are soluble in 1 m L of normal saline. Atracurium besylate may also be known as: 33A74, atracurium besilate, BW-33A, Abbottracurium®, Atracur®, Faulcurium®, Ifacur®, Laurak®, Mycurium®, Relatrac®, Sitrac®, Trablok®, Tracrium®, or Tracur®. Storage/Stability/Compatibility The commercially available injection occurs as clear, colorless solu-tion and is a sterile solution of the drug in sterile water for injection. The p H of this solution is 3. 25-3. 65. Atracurium injection should be stored in the refrigerator and protected against freezing. At room temperature, approximately 5% potency loss occurs each month; when refrigerated, a 6% potency loss occurs over a years' time. Atracurium is compatible with the standard IV solutions, but while stable in lactated Ringer's for 8 hours, degradation occurs more rapidly. It should not be mixed in the same IV bag or syringe, or given through the same needle with alkaline drugs (e. g., barbitu-rates) or solutions (sodium bicar bonate) as precipitation may occur. It is incompatible with propofol, diazepam, thiopental, aminophyl-line, cefazolin, heparin, ranitidine, and sodium nitroprusside.

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ATROPINE SUl FATE 83 Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Atracurium Besylate Injection: 10 mg/m L in 5 m L single-use and 10 m L multi-use vials; Tracrium® (Glaxo Wellcome); Atracurium Besylate (Bedford Labs); (Rx) Atropine sulf Ate (a-troe-peen) antich Olinergic Prescriber Highlights Prototype antimuscarinic agent used for a variety of indi-T T cations (bradycardia, premed, antidote, etc. ) Contraindicated in conditions where anticholinergic ef-T T fects would be detrimental (e. g., narrow angle glaucoma, tachycardias, ileus, urinary obstruction, etc. ) Adverse effects are dose related & anticholinergic in T T nature: 1) dry secretions, 2) ini tial bradycardia, then tachycardia, 3) slow gut & urinary tract, 4) mydriasis/ cycloplegia Drug interactions T T Uses/Indications The principal veterinary indications for systemic atropine include: Preanesthetic to prevent or reduce secretions of the respiratory T! tract Treat sinus bradycardia, sinoatrial arrest, and incomplete A V T! block Differentiate vagally-mediated bradycardia for other causes T! As an antidote for overdoses of cholinergic agents (T! e. g., phys-ostigmine, etc. )As an antidote for organophosphate, carbamate, muscarinic T! mushroom, blue-green algae intoxication Hypersialism T! Treatment of bronchoconstrictive disease T! Pharmacology/Actions Atropine, like other antimuscarinic agents, competitively inhib-its acetylcholine or other cholinergic stimulants at postganglionic parasympathetic neuroeffector sites. High doses may block nico-tinic receptors at the autonomic ganglia and at the neuromuscu-lar junction. Pharmacologic effects are dose related. At low doses salivation, bronchial secretions, and sweating (not horses) are in-hibited. At moderate systemic doses, atropine dilates and inhibits accommodation of the pupil, and increases heart rate. High doses will decrease GI and urinary tract motility. Very high doses will in-hibit gastric secretion. Pharmacokinetics Atropine sulfate is well absorbed after oral administration, IM in-jection, in halation, or endotracheal administration. After IV ad-ministration peak effects in heart rates occur within 3-4 minutes. Atropine is well distributed throughout the body and crosses into the CNS, across the placenta, and can distribute into the milk in small quantities. Atropine is metabolized in the liver and excreted into the urine. Approximately 30-50% of a dose is excreted unchanged into the urine. The plasma half-life in humans has been reported to be be-tween 2-3 hours. Contraindications/Precautions/Warnings Atropine is contraindicated in patients with narrow-angle glau-coma, synechiae (adhesions) between the iris and lens, hypersen-sitivity to anticholinergic drugs, tachycardias secondary to thyro-toxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ulcerative coli tis, obstructive uropathy, and myasthenia gravis (unless used to reverse adverse muscarinic ef-fects secondary to therapy). Atropine may aggravate some signs seen with amitraz toxicity, leading to hy pertension and further in-hibition of peristalsis. Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections. Atropine or other antimuscarinic agents can decrease GI motility and prolong reten-tion of the causative agent(s) or toxin(s) resulting in prolonged clinical signs. Antimuscarinic agents must also be used with ex-treme caution in patients with autonomic neuropathy. Antimuscarinic agents should be used with caution in patients with hepatic or renal disease, geri atric or pediatric patients, hyper-thyroidism, hypertension, CHF, tachyarrhythmias, prostatic hyper-trophy, or esophageal reflux. Systemic atropine should be used cau-tiously in horses as it may de crease gut motility and induce colic in susceptible animals. It may also reduce the arrhythmogenic doses of epinephrine. Use of atropine in cattle may result in inappetence and rumen stasis that may persist for several days. When used in food animals at doses up to 0. 2 mg/kg, FARAD recommends a 28 day meat and 6 day milk withdrawal time. (Haskell, Payne et al. 2005) Adverse Effects Adverse effects are basically extensions of the drug's pharmacologic effects and are generally dose related. At usual doses, effects tend to be mild in relatively healthy pa tients. The more severe effects listed tend to occur with high or toxic doses. GI effects can include dry mouth (xerostomia), dysphagia, constipation, vomiting, and thirst. GU effects may include uri nary retention or hesitancy. CNS effects may include stimulation, drowsiness, ataxia, seizures, respi ratory depression, etc. Ophthalmic effects include blurred vision, pupil dilation, cycloplegia, and photophobia. Cardiovascular effects in-clude sinus tachycardia (at higher doses), bradycardia (initially or at very low doses), hypertension, hypotension, arrhythmias (ectopic complexes), and cir culatory failure. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Atropine use in pregnancy may cause fetal tachycardia.

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84 ATROPINE SUl FATE Overdosage/Acute Toxicity For signs and symptoms of atropine toxicity see adverse effects above. If a recent oral ingestion, emptying of gut contents and administra-tion of activated charcoal and saline cathartics may be warranted. Treat clinical signs supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholinergic effects. Fluid therapy and standard treatments for shock may be instituted. The use of physostigmine is controversial and should probably be reserved for cases where the pa tient exhibits either extreme agi-tation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are se-vere or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult). If no response, may re-peat every 20 minutes until reversal of toxic antimuscarinic effects or cholinergic effects takes place. The human pediatric dose is 0. 02 mg/kg slow IV (repeat q10 minutes as above) and may be a rea-sonable choice for initial treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atropine and may be of significance in veterinary patients: The following drugs may enhance the activity or toxicity of atro-pine and its derivatives: Am ANTADINET! ANTICHOl INERg IC Ag ENTST! (other ) ANTICHOl INERg IC m USCl E REl Ax ANTST! ANTIHISTAm INEST! (e. g., diphenhydramine ) DISOPy RAm IDET! m EPERIDINET! PHENOTHIAz INEST! PROCAINAm IDET! PRIm IDONE T! TRICy Cl IC ANTIDEPRESSANTST! (e. g., amitriptyline, clomipramine ) Am ITRAz T! : Atropine may aggravate some signs seen with amitraz toxicity; leading to hypertension and further inhibition of peri-stalsis ANTACIDST! : May decrease PO atropine absorption; give oral atro-pine at least 1 hour prior to oral antacids CORTICOSTEROIDST! (long­term use ): may increase intraocular pressure DIg Ox INT! (slow­dissolving ): Atropine may increase serum digoxin levels; use regular digoxin tablets or oral liquid KETOCONAz Ol ET! : Increased gastric p H may decrease GI absorption; administer oral atropine 2 hours after ketoconazole m ETOCl OPRAm IDET! : Atropine and its derivatives may antagonize the actions of metoclopramide Doses DOg S:T! As a preanesthetic adjuvant: a) 0. 022-0. 044 mg/kg IM or SC (Muir) b) 0. 074 mg/kg IV, IM or SC (Package Insert; Atropine Injectable, S. A. —Fort Dodge) c) 0. 02-0. 04 mg/kg SC, IM or IV (Morgan 1988) For adjunctive treatment of bradycardias, Incomplete A V block, etc. :a) 0. 022-0. 044 mg/kg IM, SC, or IV as needed; or 0. 04 mg/kg PO three to four times daily (Morgan 1988) b) 0. 02-0. 04 mg/kg IV or IM (Russell and Rush 1995)T o differentiate vagally-mediated bradyarrhythmias from non-vagal bradyarrhythmias (Atropine Response T est): RISHNIW PREFERENCE: 1) Record ECG at baseline; 2) Administer 0. 04 mg/kg atropine IV; 3) Wait 15 minutes; 4) Record ECG for at least 2 minutes (use slow paper speed). If the response is incomplete, repeat steps 2-4. Persistent sinus tachycardia at >140 bpm is expected in most dogs with vagally-mediated bradycardia. KITTl ESON PREFERENCE: 1) Record ECG at baseline; 2) Admin-ister 0. 04 mg/kg atropine SQ; 3) Wait 30 minutes; 4) Record ECG for at least 2 minutes (use slow paper speed). Persistent sinus tachycardia at >140 bpm is expected in most dogs with vagally-mediated bradycardia. (Rishniw and Kittleson 2007) For treatment of cholinergic toxicity: a) 0. 2-2 mg/kg; give G th of the dose IV and the remainder SC or IM (Morgan 1988) b) 0. 2-0. 5 mg/kg; G of the dose IV and the remainder IM or SC (Firth 2000) For treatment of bronchoconstriction: a) 0. 02-0. 04 mg/kg for a duration of effect of 1-1. 5 hours (Papich 1986) CATS:T! As a preanesthetic adjuvant:a) 0. 022-0. 044 mg/kg IM or SC (Muir) b) 0. 074 mg/kg IV, IM or SC (Package Insert; Atropine Injectable, S. A. —Fort Dodge) c) 0. 02-0. 04 mg/kg SC, IM or IV (Morgan 1988) For treatment of bradycardias:a) 0. 022-0. 044 mg/kg IM, SC, or IV as needed; or 0. 04 mg/kg PO three to four times daily (Morgan 1988) b) 0. 02-0. 04 mg/kg SC, IM or IV q4-6h (Miller 1985) For treatment of cholinergic toxicity: a) 0. 2-2 mg/kg; give G th of the dose IV and the remainder SC or IM (Morgan 1988) b) 0. 2-0. 5 mg/kg; G of the dose IV and the remainder IM or SC (Post and Keller 2000) FERRETS:T! a) As a premed: 0. 05 mg/kg SC or IM (Williams 2000) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: For prevention of bradycardia, and to decrease air-way secretions: 0. 04-2 mg/kg; re-dosed q10-15 minutes as needed to produce mydriasis. b) T o treat organophosphate toxicity: 10 mg/kg SC q20 minutes (Ivey and Morrisey 2000) CATTl E:T! Note : When used in food animals at doses up to 0. 2 mg/kg, FAR-AD recommends a 28 day meat and 6 day milk withdrawal time. (Haskell, Payne et al. 2005)As a preanesthetic: a) Because of a lack of extended efficacy and potential adverse reactions, atropine is not used routinely as a preoperative agent in ruminants. If it is desired for use, a dose of 0. 06-0. 12 mg/kg IM has been suggested. (Thurmon and Benson 1986) For adjunctive treatment of bovine hypersensitivity disease: a) 1 gram per cow once daily followed by 0. 5 gram/cow in 2-3 days (method of administra tion not specified) (Manning and Scheidt 1986)

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