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TRIAMCINOLONE ACETONIDE 901 T ! QUINIDINE : May increase tramadol concentrations and decrease M1 (active metabolite) concentrations T ! SAMe: Theoretically, concurrent use of SAMe with tramadol could cause additive serotonergic effects T ! SSRI ANTIDEPRESSANTS (fluoxetine, sertraline, paroxetine, etc. ): Po-tential for serotonin syndrome; use together should be avoided; fluoxetine or paroxetine may inhibit tramadol metabolism T ! TRICYCLIC ANTIDEPRESSANTS (clomipramine, amitriptyline, etc. ): Increased risk for seizures; amitriptyline may inhibit tramadol metabolism T ! WARFARIN : In humans, increased PT and INR in patients taking tramadol has been reported (relatively rare) Laboratory Considerations No specific laboratory interactions or considerations were noted. Doses T ! DOGS: a) For analgesia: 1-4 mg/kg PO q8-12h (Hardie, Lascelles et al. 2003) b) For treating chronic cancer pain: 1-4 mg/kg PO q6h (Las-celles 2003) c) As an analgesic: Recent investigations and clinical use sug-gest a starting dose of 2-5 mg/kg four times daily. (Hellyer 2006) d) 5 mg/kg q6-8h PO (Papich 2006) T ! CATS: a) For chronic pain: 4 mg/kg PO twice daily (Note: Dose ex-trapolated from human medicine. Tramadol has not been evaluated for toxicity in cats and has not been used exten-sively, but early results encouraging) (Lascelles, Robertson et al. 2003) b) Plumb's Note : Several clinicians report anecdotally that they use 1/4 of a 50 mg tablet (12. 5 mg) orally twice daily in an average sized cat. Monitoring T ! Clinical efficacy T ! Adverse effects Client Information T ! May be given with or without food T ! Keep out of reach of children T ! May cause changes in alertness or behavior T ! Clients should understand that the clinical experience with this drug in animals is limited and to report adverse effects to the veterinarian Chemistry/Synonyms A m u-receptor opiate agonist, tramadol HCl occurs as a white crystalline powder that is freely soluble in water or alcohol, and very slightly soluble in acetone. Tramadol is not derived from opi-um nor is it a semi-synthetic opioid, but is entirely synthetically produced. Tramadol HCl may also be known as: CG-315; CG-315E; trama-doli hydrochloridum; U-26225A; many trade names are available. Storage/Stability/Compatibility Unless otherwise labeled, tramadol tablets should be stored at room temperature 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Dispense in tight, light-resistant containers. Tramadol HCl injection 50 mg/m L (not available commercially in the USA) is reportedly not compatible when mixed in the same sy-ringe with injectable diazepam, diclofenac sodium, indomethacin, midazolam, piroxicam, phenylbutazone, or lysine aspirin. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Tramadol HCl Tablets (film-coated) 50 mg; Ultram® (Ortho-Mc-Neil); generic; (Rx) Tramadol HCl Extended-Release Tablets: 100 mg, 200 mg & 300 mg; Ultram ER® (Ortho-Mc Neil); (Rx). Note : Dogs apparently do not ab-sorb this product as well as humans, and potentially could “overdose” if the tablet is chewed. Tramadol is also available in a fixed dose combination of tramadol HCl 37. 5 mg and acetaminophen 325 mg tablets. USA trade name is Ultracet® (Ortho-Mc Neil); (Rx). Warning : Be certain this combina-tion product is not dispensed for cats. In several countries (but not the USA), tramadol injection is available commercially. TRIAMCINOLONE ACETONIDE (trye-am-sin-oh-lone) Vetalog® GLUCOCORTICOID Prescriber Highlights TT Oral, parenteral, topical & inhaled glucocorticoid that is 4-10X more potent than hydrocortisone; no appreciable mineralocorticoid activity TT Contraindications (relatively): Systemic fungal infections, manufacturer lists: “in viral infections,... animals with arrested tuberculosis, peptic ulcer, acute psychoses, corneal ulcer, & Cushingoid syndrome. The presence of diabetes, osteoporosis, chronic psychotic reactions, pre-disposition to thrombophlebitis, hypertension, CHF, renal insufficiency, & active tuberculosis necessitates carefully controlled use. ” TT If using for therapy, goal is to use as much as is required & as little as possible for as short an amount of time as possible TT Primary adverse effects are “Cushingoid” in nature with sustained use TT Many potential drug & lab interactions Uses/Indications The systemic veterinary labeled product (Vetalog® Injection) is la-beled as “indicated for the treatment of inflammation and related disorders in dogs, cats, and horses. It is also indicated for use in dogs and cats for the management and treatment of acute arthritis, allergic and dermatologic disorders. ” Glucocorticoids have been used in an attempt to treat practically every malady that afflicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufficiency, 2) as an antiinflammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of:

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902 TRIAMCINOLONE ACETONIDE endocrine conditions (e. g., adrenal insufficiency), rheumatic dis-eases (e. g., rheumatoid arthritis), collagen diseases (e. g., systemic lupus), allergic states, respiratory diseases (e. g., asthma), dermato-logic diseases (e. g., pemphigus, allergic dermatoses), hematologic disorders (e. g., thrombocytopenias, autoimmune hemolytic ane-mias), neoplasias, nervous system disorders (increased CSF pres-sure), GI diseases (e. g., ulcerative colitis exacerbations), and renal diseases (e. g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intra-lesionally. The above listing is certainly not complete. Pharmacology/Actions Glucocorticoids have effects on virtually every cell type and system in mammals. An overview of the effects of these agents follows. Cardiovascular System : Glucocorticoids can reduce capillary per-meability and enhance vasoconstriction. A relatively clinically in-significant positive inotropic effect can occur after glucocorticoid administration. Increased blood pressure can result from both the drugs' vasoconstrictive properties and increased blood volume that may be produced. Cells : Glucocorticoids inhibit fibroblast proliferation, macrophage response to migration inhibiting factor, sensitization of lympho-cytes and the cellular response to mediators of inflammation. Glucocorticoids stabilize lysosomal membranes. CNS/Autonomic Nervous System : Glucocorticoids can lower sei-zure threshold, alter mood and behavior, diminish the response to pyrogens, stimulate appetite, and maintain alpha rhythm. Glucocorticoids are necessary for normal adrenergic receptor sensitivity. Endocrine System : When animals are not stressed, glucocorticoids will suppress the release of ACTH from the anterior pituitary, thereby reducing or preventing the release of endogenous corticos-teroids. Stress factors (e. g., renal disease, liver disease, diabetes) may sometimes nullify the suppressing aspects of exogenously admin-istered steroids. Release of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin and luteinizing hormone (LH) may all be reduced when glucocorticoids are ad-ministered at pharmacological doses. Conversion of thyroxine (T 4) to triiodothyronine (T 3) may be reduced by glucocorticoids; and plasma levels of parathyroid hormone increased. Glucocorticoids may inhibit osteoblast function. Vasopressin (ADH) activity is re-duced at the renal tubules and diuresis may occur. Glucocorticoids inhibit insulin binding to insulin-receptors and the post-receptor effects of insulin. Hematopoietic System : Glucocorticoids can increase the numbers of circulating platelets, neutrophils and red blood cells, but platelet aggregation is inhibited. Decreased amounts of lymphocytes (pe-ripheral), monocytes and eosinophils are seen as glucocorticoids can sequester these cells into the lungs and spleen and prompt de-creased release from the bone marrow. Removal of old red blood cells is diminished. Glucocorticoids can cause involution of lym-phoid tissue. GI Tract and Hepatic System : Glucocorticoids increase the secretion of gastric acid, pepsin, and trypsin. They alter the structure of mu-cin and decrease mucosal cell proliferation. Iron salts and calcium absorption are decreased while fat absorption is increased. Hepatic changes can include increased fat and glycogen deposits within he-patocytes, increased serum levels of alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT). Significant increases can be seen in serum alkaline phosphatase levels. Glucocorticoids can cause minor increases in BSP (bromosulfophthalein) retention time. Immune System (also see Cells and Hematopoietic System): Glucocorticoids can decrease circulating levels of T-lymphocytes; inhibit lymphokines; inhibit neutrophil, macrophage, and mono-cyte migration; reduce production of interferon; inhibit phagocyto-sis and chemotaxis; antigen processing; and diminish intracellular killing. Specific acquired immunity is affected less than nonspecific immune responses. Glucocorticoids can also antagonize the com-plement cascade and mask the clinical signs of infection. Mast cells are decreased in number and histamine synthesis is suppressed. Many of these effects only occur at high or very high doses and there are species differences in response. Metabolic Effects : Glucocorticoids stimulate gluconeogenesis. Lipogenesis is enhanced in certain areas of the body (e. g., abdomen) and adipose tissue can be redistributed away from the extremities to the trunk. Fatty acids are mobilized from tissues and their oxi-dation is increased. Plasma levels of triglycerides, cholesterol and glycerol are increased. Protein is mobilized from most areas of the body (not the liver). Musculoskeletal : Glucocorticoids may cause muscular weakness (also caused if there is a lack of glucocorticoids), atrophy, and os-teoporosis. Bone growth can be inhibited via growth hormone and somatomedin inhibition, increased calcium excretion and inhibi-tion of vitamin D activation. Resorption of bone can be enhanced. Fibrocartilage growth is also inhibited. Ophthalmic : Prolonged corticosteroid use (both systemic or topically to the eye) can cause increased intraocular pressure and glaucoma, cataracts and exophthalmos. Renal, Fluid, & Electrolytes : Glucocorticoids can increase potas-sium and calcium excretion; sodium and chloride reabsorption and extracellular fluid volume. Hypokalemia and/or hypocalce-mia occur rarely. Diuresis may occur following glucocorticoid administration. Skin: Thinning of dermal tissue and skin atrophy can be seen with glucocorticoid therapy. Hair follicles can become distended and alopecia may occur. Contraindications/Precautions/Warnings Systemic use of glucocorticoids is generally considered contrain-dicated in systemic fungal infections (unless used for replacement therapy in Addison's), when administered IM in patients with id-iopathic thrombocytopenia or hypersensitive to a particular com-pound. Sustained-release injectable glucocorticoids use is consid-ered contraindicated for chronic corticosteroid therapy of systemic diseases. Animals that have received glucocorticoids systemically, other than with “burst” therapy, should be tapered off the drugs. Patients who have received the drugs chronically should be tapered off slowly as endogenous ACTH and corticosteroid function may re-turn slowly. Should the animal undergo a “stressor” (e. g., surgery, trauma, illness, etc. ) during the tapering process or until normal adrenal and pituitary function resume, additional glucocorticoids should be administered. Corticosteroid therapy may induce parturition in large animal species during the latter stages of pregnancy. Adverse Effects Adverse effects are generally associated with long-term administra-tion of these drugs, especially if given at high dosages or not on an alternate day regimen. Effects generally are manifested as clini-cal signs of hyperadrenocorticism. When administered to young, growing animals, glucocorticoids can retard growth. Many of the potential effects, adverse and otherwise, are outlined above in the Pharmacology section.

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TRIAMCINOLONE ACETONIDE 903 In dogs, polydipsia (PD), polyphagia (PP) and polyuria (PU), may all be seen with short-term “burst” therapy as well as with alternate-day maintenance therapy on days when giving the drug. Adverse effects in dogs can include dull, dry haircoat, weight gain, panting, vomiting, diarrhea, elevated liver enzymes, pancreatitis, GI ulceration, lipidemias, activation or worsening of diabetes mellitus, muscle wasting and behavioral changes (depression, lethargy, vi-ciousness). Discontinuation of the drug may be necessary; chang-ing to an alternate steroid may also alleviate the problem. With the exception of PU/PD/PP, adverse effects associated with antiinflam-matory therapy are relatively uncommon. Adverse effects associated with immunosuppressive doses are more common and potentially, more severe. Cats generally require higher dosages than dogs for clinical effect, but tend to develop fewer adverse effects. Occasionally polydipsia, polyuria, polyphagia with weight gain, diarrhea, or depression can be seen. Long-term, high dose therapy can lead to “Cushingoid” ef-fects, however. Administration of dexamethasone or triamcinolone may play a role in the development of laminitis in horses. Reproductive/Nursing Safety Glucocorticoids are probably necessary for normal fetal develop-ment. They may be required for adequate surfactant production, myelin, retinal, pancreas and mammary development. Excessive dosages early in pregnancy may lead to teratogenic ef-fects. In horses and ruminants, exogenous steroid administration may induce parturition when administered in the latter stages of pregnancy. 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. ) Glucocorticoids unbound to plasma proteins will enter milk. High dosages or prolonged administration to mothers may poten-tially inhibit the growth of nursing newborns. Overdosage/Acute Toxicity Glucocorticoids when given short-term are unlikely to cause harm-ful effects, even in massive dosages. One incidence of a dog develop-ing acute CNS effects after accidental ingestion of glucocorticoids has been reported. Should clinical signs occur, use supportive treat-ment if required. Chronic usage of glucocorticoids can lead to serious adverse ef-fects. Refer to Adverse Effects above for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving triamcinolone and may be of significance in veterinary patients: !TAMPHOTERICIN B : Administered concomitantly with glucocorti-coids may cause hypokalemia !TANALGESICS, OPIATE and/or ANESTHETICS, LOCAL (epidural injections ): Combination with glucocorticoids in epidurals has caused seri-ous CNS injuries and death; do not use more volume than very small intrathecal test doses of these agents with glucocorticoids !TANTICHOLINESTERASE AGENTS (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant gluco-corticoid and anticholinesterase agent administration may lead to profound muscle weakness. If possible, discontinue anticho-linesterase medication at least 24 hours prior to corticosteroid administration !TASPIRIN : Glucocorticoids may reduce salicylate blood levels !TBARBITURATES : May increase the metabolism of glucocorticoids and decrease blood levels !TCYCLOPHOSPHAMIDE : Glucocorticoids may also inhibit the hepatic metabolism of cyclophosphamide; dosage adjustments may be required !TCYCLOSPORINE : Concomitant administration of glucocorticoids and cyclosporine may increase the blood levels of each, by mutu-ally inhibiting the hepatic metabolism of each other; the clinical significance of this interaction is not clear !TDIURETICS, POTASSIUM-DEPLETING (e. g., spironolactone, triamterene ): Administered concomitantly with glucocorticoids may cause hypokalemia !TERYTHROMYCIN, CLARITHROMYCIN : May increase TMC levels !TESTROGENS : The effects of TMC, and possibly other glucocorti-coids, may be potentiated by concomitant administration with estrogens !TINSULIN : Insulin requirements may increase in patients receiving glucocorticoids !TISONIAZID : TMC may decrease isoniazid levels !TKETOCONAZOLE and other AZOLE ANTIFUNGALS : May decrease the metabolism of glucocorticoids and increase TMC blood levels; ketoconazole may induce adrenal insufficiency when gluco-corticoids are withdrawn by inhibiting adrenal corticosteroid synthesis !TMITOTANE : May alter the metabolism of steroids; higher than usu-al doses of steroids may be necessary to treat mitotane-induced adrenal insufficiency !TNSAIDS : Administration of ulcerogenic drugs with glucocorticoids may increase the risk of gastrointestinal ulceration !TPHENOBARBITAL : May increase the metabolism of glucocorticoids and decrease TMC blood levels !TRIFAMPIN : May increase the metabolism of glucocorticoids and decrease TMC blood levels !TVACCINES : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live attenuated-virus vaccines as virus replication may be augmented; a diminished immune response may occur after vaccine, toxoid, or bacterin administration in patients receiving glucocorticoid !TWARFARIN : TMC may affect INR's; monitor Laboratory Considerations !TGlucocorticoids may increase serum cholesterol !TGlucocorticoids may increase serum and urine glucose levels !TGlucocorticoids may decrease serum potassium !TGlucocorticoids can suppress the release of thyroid stimulat-ing hormone (TSH) and reduce T3 & T4 values. Thyroid gland atrophy has been reported after chronic glucocorticoid ad-ministration. Uptake of I131 by the thyroid may be decreased by glucocorticoids. !TReactions to skin tests may be suppressed by glucocorticoids !TFalse-negative results of the nitroblue tetrazolium test for systemic bacterial infections may be induced by glucocorticoids !TGlucocorticoids may cause neutrophilia within 4-8 hours after dosing and return to baseline within 24-48 hours after drug discontinuation !TGlucocorticoids can cause lymphopenia which can persist for weeks after drug discontinuation in dogs

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904 TRIAMCINOLONE ACETONIDE TDoses !TDOGS: For glucocorticoid effects: a) 2 mg PO once daily for 7 days; 0. 11-0. 22 mg/kg IM or SC (Kirk 1989) b) For antiinflammatory effects: 0. 05 mg/kg PO two to three times daily (Williamson 2003) c) For tablets: 0. 11 mg/kg PO initially once a day, may increase to 0. 22 mg/kg PO once daily if initial response is unsatisfac-tory. As soon as possible, but not later than 2 weeks, reduce dose gradually to 0. 028-0. 055 mg/kg/day. (Booth 1988), (Package insert; Vetalog® Tablets—Solvay) d) For injectable product: 0. 11-0. 22 mg/kg for inflammatory or allergic disorders, and 0. 22 mg/kg for dermatological dis-orders. Effects generally persist for 7-15 days; if symptoms recur, may repeat or institute oral therapy. For intralesional injection: Usual dose is 1. 2-1. 8 mg; inject around lesion at 0. 5-2. 5 cm intervals. Do not exceed 0. 6 mg at any one site or 6 mg total dose. May repeat as necessary. (Package insert; Vetalog® Injection—Solvay) e) T o prevent re-stricture after esophageal dilation: Using an endoscopically directed needle, inject 0. 5-1 m L of Vetalog® (2 mg/m L) submucosally at time of dilation procedure. In-filtration is done circumferentially at four points around the site. (Marks 2004b) !TCATS: For glucocorticoid effects: a) 0. 25-0. 5 mg PO once daily for 7 days (Kirk 1989) b) For pododermatitis, feline plasmacytic pharyngitis: 2-4 mg (total dose) PO once a day or every other day 0. 4-0. 6 mg/kg PO once daily, then taper. For pemphigus complex: 0. 4-0. 8 mg/kg/day PO (Williamson 2003) c) For tablets: 0. 11 mg/kg PO initially once a day, may increase to 0. 22 mg/kg PO once daily if initial response is unsatisfac-tory. As soon as possible, but not later than 2 weeks, reduce dose gradually to 0. 028-0. 055 mg/kg/day (Booth 1988), (Package insert; Vetalog® Tablets—Solvay) d) For injectable product: 0. 11-0. 22 mg/kg for inflammatory or allergic disorders, and 0. 22 mg/kg for dermatological dis-orders. Effects generally persist for 7-15 days; if symptoms recur, may repeat or institute oral therapy. For intralesional injection: Usual dose is 1. 2-1. 8 mg; inject around lesion at 0. 5-2. 5 cm intervals. Do not exceed 0. 6 mg at any one site or 6 mg total dose. May repeat as necessary. (Package insert; Vetalog® Injection—Solvay) T o prevent re-stricture after esophageal dilation: Using an endoscopically directed needle, inject 0. 5-1 m L of Vetalog® (2 mg/m L) submucosally at time of dilation procedure. In-filtration is done circumferentially at four points around the site. (Marks 2004b) For feline plasma cell gingivitis-pharyngitis: a) 2-4 mg PO once a day to every other day (De Novo, Potter, and Woolfson 1988) For feline polymyopathy: a) 0. 5-1 mg/kg PO once a day (Knaack 1988) !TCATTLE: For glucocorticoid effects: a) 0. 02-0. 04 mg/kg IM; 6-18 mg intra-articularly (Howard 1986) !THORSES: (Note : ARCI UCGFS Class 4 Drug) For glucocorticoid effects: a) 0. 1-0. 2 mg/kg IM or SC; 3-6 mg subconjunctivally (Robin-son 1987) b) 0. 011-0. 022 mg/kg PO twice daily; 0. 011-0. 022 mg/kg IM or SC; 6-18 mg intra-articularly or intrasynovially, may repeat after 3-4 days (Package inserts; Vetalog® Powder and Injection— Solvay) c) For intra-articular injection: 12 mg IA on days 0, 13, 27 (Mc-Clure 2002) Monitoring Monitoring of glucocorticoid therapy is dependent on its reason for use, dosage, agent used (amount of mineralocorticoid activity), dosage schedule (daily versus alternate day therapy), duration of therapy, and the animal's age and condition. The following list may not be appropriate or complete for all animals; use clinical assess-ment and judgment should adverse effects be noted: !TWeight, appetite, signs of edema !TSerum and/or urine electrolytes !Total plasma proteins, albumin !TBlood glucose !TGrowth and development in young animals !TACTH stimulation test if necessary Chemistry/Synonyms Triamcinolone acetonide, a synthetic glucocorticoid, occurs as slightly odorous, white to cream-colored, crystalline powder with a melting point between 290-294°C. It is practically insoluble in water, very soluble in dehydrated alcohol and slightly soluble in alcohol. The commercially available sterile suspensions have a p H range of 5-7. 5. Triamcinolone acetonide may also be known as: triamcinoloni acetonidum; many trade names are available. Storage/Stability Triamcinolone acetonide products should be stored at room tem-perature (15-30°C); the injection should be protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Triamcinolone Acetonide Tablets: 0. 5 mg, 1. 5 mg; Cortalone Tablets® (Vedco), generic (Boehringer Ingelheim), Triacet® Tablets (Phoenix), Triamtabs® (Butler); (Rx). Approved for use in dogs and cats. Triamcinolone acetonide Suspension for Injection: 2 mg/m L; 6 mg/ m L; Vetalog® Parenteral (Fort Dodge); (Rx). Approved for use in dogs, cats, and horses not intended for food. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Triamcinolone Acetonide Injection: 10 mg/m L suspension & 40 mg/ m L suspension in 1 m L, 5 m L and 10 m L vials; Kenalog-10 &-40 (Bristol-Myers Squibb); (Rx) Triamcinolone Hexacetonide Injection: 5 mg/m L & 20 mg/m L sus-pension in 1 m L & 5 m L vials; Aristospan Intralesional® (Fujisawa); (Rx) Many topical preparations are available, alone and in combination with other agents. Oral mucosal paste & Inhaled products are also approved. All are Rx.

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TRIAMTERENE 905 TRIAMTERENE (trye-am-the-reen) Dyrenium® POTASSIUM-SPARING DIURETIC Prescriber Highlights TT Potassium-sparing diuretic that may be considered as an alternative to spironolactone for treating CHF in dogs; limited clinical experience with this drug in dogs/cats TT Contraindications: Anuria, severe or progressive renal disease, severe hepatic disease, hypersensitivity to tri-amterene, preexisting hyperkalemia, concurrent therapy with another potassium-sparing agent (spironolactone, amiloride) or potassium supplementation TT Hyperkalemia possible; must monitor serum K+ Uses/Indications Triamterene is a potassium-sparing diuretic that potentially could be used as an alternative to spironolactone for the adjunctive treat-ment of congestive heart failure in dogs, however, there is little ex-perience associated with its use in dogs or cats. Pharmacology/Actions By exerting a direct effect on the distal renal tubule, triamterene inhibits the reabsorption of sodium in exchange for hydrogen and potassium ions. Unlike spironolactone, it does not competitively inhibit aldosterone. Triamterene increases excretion of sodium, calcium, magnesium and bicarbonate; urinary p H may be slightly increased. Serum concentrations of potassium and chloride may be increased. When used alone, triamterene has little effect on blood pressure. Triamterene can reduce GFR slightly, probably by affect-ing renal blood flow. This effect is reversible when the medication is discontinued. Pharmacokinetics Pharmacokinetic data for dogs or cats was not located. In humans, triamterene is rapidly absorbed after oral administration and oral bioavailability is about 85%. Onset of diuresis occurs in 2-4 hours and diminishes after about 8 hours. Triamterene is metabolized in the liver to 6-p-hydroxytriamterine and its sulfate conjugate. These metabolites are eliminated in the bile/feces and urine; elimination half-life is about 2 hours. Contraindications/Precautions/Warnings Triamterene is contraindicated for human patients (and presum-ably dogs and cats) with anuria, severe or progressive renal disease, severe hepatic disease, hypersensitivity to triamterene, preexisting hyperkalemia, history of triamterene-induced hyperkalemia, con-current therapy with another potassium-sparing agent (spironolac-tone, amiloride) or potassium supplementation. Adverse Effects Because triamterene has been infrequently used in veterinary medicine, an accurate adverse effect profile for small animals is not known, however, hyperkalemia is a definite possibility and moni-toring of electrolytes and renal function are necessary. In humans, hyperkalemia rarely occurs in patients with normal urine output and potassium intake. Less common adverse effects reported in humans include head-ache/dizziness, GI effects, hyponatremia, and an increased sensi-tivity to sunlight. Rarely, hypersensitivity reactions have occurred in human patients taking triamterene. Other rare adverse effects include triamterene-nephrolithiasis, agranulocytosis, thrombocy-topenia, or megaloblastosis. Reproductive/Nursing Safety Studies to determine triamterene's effects on fertility have not been performed. Studies in pregnant rats given triamterene at 6-20X (human dose) did not show adverse effects to the fetuses. Triamterene cross-es the placental barrier. For humans, triamterene is either in FDA category B or category C, depending on the reference. Category C for use during pregnancy states: Animal studies have shown an ad-verse 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 considering use of this product in a pregnant animal, weigh the potential benefits of treatment versus the risks. Triamterene is distributed into milk. Although unlikely to pose much risk to nursing animals, safety during nursing cannot be assured. Overdosage/Acute Toxicity The oral LD50 for triamterene in mice is 380 mg/kg. Fluid and elec-trolyte imbalance is the most likely risk associated with an overdose. GI effects or hypotension are also possible. Consider gut empty-ing protocols for very large or quantity unknown ingestions. Acute overdoses should generally be managed by observation, with fluid, electrolyte (especially serum potassium) and acid-base monitoring. Supportive treatment should be initiated if required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving triamterene and may be of significance in veterinary patients: T ! ACE INHIBITORS (e. g., enalapril, benazepril ): Increased risks for hyperkalemia T ! ANTIDIABETIC AGENTS (insulin, oral hypoglycemic agents ): Triam-terene may increase blood glucose T ! Antihypertensive agents : Possible potentiation of hypotensive effects T ! DIURETICS, POTASSIUM-SPARING (spironolactone, amiloride ): Increase risk of hyperkalemia; use of these drugs with triamterene in hu-mans is contraindicated T ! LITHIUM : Triamterene may reduce lithium clearance T ! NSAIDs : Triamterene with NSAIDs (esp. indomethacin ) may in-crease the risks of nephrotoxicity T ! POTASSIUM SUPPLEMENTS or HIGH POTASSIUM FOODS : Increased risk for hyperkalemia Laboratory Considerations T ! Quinidine : Triamterene may interfere with fluorescent assay of quinidine Doses T ! DOGS: a) For adjunctive treatment of recurrent heart failure associated with chronic mitral valve insufficiency: 1-2 mg/kg PO q12h. Documentation of use is limited; spironolactone is drug of choice. (Haggstrom, Kvart et al. 2005) b) As a diuretic for adjunctive treatment of CHF: 2-(4) mg/kg/ day PO (Ware 2003)

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906 TRIENTINE HCL Monitoring T ! Serum electrolytes (especially potassium), BUN, creatinine T ! Hydration status T ! Blood pressure, if indicated T ! Signs of edema; patient weight, if indicated Client Information T ! Give this medication with food to help prevent stomach upset T ! Urine may develop a bluish hue, this is normal T ! Because this medication has not been used very much in dogs or cats; report any unusual effects to the veterinarian Chemistry/Synonyms Triamterene is structurally related to folic acid and occurs as a yel-low, odorless, crystalline powder. It is practically insoluble in wa-ter and very slightly soluble in alcohol. At 50°C, it is slightly sol-uble in water. In acidified solutions, triamterene gives off a blue fluorescence. Triamterene may also be known as NSC-77625, KF-8542, FI-6143, triamteren, trimaterenum or triamtereen, Dyrenium®,. International trade names include Dytac®, Dyazide®, Maxzide-25® and Triteren®. There are many international trade names for com-bination products with hydrochlorothiazide. Storage/Stability Triamterene capsules should be stored between 15-30°C (59-86°F) in tight, light-resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. HUMAN-LABELED PRODUCTS: Triamterene Capsules: 50 mg, 100 mg; Dyrenium® (Wellspring); (Rx) In humans, triamterene is often prescribed as a fixed-dose combi-nation with hydrochlorothiazide. Products include: Triamterene 37. 5 mg/Hydrochlorothiazide 25 mg Tablets and Capsules; generic, Dyazide®, Maxzide-25®; (Rx) Triamterene 50 mg/Hydrochlorothiazide 25 mg Capsules; generic; (Rx) Triamterene 75 mg/Hydrochlorothiazide 50 mg Tablets; generic, Maxzide®; (Rx) TRIENTINE HCL (trye-en-teen) Syprine® CHELATING AGENT Prescriber Highlights TT Oral copper chelating agent for copper hepatopathy TT Probably fewer adverse effects then penicillamine, but acute renal failure possible TT Very limited experience with this drug TT More expensive than penicillamine; may need to be com-pounded into smaller dosages TT Give on an empty stomach Uses/Indications Trientine may be useful for the treatment of copper-associated he-patopathy in dogs, particularly when dogs cannot tolerate the ad-verse effects (e. g., vomiting) associated with penicillamine. Pharmacology/Actions Trientine is an effective chelator of copper and increases its elimi-nation via urinary excretion. It apparently has a greater affinity for copper in plasma than penicillamine, but penicillamine has a great-er affinity for tissue copper. Pharmacokinetics No data was located. Contraindications/Precautions/Warnings Trientine is contraindicated in patients hypersensitive to it. It is not indicated for cystinuria, rheumatoid arthritis, or biliary cirrhosis. Adverse Effects Albeit with limited veterinary experience, trientine has had relative-ly minimal adverse effects in dogs treated for copper hepatotoxic-ity, but acute renal failure has been reported. Human patients have developed iron deficiency anemia after taking trientine long-term. There is a chance for topical dermatitis developing if trientine gets on skin; wash off immediately. The drug should be given in a cap-sule (may need to be compounded) and not sprinkled on food. Reproductive/Nursing Safety Trientine is a potential teratogen. It was teratogenic in rats given doses similar to those for humans and should only be used in preg-nancy when the benefits to the mother outweigh the risks to off-spring. 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. ) It is not known whether this drug is excreted in breast milk. Exercise caution when administering to nursing patients. Overdosage/Acute Toxicity Little information is available; a case of a human ingesting 30 g of trientine without significant morbidity has been reported. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving trientine and may be of significance in veterinary patients: T ! IRON : Iron and trientine inhibit the absorption of one another; if iron therapy is needed, give doses at least 2 hours apart from one another T ! ZINC : Because trientine may also chelate zinc or other minerals, separate doses as above Doses T ! DOGS: As a chelator for copper hepatotoxicity: a) 10-15 mg/kg PO twice daily; 1-2 hours before a meal (Twedt 1999) b) 10-15 mg/kg PO q12h; give one hour before meals (Johnson 2000) c) 15-30 mg/kg PO twice daily (q12h). Give prior to meals (Richter 2002)

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TRILOSTANE 907 Monitoring T ! Periodic quantitative hepatic copper levels Client Information T ! While it is preferable to give on an empty stomach, if the drug causes vomiting or lack of appetite give with a small amount of food Chemistry/Synonyms An oral copper chelator, trientine HCl occurs as a white to pale yellow crystalline powder. It is hygroscopic and freely soluble in water. Trientine HCl may also be known as: MK-0681, 2,2,2-tetramine, trien hydrochloride, triethylenetetramine dihydrochloride, trien-tine hydrochloride or Syprine®. Storage/Stability Store trientine capsules in the refrigerator (2-8°C) in tightly closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Trientine HCl Capsules: 250 mg; Syprine® (Merck); (Rx) TRILOSTANE (trye-loe-stane) Vetoryl® ADRENAL STEROID SYNTHESIS INHIBITOR Prescriber Highlights TT Competitive inhibitor of 3-beta hydroxysteroid dehydroge-nase thereby reducing synthesis of cortisol, aldosterone, & adrenal androgens TT May be useful in dogs for treatment of pituitary-depen-dent hyperadrenocorticism, adrenal dependent hypera-drenocorticism, Alopecia X in Pomeranians & Alaskan malamutes; in cats for treatment of feline pituitary dependent hyperadrenocorticism, & in horses for equine hyperadrenocorticism (HAC) TT In USA, must presently be imported TT Potential adverse effects in dogs include lethargy, inap-petence, vomiting, electrolyte abnormalities, & diarrhea TT Rare case reports of hypoadrenocorticism & death TT Expense of treatment may be an issue Uses/Indications Trilostane may be useful for treating pituitary-dependent hypera-drenocorticism or adrenal dependent hyperadrenocorticism in dogs, feline pituitary-dependent hyperadrenocorticism, and equine hyperadrenocorticism (HAC). It may also be useful in treating Pomeranians with Alopecia X and Alaskan malamutes with adult-onset alopecia. Pharmacology/Actions Trilostane is a competitive inhibitor of 3-beta hydroxysteroid de-hydrogenase thereby reducing synthesis of cortisol, aldosterone, and adrenal androgens. Inhibition is reversible and apparently dose dependent. Pharmacokinetics In dogs, orally administered trilostane is rapidly, but erratically ab-sorbed with peak levels occurring between 1. 5-2 hours post dose. It is unknown whether the presence of food in the gut significantly alters absorption characteristics. After 18 hours, the drug report-edly returns to baseline levels. Effects on cortisol production appar-ently last for no more than 20 hours, and more likely wane within 10 hours of dosing. Trilostane is metabolized in the liver to several metabolites including ketotrilostane, which is active. Contraindications/Precautions/Warnings Trilostane is contraindicated in animals hypersensitive to it. It should be used with caution in patients with renal or hepatic impairment. Adverse Effects Trilostane appears to be relatively well tolerated in dogs. Lethargy, mild electrolyte abnormalities and inappetence are commonly not-ed during the first few days of therapy secondary to steroid with-drawal. Vomiting and diarrhea may also be seen. Withholding the drug for a few days and then giving it every other day for a week may alleviate lethargy and vomiting. Rarely, acute death or development of hypoadrencorticism (including adrenal necrosis) occurring in dogs after receiving trilostane have been anecdotally reported. In one study of trilostane given to 20 horses with equine Cushing's (Mc Gowan and Neiger 2003), no adverse effects were noted. Reproductive/Nursing Safety Because trilostane can significantly reduce the synthesis of proges-terone in vivo, it should not be used in pregnancy. Trilostane report-edly (not confirmed) is classified by the FDA as a category X drug (Contraindicated in pregnancy). Information on trilostane levels in maternal milk were not lo-cated; use with caution in lactating animals. Overdosage/Acute Toxicity Specific information on trilostane acute toxicity was not located. One source states that trilostane overdoses would be unlikely to threaten life and no clinical signs would be expected. However, blood pressure, hydration status, and electrolyte balance should be monitored. If the animal is stressed, consider giving exogenous corticosteroids short-term. Because the drug's effects are relatively short lived, monitoring of patients without complications should only be required for a few days post ingestion. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving trilostane and may be of significance in veterinary patients: T ! ACE INHIBITORS (e. g., benazepril, enalapril ): Could increase risk for hyperkalemia T ! AMINOGLUTETHIMIDE : May potentiate the effects of trilostane and lead to hypoadrenocorticism T ! KETOCONAZOLE : May potentiate the effects of trilostane and lead to hypoadrenocorticism T ! MITOTANE : May potentiate the effects of trilostane and lead to hy-poadrenocorticism T ! POTASSIUM-SPARING DIURETICS (e. g., spironolactone ): Could in-crease risk for hyperkalemia T ! POTASSIUM-SUPPLEMENTS; HIGH POTASSIUM FOODS : Could increase risk for hyperkalemia

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908 TRILOSTANE Laboratory Considerations !TNo specific laboratory interactions or considerations were located. Doses !TDOGS: For treatment of canine hyperadrenocorticism (HAC): a) For treatment of canine hyperadrenocorticism (HAC) wheth-er due to adrenal tumor or PDH: Initial therapy at 2-10 mg/ kg PO once daily. Adjust dosage per monitoring parameters below. Doses of up to 50 mg/kg/day divided twice daily have been given without untoward side effects. Give with food. Some dogs require twice daily administration. ACTH stimulation test done at 10-14 days, 30 days and 90 days after starting therapy. ACTH stimulation tests should be performed 4-6 hours post-trilostane dose. Interpret ACTH test in light of physical exam. If ACTH Stim results are <20 nmol/L (0. 72 mcg/dl), then the drug is discontin-ued for 48-72 hours and then re-started at a lower dosage. If ACTH Stim results are >200 nmol/L (7. 2 mcg/dl), then the dose is increased. If the ACTH Stim results are between these two values and the dog is clinically well-controlled, then no change. If between these two results and the patient appears not to be clinically well-controlled, then the drug may need to be given twice daily. Once the dog is stable, repeat ACTH Stim test every 3-6 months. (Neiger 2004) b) Author's (Feldman) experience is that trilostane is not more effective or safer than mitotane and that trilostane is less pre-dictable (under dose, over dose, resolution of signs, or the need for dosing more than once per day) than mitotane. If using trilostane current recommendation is: Initiate at 1 mg/kg PO once daily and continue for about one week until a veterinary recheck can occur. Have owners collect a small urine sample from their dog before leaving home the morn-ing of the scheduled recheck prior to trilostane administra-tion. Trilostane should then be given and the dog should be seen by veterinarian 2 to 3 hours later. The goal of therapy is an owner who is completely pleased with the response. The urine should be checked, at a minimum, for specific grav-ity, glucose and urine cortisol:creatinine ratio (UCCR). An ACTH stimulation test should be started at the time that the dog is seen (about 2 to 3 hours after trilostane dose). The UCCR result should be within the reference interval and the post-ACTH serum cortisol concentration should be between 1. 5 and 5. 5 mcg/d L. If the serum cortisol concentration is within that goal and the UCCR is abnormal, the medication should be given twice daily. If the serum cortisol concentra-tion is too high, the trilostane dose should be increased and if the serum cortisol concentration is too low, the dose should be decreased. This approach should be utilized at each re-check until the dog is doing well. (Feldman 2007) For treatment of Alopecia X: a) In Alaskan Malamutes: 3-3. 6 mg/kg PO twice a day for 4-6 months. Three dogs treated; no adverse effects reported. (Le-one, Vercelli et al. 2005) b) In Miniature poodles and Pomeranians: Average dose was 10. 85 mg/kg per day given either once a day or divided twice a day for 4-8 weeks. (Cerundolo, Lloyd et al. 2004) !TCATS: a) For treatment of feline hyperadrenocorticism: 7 mg/kg/day divided and given twice daily. Doses of up to 60 mg per cat per day have been used in a small number of cats with PDH. (Greco 2007a) !THORSES: a) For treatment of equine Cushing's syndrome: 0. 4-1 mg/ kg (total dose 120-240 mg) PO once daily. (Mc Gowan and Neiger 2003) Monitoring !TClinical effects !TAdverse effects !TSerum electrolytes !TUrinalysis including specific gravity, glucose and urine cortisol:creatinine ratio (UCCR) !TACTH stimulation tests (see doses for recommendations) Client Information !TKeep out of reach of children and pets !TWear gloves or wash hands thoroughly after handling !TClients should report any adverse effects to the veterinarian !TGive the drug with food, unless otherwise directed by veterinarian !TClients should understand that trilostane is a treatment for the condition and not a cure Chemistry/Synonyms A synthetic steroid analog, trilostane has a molecular weight of 329. 4 and its chemical name is 4-alpha, 5-alpha-Epoxy-17-beta-hydroxy-3-oxoandrostane-2-alpha-carbonitrile. It reportedly is relatively insoluble in water. Trilostane may also be know n as: WIN 24540, Vetoryl®, Desopan®, Modrastane® or Modrenal®. Storage/Stability/Compatibility Commercially available trilostane capsules should be stored at room temperature in tight, light-resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA. In the UK, Trilostane Oral Capsules 60 mg, 120 mg are available. Trade name is Vetoryl® (Arnolds Veterinary Products, Cartmel Drive, Harlescott, Shrewsbury, Shropshire SY1 3TB, U. K. ; FAX Number: +44 0174346211). Vetoryl® can be legally imported into the USA by obtaining prior approval from the FDA. See the appendix for step-wise instructions. One source that has been recommended for obtaining trilostane af-ter obtaining FDA approval is: www. mastersmarketing. com (Mealey 2007) HUMAN-LABELED PRODUCTS: Modrastane® is reportedly still an approved human drug, but was withdrawn from the market in the USA in 1994.

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TRIMEPRAZINE TARTRATE WITH PREDNISOLONE 909 TRIMEPRAZINE TARTRATE WITH PREDNISOLONE (trye-mep-ra-zeen) Temaril-P® PHENOTHIAZINE ANTIHISTAMINE & CORTICOSTEROID Prescriber Highlights TT Combination phenothiazine antihistamine & corticoster-oid used for pruritus & potentially as an antitussive TT Relatively Contraindicated: Systemic fungal infections, hypovolemia, or shock & in patients with tetanus or strychnine intoxication. Caution: Hepatic dysfunction, car-diac disease, active bacterial or viral infections, peptic ul-cer, acute psychoses, corneal ulcer, Cushingoid syndrome, diabetes, osteoporosis, chronic psychotic reactions, pre-disposition to thrombophlebitis, hypertension, CHF, renal insufficiency, general debilitation, very young animals TT Goal is to use as much as is required & as little as pos-sible for as short an amount of time as possible TT Primary adverse effects: Sedation, may cause significant hypotension, cardiac rate abnormalities, hypo-or hyper- thermia, “Cushingoid” effects with sustained use TT Many potential drug & lab interactions Uses/Indications Trimeprazine with prednisolone is used for the treatment of pru-ritic conditions, especially if induced by allergic conditions. Many dermatologists believe that when prednisolone is combined with trimeprazine (Temaril-P®), less prednisolone is required to control pruritus. The manufacturer suggests the drug is for use in dogs ei-ther for pruritic conditions or as an antitussive. Pharmacology/Actions Trimeprazine has antihistaminic, sedative, antitussive, and antipru-ritic qualities. The veterinary-approved product also has predniso-lone in its formulation that provides additional antiinflammatory effects. Pharmacokinetics The pharmacokinetics of trimeprazine have apparently not been studied. Contraindications/Precautions/Warnings The contraindications and precautions of this product follow those of the other phenothiazines and antihistaminic agents. For more information, it is suggested to review the acepromazine and chlo-rpheniramine monographs. Adverse Effects For trimeprazine, possible adverse reactions include: sedation, de-pression, hypotension and extrapyramidal reactions (rigidity, trem-ors, weakness, restlessness, etc. ). Additional adverse effects, if using the product containing ste-roids include: elevated liver enzymes, weight loss, polyuria/poly-dipsia, vomiting, and diarrhea. If used chronically, therapy must be withdrawn gradually and Cushing's syndrome may develop. The manufacturer of the veterinary combination product (Temaril®-P) includes the following adverse effects in its package insert: sodium retention and potassium loss, negative nitrogen bal-ance, suppressed adrenocortical function, delayed wound healing, osteoporosis, possible increased susceptibility to and/or exacerba-tion of bacterial infections, sedation, protruding nictitating mem-brane, blood dyscrasias. In addition, intensification and prolonga-tion of the action of sedatives, analgesics or anesthetics can be noted and potentiation of organophosphate toxicity and of procaine HCl activity. Reproductive/Nursing Safety The manufacturer of the veterinary combination product (Temaril®-P) warns that corticosteroids can induce the first stages of parturition if administered during the last trimester of pregnancy. Overdosage/Acute Toxicity Acute overdosage should be handled as per the acepromazine monograph found at the beginning of the book. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving promethazine (a related phenothiazine antihistamine) or prednisolone and may be of sig-nificance in veterinary patients: T ! ACE INHIBITORS : Phenothiazines may increase effects T ! AMPHOTERICIN B : When administered concomitantly with gluco-corticoids may cause hypokalemia T ! ANTACIDS : May cause reduced GI absorption of oral phenothiazines T ! ANTIDIARRHEAL MIXTURES (e. g., Kaolin/pectin, bismuth subsali-cylate mixtures ): May cause reduced GI absorption of oral phenothiazines T ! ANTICHOLINESTERASE AGENTS (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant glucocor-ticoid with these agents may lead to profound muscle weakness. If possible, discontinue anticholinesterase medication at least 24 hours prior to corticosteroid administration. T ! ASPIRIN (salicylates ): Glucocorticoids may reduce salicylate blood levels T ! CISAPRIDE : Increased risk for cardiac arrhythmias when used with phenothiazines T ! CNS DEPRESSANT AGENTS (barbiturates, narcotics, anesthetics, etc. ): May cause additive CNS depression if used with phenothiazines T ! CYCLOPHOSPHAMIDE : Glucocorticoids may also inhibit the hepatic metabolism of cyclophosphamide; dosage adjustments may be required. T ! CYCLOSPORINE : Concomitant administration of may increase the blood levels of each, by mutually inhibiting the hepatic metabo-lism of each other; clinical significance of this interaction is not clear T ! DIGOXIN : Secondary to hypokalemia, increased risk for arrhythmias T ! DIURETICS, POTASSIUM-DEPLETING (furosemide, thiazides ): When administered concomitantly with glucocorticoids may cause hypokalemia T ! EPHEDRINE : May increase metabolism T ! ESTROGENS : The effects of hydrocortisone, and possibly other glu-cocorticoids, may be potentiated by concomitant administration with estrogens T ! INSULIN : Requirements may increase in patients receiving glucocorticoids T ! KETOCONAZOLE : May decrease metabolism

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910 TRIPELENNAMINE HCL T ! MITOTANE : May alter the metabolism of steroids; higher than usu-al doses of steroids may be necessary to treat mitotane-induced adrenal insufficiency T ! NSAIDS : Administration of other ulcerogenic drugs with gluco-corticoids may increase risk T ! PAROXETINE : May increase phenothiazine plasma levels T ! PHENOBARBITAL : May increase the metabolism of glucocorticoids T ! PHENYTOIN : May increase the metabolism of glucocorticoids T ! RIFAMPIN : May increase the metabolism of glucocorticoids T ! VACCINES : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live attenuated-virus vaccines as virus replication may be augmented; a diminished immune response may occur after vaccine, toxoid, or bacterin administration in patients receiving glucocorticoids Laboratory Considerations T ! Glucocorticoids may increase serum cholesterol and urine glucose levels. T ! Glucocorticoids may decrease serum potassium. T ! Glucocorticoids can suppress the release of thyroid stimulat-ing hormone (TSH) and reduce T3 & T4 values. Thyroid gland atrophy has been reported after chronic glucocorticoid admin-istration. Uptake of I131 by the thyroid may be decreased by glucocorticoids. T ! Reactions to skin tests may be suppressed by glucocorticoids or trimeprazine. T ! False-negative results of the nitroblue tetrazolium test for systemic bacterial infection s may be induced by glucocorticoids. Doses T ! DOGS: a) For antipruritic and antitussive therapy: Weight up to 10 lb = 1/2 tab PO twice daily; 11-20 lb = 1 tablet twice daily; 21-40 lb = 2 tablets twice daily; over 40 lb = 3 tablets twice daily. Af-ter 4 days reduce dose to 1/2 of initial dose or to an amount just sufficient to maintain remission of symptoms; adjust as necessary. (Package Insert; Temaril®-P—Pfizer) b) For treatment of pruritus: 1 tablet per 10 kg of body weight once daily for 3-5 days, then every other day. Giving with an EFA (essential fatty acid) may reduce the dose and frequency, if not the need for, glucocorticoids. (White 2003a) c) For atopic dermatitis: 1 tablet of Temaril®-P per 5 kg body weight q12h for one week, then once daily for one week, then q48h (every other day). (Hillier 2006e) Monitoring T ! Efficacy T ! Degree of sedation, and anticholinergic effects T ! Adverse effects associated with corticosteroids Client Information T ! Follow veterinarians dosage recommendations carefully T ! Dog's appetite and water consumption may increase T ! If side effects are worrisome, contact veterinarian Chemistry/Synonyms A phenothiazine antihistamine related to promethazine, trimepra-zine tartrate occurs as an odorless, white, to off-white crystalline powder with a melting range of 160-164°C. Approximately 0. 5 gm is soluble in 1 m L water, and 0. 05 gm is soluble in 1 m L of alcohol. Trimeprazine Tartrate may also be known as: trimeprazine tar-trate, alimemazine tartrate, Chemists Own Peetalix®, Nedeltran®, Panectyl®, Repeltin®, Temaril®, Theralen®, Theralene®, Theralene®, Vallergan®, or Variargil®. Storage/Stability Store trimeprazine products at room temperature (15-30°C); pro-tect tablets from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: No single agent trimeprazine products are approved for veterinary medicine. Trimeprazine Tartrate 5 mg; Prednisolone 2 mg Tablets; Temaril-P® Tablets (Pfizer); (Rx). Approved for use in dogs. Trade name in Can-ada is Vanectyl-P®. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None Trimethoprim/Sulfa—See Sulfadiazine/Trimethoprim TRIPELENNAMINE HCL (tri-pel-ehn-a-meen) Re-Covr® ANTIHISTAMINE Prescriber Highlights TT Oral & injectable antihistamine TT Contraindications: Do not give IV to horses TT Adverse Effects: CNS stimulation (if given IV to horses), sedation, depression, ataxia, GI effects (oral use) Uses/Indications Antihistamines are used in veterinary medicine to reduce or help prevent histamine mediated adverse effects. Tripelennamine has been used as a CNS stimulant in “Downer cows” when adminis-tered slow IV. Pharmacology/Actions Antihistamines (H 1-receptor antagonists) competitively inhibit histamine at H 1 receptor sites. They do not inactivate or prevent the release of histamine, but can prevent histamine's action on the cell. Besides their antihistaminic activity, these agents also have varying degrees of anticholinergic and CNS activity (sedation). Tripelennamine is considered to have moderate sedative activ-ity and minimal anticholinergic activity when compared to other antihistamines. Pharmacokinetics The pharmacokinetics of tripelennamine have apparently not been thoroughly studied in domestic animals or humans. Contraindications/Precautions/Warnings Do not administer Tripelennamine IV in horses (see Adverse Effects). Adverse Effects CNS stimulation (hyperexcitability, nervousness, and muscle trem-ors) lasting up to 20 minutes, has been noted in horses after receiv-ing tripelennamine intravenously. Other effects seen (in all species) include CNS depression, incoordination, and GI disturbances.

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TULAT HROMYCIN 911 Overdosage/Acute Toxicity Overdosage of tripelennamine reportedly can cause CNS excita-tion, seizures and ataxia. Treat symptomatically and supportively if clinical signs are severe. Phenytoin (IV) is recommended in the treatment of seizures caused by antihistamine overdose in humans; barbiturates and diazepam are generally avoided. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving tripelennamine and may be of significance in veterinary patients: T ! CNS DEPRESSANTS, OTHER : Increased sedation can occur if chlo-rpheniramine is combined with other CNS depressant drugs T ! HEPARIN, WARFARIN : Antihistamines may partially counteract the anti-coagulation effects of heparin or warfarin. Laboratory Considerations T ! Antihistamines can decrease the wheal and flare response to anti-gen skin testing. In humans, it is suggested that antihistamines be discontinued at least 4 days prior to testing. Doses It is recommended to warm the solution to near body temperature before injecting; give IM injections into large muscle areas. T ! DOGS: a) 1mg/kg PO q12h; 1 mg/kg IM (Kirk 1986) T ! CATS: a) 1 mg/kg PO q12h; 1 mg/kg IM (Kirk 1986) T ! CATTLE: a) 1. 1 mg/kg (2. 5 m L per 100 lbs body weight) IV (for more immediate effect) or IM q6-12h as needed (Package Insert; Re-Covr®—Solvay) b) As adjunctive treatment in “Downer Cow Syndrome” as a CNS stimulant: 0. 5 mg/kg slow IV in conjunction with par-enteral mineral treatment (Caple 1986) c) 1 mg/kg IV or IM (Howard 1986) T ! HORSES: (Note: ARCI UCGFS Class 3 Drug) a) 1. 1 mg/kg (2. 5 m L per 100 lbs body weight) IM q6-12h as needed (Package Insert; Re-Covr®—Solvay) b) 1 mg/kg IM (Robinson 1987) T ! SWINE: a) 1 mg/kg IV or IM (Howard 1986) Monitoring T ! Clinical efficacy T ! Adverse effects Chemistry/Synonyms An ethylenediamine-derivative antihistamine, tripelennamine HCl occurs as a white, crystalline powder that will slowly darken upon exposure to light. It has a melting range of 188-192°C and p K as of 3. 9 and 9. 0. One gram is soluble in 1 m L of water or 6 m L of alcohol. Tripelennamine HCl may also be known as: tripelennamin-ium chloride, Azaron®, Etono®, Fenistil®, PBZ®, Pelamine®, Pyribenzamine®, Re-Covr® or Vaginex®. Storage/Stability Store the injection at room temperature and protect from light; avoid freezing or excessive heat. Tablets should also be stored at room temperature in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Tripelennamine HCl for Injection: 20 mg/m L in 20 m L, 100 m L, and 250 m L vials; Re-Covr® (Fort Dodge), generic (various manufacturers and trade names); (Rx). Tripelennamine HCl injection is approved for use in cattle and horses. Treated cattle must not be slaughtered for food purposes for 4 days following the last treatment. Milk must not be used for food for 24 hours (2 milkings) after treatment. No specific tolerance for residues has been published. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None TSH—See Thyrotropin TULATHROMYCIN (too-la-throe-mye-sin) Draxxin® INJECTABLE MACROLIDE ANTIBIOTIC Prescriber Highlights TT Injectable macrolide antibiotic for cattle & swine TT Very long tissue half-lives; one dose treatment TT Not for lactating dairy cattle or veal calves TT Local injection site reactions most likely adverse effect Monograph by Elaine Lust, Pharm D Uses/Indications In beef and non-lactating dairy cattle, tulathromycin is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus) and Mycoplasma bovis; and for the control of respiratory disease in cattle at high risk of developing BRD, associated with Mannheimia haemolytica, Pasteurella multo-cida and Histophilus somni (Haemophilus somnus). In swine, tulathromycin is indicated for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuro-pneumoniae, Pasteurella multocida, Bordetella bronchiseptica, and Haemophilus parasuis. Pharmacology/Actions While tulathromycin is a macrolide antibiotic such as erythromycin or azithromycin, it is structurally unique in that it has three amine groups (tribasic), while erythromycin and azithromycin have one (monobasic) and two (dibasic) groups, respectively. The tribasic group of compounds are called triamilide macrolides. It is believed that tulathromycin's tribasic structure allows it to better penetrate gram-negative pathogenic bacteria and its low af-finity for bacterial efflux pumps may allow the drug to remain and accumulate within the bacteria. The mechanism of action of tulathromycin is similar to other macrolides in that it inhibits protein synthesis by penetrating the cell wall and binding to the 50S ribosomal subunits in susceptible bacteria. It is considered a bacteriostatic antibiotic, but it possesses some bactericidal activity as well, particularly for Mannheimia hae-molytica and Pasteurella multocida.

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912 TULAT HROMYCIN Tulathromycin's efficacy is probably enhanced by its ability to accumulate and be released by host phagocytic cells. Neither time-dependent nor concentration-dependent models may accurately predict or describe the drug's efficacy. Some modern macrolides (e. g., azithromycin) efficacy may be more predictive by assessing the total drug exposure to the pathogen; the AUC:MIC ratio may be helpful. Pharmacokinetics In feeder calves given 2. 5 mg/kg SC (in the neck), tulathromycin is rapidly and nearly completely absorbed (bioavailability >90%). Peak plasma concentrations generally occur within 15 minutes af-ter dosing. Volume of distribution is very large (approximately 11 L/kg) and total systemic clearance is approximately 170 m L/hr/kg. This extensive volume of distribution is largely responsible for the long elimination half-life of this compound. In plasma, elimination half life is approximately 2. 75 days, but in lung tissue it is about 8. 75 days. Tulathromycin is eliminated from the body primarily un-changed via biliary excretion. Following intramuscular administration to feeder pigs at a dos-age of 2. 5 mg/kg, tulathromycin is readily and rapidly absorbed (bioavailability 88%) with peak levels occurring in about 15 min-utes. Tulathromycin rapidly distributes into body tissues, and the volume of distribution is 13-15 L/kg. Plasma half-life is approxi-mately 60-90 hours, but lung tissue half life is about 5. 9 days. Tulathromycin is eliminated from the body primarily unchanged via the feces and urine. Contraindications/Precautions/Warnings Tulathromycin is contraindicated in animals with a prior hypersen-sitivity reaction to the drug. Cattle intended for human consumption must not be slaugh-tered within 18 days from the last treatment. Do not use in female dairy cattle 20 months of age or older. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal. Swine intended for human consumption must not be slaugh-tered within 5 days from the last treatment. Adverse Effects At labeled doses, adverse effects appear to be minimal in cattle and swine. Transient hypersalivation has been reported and one feeder calf in field studies developed transient dyspnea. Injection site reac-tions are most commonly reported and there have been some re-ports to the FDA 's Adverse Drug Reporting database of anorexia in cattle. Hypersensitivity reactions are possible, but no reports were located. Subcutaneous or intramuscular injection can cause a transient local tissue reaction that may result in trim loss at slaughter. Reproductive/Nursing Safety Reproductive safety is not known, the product is labeled: “The ef-fects of Draxxin® on bovine (and porcine) reproductive perfor-mance, pregnancy and lactation have not been determined. Overdosage/Acute Toxicity In cattle (feeder calves), single subcutaneous doses of up to 25 mg/ kg caused transient indications of pain at the injection, including head shaking and pawing at the ground. Injection site swelling, discoloration of the subcutaneous tissues at the injection site and corresponding histopathologic changes were seen in animals in all dosage groups. In swine, single IM doses of up to 25 mg/kg caused transient indications of pain at the injection site, restlessness, and excessive vocalization. Tremors occurred briefly in one animal receiving 7. 5 mg/kg BW. No systemic treatment for single overdoses should be necessary, localized treatment at the injection site (e. g., ice pack) to reduce swelling and pain as well as approved analgesic medications can be considered. Drug Interactions No drug interactions are noted in the manufacturer's label and none could be found in other references for tulathromycin. Laboratory Considerations No concerns were noted Doses !TCATTLE: For labeled indications: a) Inject subcutaneously as a single dose in the neck at a dos-age of 2. 5 mg/kg (1. 1 m L/100 lb) body weight (BW). Do not inject more than 10 m L per injection site. (Label directions; Draxxin®—Pfizer) !TSWINE: For labeled indications: a) Inject intramuscularly as a single dose in the neck at a dosage of 2. 5 mg/kg (0. 25 m L/22 lb) BW. Do not inject more than 2. 5 m L per injection site. (Label directions; Draxxin®—Pfizer) Monitoring !TClinical efficacy Client Information !TFollow dosing guidelines exactly; adhere to withdrawal times !TNot for female dairy cattle (20 months or older) or veal calves !TCattle are dosed subcutaneously in the neck, not more than 10 m L per injection site !TSwine are dosed intramuscularly in the neck, not more than 2. 5 m L per injection site Chemistry/Synonyms Tulathromycin is a semi-synthetic macrolide antibiotic of the sub-class triamilide. It occurs as white to of-white-crystalline powder that is readily soluble in water at p H<8. At a p H of 7. 4 (physiologi-cal p H), tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. The commercially available injection contains 100 mg/m L of tu-lathromycin in an equilibrated mixture of the two isomeric forms of tulathromycin in a 9:1 ratio. The injectable vehicle consists of 50% propylene glycol, monothioglycerol (5 mg/m L); citric and hydrochloric acids are added to adjust p H. It has a relatively low viscosity. Tulathromycin may also be known as tulathromycine, tulathro-mycinum, CP-472295 (component A), CP-547272 (component B), or Draxxin®. Storage/Stability/Compatibility Tulathromycin injection should be stored at, or below 25°C (77°F). The product is stable at room temperature for up to 36 months.

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TYLOSIN 913 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Tulathromycin Injection 100 mg/m L in 50, 100, 250, & 500 m L vi-als: Draxxin® (Pfizer); Approved for use in cattle and swine. Cattle intended for human consumption must not be slaughtered within 18 days from the last treatment. Do not use in female dairy cattle 20 months of age or older. A withdrawal period has not been es-tablished for this product in pre-ruminating calves. Do not use in calves to be processed for veal. Swine intended for human consumption must not be slaughtered within 5 days from the last treatment. HUMAN-LABELED PRODUCTS: None TYLOSIN (tye-loe-sin) Tylan® MACROLIDE ANTIBIOTIC Prescriber Highlights TT Macrolide antibiotic related to erythromycin, used primar-ily in cattle & swine; sometimes used orally in cats/dogs for chronic colitis TT Contraindications: hypersensitivity to it or other mac-rolide antibiotics; probably contraindicated in horses TT Adverse Effects: Pain & local reactions after IM injection, GI upset (anorexia, & diarrhea). May cause severe diar-rheas if administered PO to ruminants or by any route to horses. SWINE: edema of rectal mucosa & mild anal protrusion with pruritus, erythema, & diarrhea Uses/Indications Although the injectable form of tylosin is approved for use in dogs and cats, it is rarely used parenterally in those species. Oral tylosin is sometimes recommended for the treatment of chronic colitis in small animals (see Doses), but controlled studies documenting its efficacy have not been performed. Tylosin is also used clinically in cattle and swine for infections caused by susceptible organisms. Pharmacology/Actions Tylosin is thought to have the same mechanism of action as eryth-romycin (binds to 50S ribosome and inhibits protein synthesis) and exhibits a similar spectrum of activity. It is a bacteriostatic anti-biotic. Tylosin may also have immunomodulatory effects on cell-mediated immunity. In dogs, tylosin increases concentrations of enterococci (Enterococcus fecalis) in the jejunum. Enterococci are thought to have probiotic effects. For more specific information on organisms where tylosin is usually active, refer to the erythromycin monograph; cross-resis-tance with erythromycin occurs. Pharmacokinetics Tylosin tartrate is well absorbed from the GI tract, primarily from the intestine. The phosphate salt is less well absorbed after oral ad-ministration. Tylosin base injected SC or IM is reportedly rapidly absorbed. Like erythromycin, tylosin is well distributed in the body after systemic absorption, with the exception of penetration into the CSF. The volume of distribution of tylosin is reportedly 1. 7 L/kg in small animals and 1-2. 3 L/kg in cattle. In lactating dairy cattle, the milk to plasma ratio is reported to be between 1-5. 4. Tylosin is eliminated in the urine and bile apparently as un-changed drug. The elimination half-life of tylosin is reportedly 54 minutes in small animals, 139 minutes in newborn calves, and 64 minutes in calves 2 months of age or older. Contraindications/Precautions/Warnings Tylosin is contraindicated in patients hypersensitive to it or other macrolide antibiotics (e. g., erythromycin). Most clinicians feel that tylosin is contraindicated in horses, as severe and sometimes fatal diarrheas may result from its use in that species. Adverse Effects Most likely adverse effects with tylosin are pain and local reactions at intramuscular injection sites, and mild GI upset (anorexia and di-arrhea). Tylosin may induce severe diarrheas if administered orally to ruminants or by any route to horses. In swine, adverse effects reported include edema of rectal mucosa and mild anal protrusion with pruritus, erythema, and diarrhea. Reproductive/Nursing Safety In a system evaluating the safety of drugs in canine and feline preg-nancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncov-ered 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 Tylosin is relatively safe in most overdose situations. The LD 50 in pigs is greater than 5 g/kg orally, and approximately 1 g/kg IM. Dogs are reported to tolerate oral doses of 800 mg/kg. Long-term (2 year) oral administration of up to 400 mg/kg produced no organ toxicity in dogs. Shock and death have been reported in baby pigs overdosed with tylosin, however. Drug Interactions Drug interactions with tylosin have not been well documented. It has been suggested that tylosin may increase digoxin blood levels with resultant toxicity. It is suggested to refer to the erythromycin monograph for more information on potential interactions. Laboratory Considerations T ! Macrolide antibiotics may cause falsely elevated values of AST (SGOT), and ALT (SGPT) when using colorimetric assays. T ! Fluorometric determinations of urinary catecholamines can be al-tered by concomitant macrolide administration. Doses T ! DOGS: When using Tylan® Soluble (100 grams per bottle) powder: Us-ing volumetric containers to measure powders is not necessar-ily accurate, but 1 level teaspoonful (5 m L) of powder contains approximately 2. 5-2. 7 grams of tylosin; 1/8th of a teaspoonful contains approximately 325 mg tylosin. a) For small intestinal bacterial overgrowth: 10-20 mg/kg PO q12h; recommended for chronic cases, may require therapy for as long as 6 weeks. (Ludlow and Davenport 2000) b) For adjunctive treatment of IBD: 10 mg/kg PO three times daily. Therapeutic trial for 21 days to evaluate efficacy. (Simp-son 2003a)

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914 TYLOSIN c) For clostridial colitis: 10-40 mg/kg PO twice daily. Practical-ly (using the wettable powder): 1/16th of teaspoon 2-3 times daily for dogs (<7kg); Jth of a teaspoon 2-3 times a day for medium dogs (7-15 kg); and 1/4 teaspoon 2-3 times a day for larger dogs (>15 kg). Mix with food to hide unpleasant taste or put into capsules. Animals with chronic clostridial colitis can often be controlled with one treatment every 2-3 days. (Willard 2006a) d) For IBD and antibiotic responsive diarrhea: 20-40 mg/kg PO q12h (Marks 2007b) !TCATS: When using Tylan® Soluble (100 grams per bottle) powder: Us-ing volumetric containers to measure powders is not necessar-ily accurate, but 1 level teaspoonful (5 m L) of powder contains approximately 2. 5-2. 7 grams of tylosin; 1/8th of a teaspoonful contains approximately 325 mg tylosin. a) For adjunctive treatment of IBD: 10 mg/kg PO three times daily. Therapeutic trial for 21 days to evaluate efficacy. (Simp-son 2003a) b) For treatment of IBD or diarrheas caused by C. perfringens: 20-40 mg/kg PO twice daily (Marks 2002) c) For IBD: 40 mg/kg PO q12h (Zoran 2007) d) For clostridial colitis: 10-40 mg/kg PO twice daily. Practi-cally (using the wettable powder): 1/16th of teaspoon 2-3 times daily. Mix with food to hide unpleasant taste or put into capsules. Animals with chronic clostridial colitis can of-ten be controlled with one treatment every 2-3 days. (Wil-lard 2006a) !TFERRETS: For susceptible infections: a) 10 mg/kg PO once to twice daily (Williams 2000) !TRABBITS, RODENTS, SMALL MAMMALS: a) Rabbits: 10 mg/kg PO, SC, IM q12-24h (Ivey and Morrisey 2000) b) Gerbils, Hamsters, Rats: 10 mg/kg SC q24h (Adamcak and Otten 2000) !TCATTLE: For susceptible infections: a) 17. 6 mg/kg IM once daily. Continue treatment for 24 hours after symptoms have stopped, not to exceed 5 days. Do not inject more than 10 m L per site. Use the 50 mg/m L formula-tion in calves weighing less than 200 pounds. (Package insert; Tylosin® Injection—T ech America) b) For bronchopneumonia and fibrinous pneumonia in cattle associated with penicillin G-refractory C. pyogenes infections or other bacteria sensitive to tylosin and resistant to sulfas, penicillin G and tetracyclines: using Tylosin 200 mg/m L: 44 mg/kg IM q24h. Recommend a 21-day slaughter withdrawal at this dosage. (Hjerpe 1986) c) 5-10 mg/kg IM or slow IV once daily; not to exceed 5 days (Huber 1988a) d) Tylosin base injectable: 10 mg/kg IM initially, then 6 mg/kg IM q8h (q8-12h in calves) (Baggot 1983) !TSWINE: For susceptible infections: a) 8. 8 mg/kg IM twice daily. Continue treatment for 24 hours after symptoms have stopped, not to exceed 3 days. Do not inject more than 5 m L per site. (Package insert; Tylosin® In-jection—T ech America) b) 5-10 mg/kg until 24 hours after remission of disease signs; not to exceed 3 days therapy (Huber 1988a) c) Tylosin base injectable: 12. 5 mg/kg IM q12h (Baggot 1983) !TSHEEP & GOATS: For susceptible infections: a) 10 mg/kg, treatment not to exceed 5 days (Huber 1988a) !TBIRDS: For susceptible infections: a) For initial therapy in caged birds for upper respiratory infec-tions (especially if mycoplasma suspected). Using 200 mg/m L injectable: 40 mg/kg IM. Used in combi-nation with aminoglycosides. (Mc Donald 1989) b) For initial therapy of upper respiratory infections and air sacculitis. Using 50 mg/m L or 200 mg/m L injectable: 10-40 mg/kg IM twice daily or three times daily (Clubb 1986) c) 30 mg/kg IM q12h (Hoeffer 1995) !TREPTILES: For susceptible infections: a) For tortoises: 5 mg/kg IM once daily for at least 10 days. Used primarily for chronic respiratory infections or when Myco-plasma is suspected (Gauvin 1993) b) All species: 5 mg/kg IM once daily (Jacobson 1999) Monitoring !TClinical efficacy !TAdverse effects Chemistry/Synonyms A macrolide antibiotic related structurally to erythromycin, tylosin is produced from Streptomyces fradiae. It occurs as an almost white to buff-colored powder with a p K a of 7. 1. It is slightly soluble in wa-ter and soluble in alcohol. Tylosin is considered highly lipid soluble. The tartrate salt is soluble in water. The injectable form of the drug (as the base) is in a 50% propylene glycol solution. Tylosin may also be known as Desmycosin, tilosina, tylozin, ty-losiini, tylosinum, tylozyna or Tylan®. Storage/Stability/Compatibility Unless otherwise instructed by the manufacturer, injectable tylosin should be stored in well-closed containers at room temperature. Tylosin, like erythromycin, is unstable in acidic (p H <4) media. It is not recommended to mix the parenteral injection with other drugs. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Note : The product Tylan® Plus Vitamins was used extensively orally in companion animals, but has been withdrawn from the market. Tylan® Soluble may be substituted, but is significantly more concen-trated than Tylan® Plus Vitamins and dosage sizes (teaspoons are not equivalent) will be different. Tylosin Injection: 50 mg/m L, 200 mg/m L; Tylan® (Elanco); generic; (OTC). Approved for use in nonlactating dairy cattle, beef cattle, swine, dogs, and cats. Slaughter withdrawal (at labeled doses): cattle = 21 days; swine = 14 days. Note : Although this author (Plumb) was unable to locate parenteral products approved for use in lactating dairy animals, one source (Huber 1988a) states that tylosin has a 72 hour milk withdrawal for dairy cattle, and 48 hour milk withdrawal in dairy goats and sheep. Contact FARAD for more information be-fore using in lactating dairy animals.

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URSODIOL 915 Tylosin Tartrate Powder: (approximately 2. 5-2. 7 grams/level tea-spoonsful) in 100 g bottles; Tylan® Soluble (Elanco); (OTC). Ap-proved for use in turkeys (not layers), chickens (not layers) and swine. Slaughter withdrawal swine = 2 days; chickens = 1 day; turkeys = 5 days. There are many approved tylosin products for addition to feed or wa-ter for use in beef cattle, swine, and poultry. Many of these products have other active ingredients included in their formulations. HUMAN-LABELED PRODUCTS: None. URSODIOL (ur-soe-dye-ole) Actigall®, Ursodeoxycholic acid BILE ACID Prescriber Highlights TT Bile acid that may be useful for treatment of hepatobil-iary disease in dogs/cats. May also be used for choles-terol containing gallstones TT Contraindications: Rabbits & other hindgut fermenters. Caution: Complications associated with gallstones (e. g., biliary obstruction, biliary fistulas, cholecystitis, pancrea-titis, cholangitis) TT Adverse Effects: Appears to be well tolerated in dogs/cats Uses/Indications In small animals, ursodiol may be useful as adjunctive therapy for the medical management of cholesterol-containing gallstones and/or in patients with chronic liver disease, particularly where cholestasis (bile toxicity) plays an important role. Ursodiol's benefit in treating canine or feline hepatobiliary disease is unknown at the time of writing (studies are ongoing), but it may be of help in slow-ing the progression of inflammatory hepatic disorders, particularly autoimmune hepatitis and acute hepatotoxicity. Pharmacology/Actions After oral administration, ursodiol suppresses hepatic synthesis and secretion of cholesterol. Ursodiol also decreases intestinal absorp-tion of cholesterol. By reducing cholesterol saturation in the bile, it is thought that ursodiol allows solubilization of cholesterol-con-taining gallstones. Ursodiol also increases bile flow and in patients with chronic liver disease, it apparently reduces the hepatocyte toxic effects of bile salts by decreasing their detergent action, and may protect hepatic cells from toxic bile acids (e. g., lithocholate, deoxy-cholate, and chenodeoxycholate). Pharmacokinetics Ursodiol is well absorbed from the small intestine after oral admin-istration. In humans, up to 90% of dose is absorbed. After absorp-tion, it enters the portal circulation. In the liver, it is extracted and combined (conjugated) with either taurine or glycine and secreted into the bile. Only very small quantities enter the systemic circula-tion and very little is detected in the urine. After each entero-he-patic cycle, some quantity of conjugated and free drug undergoes bacterial degradation; eventually most of the drug is eliminated in the feces after being oxidized or reduced to less soluble compounds. Ursodiol detected in the systemic circulation is highly bound to plasma proteins. Contraindications/Precautions/Warnings Ursodiol is contraindicated in rabbits and other hindgut ferment-ers as it is converted into lithocholic acid (toxic). Patients sensi-tive to other bile acid products may also be sensitive to ursodiol. The benefits of using ursodiol should be weighed against its risks in patients with complications associated with gallstones (e. g., biliary obstruction, biliary fistulas, cholecystitis, pancreatitis, cholangitis). While ursodiol may be useful in treating patients with chronic liver disease, some patients may experience further impairment of bile acid metabolism. Adverse Effects While ursodiol use in animals has been limited, it appears to be well tolerated in dogs and cats. Although hepatotoxicity has not been associated with ursodiol therapy, some human patients have an in-ability to sulfate lithocholic acid (a naturally occurring bile acid and also a metabolite of ursodiol). Lithocholic acid is a known hepa-totoxin; veterinary significance is unclear. Diarrhea and other GI effects have rarely been noted in humans taking ursodiol. Ursodiol will not dissolve calcified radiopaque stones or radiolucent bile pig-ment stones. 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. ) It is not known whether ursodiol is excreted in breast milk. Overdosage/Acute Toxicity Overdosage of ursodiol would most likely cause diarrhea. Treatment, if required, could include supportive therapy; oral administration of an aluminum-containing antacid (e. g., aluminum hydroxide sus-pension); gastric emptying (if large overdose) with concurrent ad-ministration of activated charcoal or cholestyramine suspension. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ursodiol and may be of significance in veterinary patients: T ! ALUMINUM-CONTAINING ANTACIDS : May bind to ursodiol, thereby reducing its efficacy T ! CHOLESTYRAMINE RESIN : May bind to ursodiol, thereby reducing its efficacy Laboratory Considerations T ! As ursodiol is detected by many serum bile acid tests, bile acids may remain falsely elevated. One study in normal dogs did not show any effects, however. Doses T ! DOGS: For adjunctive treatment of chronic hepatitis: a) 5-15 mg/kg PO divided q12h, with immunosuppressive therapy. ( Note: Use of this drug at this dose is preliminary, but promising) (Johnson and Sherding 1994) b) 10-15 mg/kg PO once daily (Leveille-Webster and Center 1995); (Twedt 1999) c) For use in chronic active hepatitis, fibrosis and cirrhosis. May use as primary or adjunctive therapy. Dose: 11-15. 4 mg/kg PO either once daily or divided twice daily (Tams 2000)

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916 VALPROIC ACID/VALPROATE SODIUM/DIVALPROEX SODIUM T ! CATS: For adjunctive treatment of chronic hepatitis: a) 10-15 mg/kg PO once daily (Leveille-Webster and Center 1995); (Trepanier 1999) b) For use in chronic active hepatitis, fibrosis, and cirrhosis. May use as primary or adjunctive therapy. Dose: 11-15. 4 mg/kg PO either once daily or divided twice daily. Cats usu-ally get 1/6th of a capsule mixed with a small amount of food. Cats may still eat their food even if drug is sprinkled on top. (Tams 2000) c) 10 mg/kg/day PO (Zoran 2006b) Monitoring T ! Efficacy (ultrasonography for gallstones; improved liver function tests for chronic hepatic disease) T ! Monitoring of SGPT/SGOT (AST/ALT) on a routine basis (in humans these tests are recommended to be performed at the ini-tiation of therapy and at 1 and 3 months after starting therapy; then every 6 months). Client Information T ! Because ursodiol dissolves more rapidly in the presence of bile or pancreatic juice, it should be given with food. Chemistry/Synonyms A naturally occurring bile acid, ursodiol, also known as ursodeoxy-cholic acid has a molecular weight of 392. 6. Ursodiol may also be known as: acidum ursodeoxycholicum, UDCA, ursodesoxycholic acid; many trade names are available. Storage/Stability Unless otherwise specified by the manufacturer, ursodiol cap-sules should be stored at room temperature (15-30°C) in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ursodiol Capsules: 300 mg; Actigall® & generic (Watson); (Rx) Ursodiol Tablets: 250 mg & 500 mg; URSO® 250 &-Forte (Axcan Pharma); (Rx) VALPROIC ACID VALPROATE SODIUM DIVALPROEX SODIUM (val-proe-ik; val-proe-ayte; die-val-proe-ex) Depakene®, Depakote®, Depacon® Prescriber Highlights TT 2nd to 4th line anticonvulsant that may be useful as adjunctive treatment in some dogs; most do not recom-mend its use in veterinary patients TT Contraindications: Significant hepatic disease or dysfunc-tion, previous hypersensitivity TT Caution: Thrombocytopenia or altered platelet aggrega-tion function TT Adverse Effects: GI effects (may be diminished by giv-ing with food) most likely; hepatotoxicity, CNS (sedation, ataxia, behavioral changes, etc. ), dermatologic reactions, (alopecia, rash, etc. ), hematologic reactions, (thrombocy-topenia, reduced platelet aggregation, leukopenias, ane-mias, etc. ), pancreatitis, & edema are possible TT May be teratogenic Uses/Indications Because of its cost, apparent unfavorable pharmacokinetic profile, and potential hepatotoxicity, valproic acid must be considered at best, a third or fourth line drug in the treatment of seizures in the dog. Some clinicians feel it is of benefit when added to phenobar-bital in patients not adequately controlled with that drug alone. Additionally, it is less protein bound in dogs than in humans, so the human serum therapeutic range of the drug (40-100 mcg/ m L) may be too high in dogs. The drug (free form) actually may concentrate in the CSF, and anticonvulsant effects may persist even after valproate levels are non-detectable in CSF, lending to the idea that serum levels do not accurately reflect clinical efficacy. Clearly, additional studies are needed to determine the clinical role, if any, for this drug. Pharmacology/Actions The mechanism of the anticonvulsant activity of valproic acid is not understood. Animal studies have demonstrated that valproic acid inhibits GABA transferase and succinic aldehyde dehydroge-nase causing increased CNS levels of GABA. Additionally, one study has demonstrated that valproic acid inhibits neuronal activity by increasing potassium conductance. Pharmacokinetics Sodium valproate is rapidly converted to valproic acid in the acidic environment of the stomach where it is rapidly absorbed from the GI tract. The bioavailability reported in dogs following oral admin-istration is approximately 80%; peak levels occur in approximately 1-hour. Food may delay absorption, but does not alter the extent of it. Divalproex in its enteric-coated form has an approximately 1-hour delay in its oral absorption. Patients' who exhibit GI (nau-sea, vomiting) adverse effects may benefit from this dosage form. Valproic acid is rapidly distributed throughout the extracellu-lar water spaces and plasma. It is approximately 80-95% plasma protein bound in humans, and 78-80% plasma protein bound in

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VALPROIC ACID/VALPROATE SODIUM/DIVALPROEX SODIUM 917 dogs. CSF levels are approximately 10% those found in plasma. Milk levels are 1-10% those found in plasma; it readily crosses the placenta. Valproic acid is metabolized in the liver and is conjugated with glucuronide. These metabolic conjugates are excreted in the urine; only very small amounts of unchanged drug are excreted in the urine. The elimination half-life in humans ranges from 5-20 hours; in dogs from 1. 5-2. 8 hours. Contraindications/Precautions/Warnings Valproic acid is contraindicated in patients with significant hepatic disease or dysfunction, or exhibiting previous hypersensitivity to the drug. It should be used with caution in patients with thrombo-cytopenia or altered platelet aggregation function. Adverse Effects Because of the limited experience with this agent, the following ad-verse effects may not be complete nor valid for dogs: Gastrointestinal effects consisting of nausea, vomiting, anorexia, and diarrhea are the most common adverse effects seen in people and also appar-ently,, in dogs. GI effects may be diminished by administration with food. Hepatotoxicity is the most serious potential adverse (human) reaction reported and must be considered for canine patients also. Dose related increases in liver enzymes may be seen and, rarely, he-patic failure and death may occur. In humans, incidences of hepa-totoxicity are greater in very young (<2 yr. old) patients, those on other anticonvulsants, or with multiple congenital abnormalities. Other potential adverse effects include: CNS (sedation, ataxia, behavioral changes, etc. ), dermatologic (alopecia, rash, etc. ), hema-tologic (thrombocytopenia, reduced platelet aggregation, leukope-nias, anemias, etc. ), pancreatitis, and edema. Reproductive/Nursing Safety A 1-2% incidence of neural tube defects in children born of moth-ers taking valproic acid during the first trimester of pregnancy has been reported. Use in pregnant dogs only when the benefits out-weigh the risks of therapy. 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 system evaluating the safety of drugs in canine and fe-line 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 cau-tiously as a last resort when the benefit of therapy clearly outweighs the risks. ) Concentrations of valproic acid in maternal milk are 1-10% of serum concentrations. It is unknown if this would have any detri-mental effect on nursing offspring. Overdosage/Acute Toxicity Severe overdoses can cause profound CNS depression, asterixis, motor restlessness, hallucinations, and death. One human patient recovered after a serum level of 2000 micrograms/m L (20 times over therapeutic) was measured. Treatment consists of supportive measures and maintenance of adequate urine output is considered mandatory. Because the drug is rapidly absorbed, emesis or gastric lavage may be of limited value. Because of its delayed absorptive characteristics, the divalproex form may be removed by lavage or emesis if ingestion occurred recently. Naloxone is reported to be of benefit in reversing some of the CNS effects of valproic acid, but may also reverse the anticonvulsant properties of the drug. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving valproic acid and may be of significance in veterinary patients: !TANTICOAGULANTS : Valproic acid may have effects on platelet aggre-gation; use with caution with other drugs that affect coagulation status !TASPIRIN : Salicylates may displace valproic acid from plasma pro-tein sites, thus increasing valproic acid levels !TCLONAZEPAM : The sedative effects of clonazepam may be en-hanced by valproic acid and the anticonvulsant efficacy of both may be diminished !TCNS DEPRESSANTS, OTHER : VPA may enhance the CNS depressant effects of other CNS active drugs. !TPHENOBARBITAL, PRIMIDONE : Valproic acid may increase serum lev-els of phenobarbital and primidone Laboratory Considerations !TA keto-metabolite of valproic acid is excreted into the urine and may yield false positive urine ketone tests. !TAltered thyroid function tests have been reported in humans with unknown clinical significance. Doses Note : Because of its very short half-life in dogs, most neurologists do not recommend using VPA in dogs. !TDOGS: a) Add on therapy with phenobarbital or bromide: 60 mg/kg PO q8h (Thomas 2000) Monitoring !TAnticonvulsant efficacy !TIf used chronically, routine CBC's and liver enzymes at least every 6 months Client Information !TCompliance with therapy must be stressed to clients for success-ful epilepsy treatment. Encourage administering daily doses at same time each day, preferably with food. !TVeterinarian should be contacted if animal develops significant adverse reactions (including clinical signs of anemia and/or liver disease) or if seizure control is unacceptable. Chemistry/Synonyms Structurally unrelated to other anticonvulsant agents; valproic acid, valproate sodium, divalproex sodium are derivatives of carboxylic acid. Valproic acid occurs as a colorless to pale yellow clear liquid. It is slightly viscous; has a characteristic odor, a p K a of 4. 8, is slightly soluble in water and freely soluble in alcohol. It is also known as Dipropylacetic acid, DPA, 2-propylpentanoic acid, and 2-propyl-valeric acid. Valproate sodium occurs as a white, crystalline, saline tasting, very hygroscopic powder. It is very soluble in water or alcohol. The commercially available oral solution has a p H of 7-8. Divalproex sodium is a stable compound in a 1:1 molar ratio of valproic acid and valproate sodium. It occurs as a white powder with a characteristic odor. It is insoluble in water and very soluble in alcohol. Valproate sodium may also be known as: Abbott-44090, natrii valproas; many trade names are available. Valproic acid may also be known as: Abbott-44089, acidum val-proicum; many trade names are available.

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918 VANADIUM/VANADYL SULFATE Storage/Stability Valproic acid capsules should be stored at room temperature (15-30°C) and in tight containers; avoid freezing. Valproate so-dium oral solution should be stored at room temperature and in tight containers; avoid freezing. Divalproex sodium enteric-coated tablets should be stored at room temperature in tight, light resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Valproic Acid Capsules: 250 mg; Depakene® (Abbott); (Rx); generic; (Rx) Valproate Sodium Syrup: 50 mg/m L in 473 m L; Depakene® (Abbott); generic; (Rx) Divalproex Sodium Delayed/Extended Release Tablets: 125 mg, 250 mg, 500 mg; Depakote® and Depakote ER® (Abbott); (Rx) Divalproex Sodium Capsules (Sprinkle): 125 mg; Depakote® (Ab-bott); (Rx) Valproate Sodium Injection: 100 mg/m L in 5 m L single-dose vials (regular and preservative free); Depacon® (Abbott); generic; (Bed-ford); (Rx) VANADIUM VANADYL SULFATE (van-aye-dee-um; van-ah-dil) Vanadyl Fuel® TRACE METAL Prescriber Highlights TT Trace metal “nutraceutical” that may be useful as an ad-junctive treatment for diabetes mellitus in cats TT Efficacy questionable, but probably safe Uses/Indications Vanadium supplementation may be useful in the adjunctive treat-ment of diabetes mellitus, particularly in cats. There is controversy whether or not this treatment is beneficial. Pharmacology/Actions In humans with non-insulin dependent diabetes mellitus (NIDDM), vanadium can reduce fasting blood glucose and glycosylated hemo-globin levels, reduces hepatic glucose release, and increases periph-eral glucose disposal and uptake into skeletal muscle mediated by insulin. Vanadium does not influence blood glucose levels in normal patients. While the exact mechanism of action of vanadium is un-known, it apparently inhibits protein tyrosine phosphatase (PTP). PTP is important in signal transduction and allows vanadium to act via both insulin-dependent and insulin-independent pathways. Pharmacokinetics Little information on the pharmacokinetics of vanadium was lo-cated. Only about 5% is absorbed from foodstuffs. In vivo it is converted to the vanadyl cation and forms complexes with ferri-tin and transferrin. Highest vanadium concentrations are found in the liver, bone and kidney. Vanadium is eliminated via renal routes. Effects on glucose in NIDDM humans may persist for weeks after discontinuation of therapy. Contraindications/Precautions/Warnings Vanadium supplements could potentially exacerbate renal insuffi-ciency; use with caution in these patients. Adverse Effects Gastrointestinal effects have been reported in some cats receiv-ing vanadium supplements; anorexia and vomiting is most com-monly reported. It has been reported that cats initially unable to tolerate vanadium, can have therapy re-instituted without ill effect. Vanadium in high dosages may have renal toxic effects. Reproductive/Nursing Safety It is unknown if supplemental vanadium is safe in pregnancy. Vanadium is unlikely to have negative effects in nursing kittens. Overdosage/Acute Toxicity Vanadyl sulfate may be mildly toxic. The oral LD50 in rats is 450 mg/kg. Consider gut removal protocols if an acute overdose oc-curs. Contact an animal poison control center for further guidance. Chronic overdoses may cause kidney damage. Drug Interactions No specific interactions of note were located. When used with other agents for diabetes management, effects may be additive. Laboratory Considerations No specific laboratory interactions or considerations were noted Doses Note : Because vanadium is given as a salt, do not confuse dosages for vanadium with vanadyl sulfate. Vanadyl sulfate reportedly con-tains 31% elemental vanadium, but labeled amounts of vanadium vary considerably. T ! CATS: a) Using Super Vanadyl Fuel® (Twin Labs; also contains chromi-um): 1/2 capsule PO once daily with food. (Dowling 2000) b) For adjunctive use in treating feline type 2 diabetes: Vana-dium (Note: salt not specified, assume elemental vanadium) 0. 2 mg/kg PO once daily in food or water. (Greco 2002a) c) For diabetes mellitus: Vanadyl sulfate 1 mg/kg PO once daily or vanadium 0. 2 mg/kg PO once daily. (Wynn 2002) d) For early NIDDM using Vanadyl Fuel® (Twin Labs; also con-tains chromium): One capsule PO once daily (q24h) (Me-lendez and Lorenz 2002) Monitoring T ! As there is no reliable way to measure vanadium in the body, a clinical trial is the only way to determine whether vanadium is effective in helping to control blood glucose. Standard methods for monitoring efficacy of diabetes treatment should be followed (e. g., fasting blood glucose, appetite, attitude, body condition, PU/PD resolution and, perhaps, serum fructosamine and/or gly-cosylated hemoglobin levels). Client Information T ! Clients should give the medication only as prescribed and not change brands without their veterinarian's guidance T ! Give with food Chemistry/Synonyms A trace element, vanadium (V, atomic number 23) is usually given in the form of the inorganic salt, vanadyl sulfate. Vanadyl sulfate occurs as blue crystals and is very soluble in water. Vanadyl sulfate reportedly contains 31% elemental vanadium.

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VANCOMYCIN HCL 919 Vanadyl sulfate may also be known as: vanadium (IV) sulfate oxide; vanadium oxysulfate, oxo[sulfato(2-)-O]-vanadium, oxy-sulfato vanadium (IV); vanadyl (IV) sulfate, or vanadyl (IV)-sulfate hydrate. Storage/Stability/Compatibility While vanadyl sulfate is stable under ordinary conditions, refer to the label for each product used. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: No oral products are approved as pharmaceuticals. Oral vanadyl sulfate products are considered nutritional supplements by the FDA. No standards have been accepted for potency, purity, safety or efficacy by regulatory bodies. Supplements are available from a wide variety of sources. Common products include 7. 5 mg, and 10 mg tablets or 15 mg capsules. One proprietary product that has been used in cats is Super Vanadyl Fuel® (Twin Labs). This is a combination product that contains per capsule (among many other ingredients): 150 mcg chromium (from chro-mium nicotinate and picolinate) and 1. 25 mg of elemental vanadium (from BMOV [bi (maltolato) oxovanadium] and vanadyl sulfate). Bioequivalence between products cannot be assumed. VANCOMYCIN HCL (van-koe-mye-sin) Vancocin® GLYCO PEPTIDE ANTIBIOTIC Prescriber Highlights TT Glycopeptide antibiotic reserved for IV use for multi-drug resistant Staph or Enterococcus infections; can also be used PO to treat Clostridium difficile diarrhea TT When used systemically, must be given IV; severe pain & tissue injury occurs with SC or IM injection TT May be synergistic with aminoglycoside therapy, but in-creased risk of nephrotoxicity, ototoxicity & neutropenia also possible TT If decreased renal dysfunction, adjust dosage Uses/Indications Vancomycin should only be used to treat infections that are docu-mented resistant to other antibiotics and susceptible to vancomy-cin, usually methicillin-resistant Staphylococcus spp. (MRSA) or multidrug-resistant Enterococcus spp. It potentially is useful for oral treatment of pseudomembranous colitis caused by Clostridia difficile. Pharmacology/Actions Vancomycin inhibits cell-wall synthesis and bacterial cell-mem-brane permeability. It also affects bacterial RNA synthesis. It is only effective against gram-positive bacteria, including many strains of streptococci, staphylococci, and enterococci. Vancomycin is gener-ally a bactericidal antibiotic, but is bacteriostatic against entero-cocci. Vancomycin also has activity against Clostridium difficile, Listeria monocytogenes, Corynebacterium, and Actinomyces spp.. Vancomycin and aminoglycosides can have synergistic action against susceptible bacteria. Resistance to vancomycin by certain strains of enterococci and staphylococci is an increasing concern in human medicine and po-tentially, for veterinary patients. Pharmacokinetics When given orally, vancomycin is not appreciably absorbed. After intravenous administration, vancomycin is widely distributed. Therapeutic levels can be found in pleural, ascitic, pericardial, and synovial fluids. At usual serum levels, it does not readily distribute into the CSF. The elimination half-life of vancomycin in patients with normal renal function is approximately 4-6 hours. Prolonged dosing can allow the drug to accumulate. The drug is eliminated primarily via glomerular filtration; small amounts are excreted into the bile. Contraindications/Precautions/Warnings Vancomycin is an important antibiotic for treating multi-drug re-sistant infections in humans. It should not be used in veterinary patients when other antibiotics can be used to successfully treat the infection. Patients with decreased renal function that require vancomycin should have dosages reduced or dosing interval increased. Serum levels should be monitored. Adverse Effects When given parenterally, nephrotoxicity and ototoxicity are the most serious potential adverse effects of vancomycin. Unlike amin-oglycosides, these effects are believed to be uncommon. In humans, dermatologic reactions and hypersensitivity can occur; it is un-known if these effects are issues for veterinary patients. Reversible neutropenia has been reported in humans, particularly when dos-age is high and prolonged. Do not administer IV rapidly or as a bolus; thrombophlebitis, severe hypotension or cardiac arrest (rare) have been reported. Vancomycin must be given over at least 30 minutes as a dilute solution. Do not give IM, SC, or IP. Severe tissue damage and pain may occur. Oral therapy may cause GI effects (nausea, inappetence). Reproductive/Nursing Safety When used orally, vancomycin is relatively safe to use during preg-nancy (FDA category B). When used IV, it is not known whether vancomycin can cause fetal harm. A limited study performed in humans did not detect fetal harm, but the numbers studied were small. In humans, the FDA categorizes IV vancomycin as a category C drug for use during pregnancy (Animal studies have shown an ad-verse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate stud-ies in humans. ) Because in veterinary patients, vancomycin should only be used for serious infections, the potential benefits of therapy will probably outweigh the risks in most circumstances. Vancomycin is excreted into milk. Because the drug is not ap-preciably absorbed, it is unlikely to pose significant harm to nursing animals, although diarrhea could occur. Overdosage/Acute Toxicity Patients with colitis associated with Clostridia difficile taking an oral overdose, could potentially absorb enough drug to cause adverse effects. The IV LD 50 for vancomycin in mice and rats is 400 mg/kg and 319 mg/kg, respectively. Intravenous overdoses of vancomycin may cause an increased risk of adverse effects, particularly ototox-icity and nephrotoxicity. Supportive care is advised. Hemodialysis does not appear to remove the drug in significant amounts.

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920 VASOPRESSIN Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving vancomycin and may be of significance in veterinary patients: T ! AMINOGLYCOSIDES : Vancomycin may increase the risk of aminogly-coside-related ototoxicity or nephrotoxicity. Because this combi-nation of drugs may be medically required (there is evidence of synergy against staphylococci and enterococci), only enhanced monitoring is suggested. T ! ANESTHETIC AGENTS : In children, vancomycin used with anesthetic agents has caused erythema and a histamine-like flushing T ! NEPHROTOXIC DRUGS, OTHER (e. g., amphotericin B, cisplatin ): Use with caution with other nephrotoxic drugs Laboratory Considerations T ! No specific concerns were noted Doses T o prepare parenteral solution using vancomycin 500 mg or 1 g powder for injection: Reconstitute the 500 mg for injection vial by adding 10 m L of sterile water for injection. Add 20 m L to the 1 gm vial. Before administering to patient, further dilute reconstituted solutions with (at least 100 m L for 500 mg; 200 m L for 1 gram vial) a compatible diluent (e. g., D 5W, lactated Ringer's, 0. 9% Na Cl). T ! DOGS: For susceptible infections: a) For confirmed bacteremia/septicemia for enterococci or staphylococci resistant to other commonly used antibiotics: 15 mg/kg IV over 30-60 minutes q6-8h. (Ford 2005) b) 15 mg/kg IV over 30-60 minutes q6h. For successful therapy of serious infections, an aminoglycoside such as gentamicin or amikacin should also be administered. (Papich 2003b) c) For oral use to treat C. difficile enterocolitis: 10-20 mg/kg PO q6h for 5-7 days; For IV use to treat skin, urinary, soft tissue infections: 10-20 mg/kg IV q12h for 7-10 days; For IV use to treat systemic infections, bacteremia: 15 mg/kg IV q6h for 10 days. (Greene, Hartmannn et al. 2006) T ! CATS: For susceptible infections: a) For confirmed bacteremia/septicemia for enterococci or staphylococci resistant to other commonly used antibiotics: 15 mg/kg IV over 30-60 minutes q6-8h. (Ford 2005) b) 15 mg/kg IV over 30-60 minutes q6h. For successful therapy of serious infections, an aminoglycoside such as gentamicin or amikacin should also be administered. (Papich 2003b) Monitoring When used parenterally: T ! Renal function, baseline and periodic T ! Vancomycin levels, maintain trough level above 5 mcg/m L (some say troughs between 10-15 mcg/m L) T ! Periodic CBC if therapy is prolonged Client Information T ! Parenteral vancomycin is used in an inpatient setting T ! Oral vancomycin may be used for outpatient therapy; clients should be counseled to give as prescribed T ! May give oral dosage forms with a small amount of food Chemistry/Synonyms A glycopeptide antibiotic, vancomycin HCl occurs as an odorless, tan to brown free-flowing powder. It is freely soluble in water. A 5% aqueous solution has a p H of 2. 5-4. 5. Vancomycin may also be known as: vanco, vancomycini, or Vancocin®; there are many registered international trade names available. Storage/Stability/Compatibility Vancomycin should be stored at room temperature in tight con-tainers that are protected from light. Once reconstituted (see direc-tions in package insert or in the Doses section), the injectable or oral solutions are stable for 14 days if refrigerated. If diluted further with D 5W or sodium chloride 0. 9% for parenteral administration, solutions are stable for 24 hours at room temperature and 2 months if refrigerated. Vancomycin is compatible with D5W, 0. 9% Na Cl, and lactated Ringer's injection. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Vancomycin HCl Capsules: 125 mg & 250 mg; Vancocin® (Viro P-harma); (Rx) Vancomycin HCl Powder for Oral Solution: 1 gram bottles; generic (ESI Lederle); (Rx) Vancomycin HCl Powder for Injection: 500 mg, 1, 5, & 10 g; Vanco-cin® (Viro Pharma); Vancoled® (Lederle); generic (various); (Rx) VASOPRESSIN (vay-soe-press-in) Pitressin® HORMONE Prescriber Highlights TT Hormone used primarily as a diagnostic agent & some-times for treatment of diabetes insipidus; it may be use-ful for the adjunctive treatment of shock syndromes TT Contraindications: Chronic nephritis until nitrogen reten-tion is resolved to reasonable levels, or patients hyper-sensitive to it; Caution: Vascular disease, seizure disor-ders, heart failure, or asthma TT Adverse Effects: Local irritation at the injection site (including sterile abscesses), skin reactions, abdominal pain, hematuria, &, rarely, a hypersensitivity (urticarial) reaction TT Overdosage can lead to water intoxication Uses/Indications Vasopressin is used in veterinary medicine as a diagnostic agent and in the treatment of diabetes insipidus in small animals. In recent years, there has been significant interest in using vasopressin for treating shock syndromes in humans and animals. Ongoing re-search is being conducted. In human medicine, vasopressin has been used to treat acute GI hemorrhage and to stimulate GI peristalsis. Vasopressin CRI is also being used for treatment of hypotensive septic patients unrespon-sive to conventional vasopressor. Prior to radiographic procedures, it has been used to dispel interfering gas shadows or help concen-trate contrast media.

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VASOPRESSIN 921 Pharmacology Vasopressin or antidiuretic hormone (ADH) promotes the renal re-absorption of solute-free water in the distal convoluted tubules and collecting duct. ADH increases cyclic adenosine monophosphate (c AMP) at the tubule which increases water permeability at the lu-minal surface resulting in increased urine osmolality and decreased urine flow. Without vasopressin, urine flow can be increased up to 90% greater than normal. At doses above those necessary for antidiuretic activity, vaso-pressin can cause smooth muscle contraction. Capillaries and small arterioles are most affected, with resultant decreased blood flow to several systems. Hepatic flow may actually be increased, however. Vasopressin can cause contraction of smooth muscle of the bladder and gall bladder and increase intestinal peristalsis, particu-larly of the colon. Vasopressin may decrease gastric secretions and increase GI sphincter pressure; gastric acid concentration remains unchanged. Vasopressin possesses minimal oxytocic effects, but at large dos-es may stimulate uterine contraction. Vasopressin also causes the release of corticotropin, growth hormone, and follicle-stimulating hormone (FSH). Pharmacokinetics Vasopressin is destroyed in the GI prior to being absorbed and therefore must be administered either intranasally or parenterally. After IM or SC administration in dogs, aqueous vasopressin has antidiuretic activity for 2-8 hours. Vasopressin is distributed throughout the extracellular fluid. The hormone apparently is not bound to plasma proteins. Vasopressin is rapidly destroyed in the liver and kidneys. The plasma half-life has been reported to be only 10-20 minutes in humans. Contraindications/Precautions/Warnings In humans, vasopressin is contraindicated in patients hypersensi-tive to it or with chronic nephritis until nitrogen retention is re-solved to reasonable levels. Because of its effects on other systems, particularly at high doses, vasopressin should be used with caution in patients with vascular disease, seizure disorders, heart failure, or asthma. Adverse Effects Adverse effects that can be seen include local irritation at the in-jection site (including sterile abscesses), skin reactions, abdominal pain, hematuria, and, rarely, a hypersensitivity (urticarial) reaction. Overdosage can lead to water intoxication (see below). Reproductive/Nursing Safety Although the drug has minimal effects on uterine contractions at usual doses, it should be used with caution in pregnant animals. 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 Early clinical signs of overdose-induced water intoxication can in-clude listlessness or depression. More severe intoxication clinical signs can include coma, seizures, and eventually death. Treatment for mild intoxication is stopping vasopressin therapy and restrict-ing water access until resolved. Severe intoxication may require the use of osmotic diuretics (mannitol, urea, or dextrose) with or with-out furosemide. Drug Interactions The following drugs may inhibit the antidiuretic activity of vasopressin: !!ALCOHOL !!DEMECLOCYCLINE !!EPINEPHRINE (large doses ) !THEPARIN !TNOREPINEPHRINE (large doses ) The following drugs may potentiate the antidiuretic effects of vasopressin: !!ANTIDEPRESSANTS, TRICYCLIC !!CARBAMAZEPINE !!CHLORPROPAMIDE !!CLOFIBRATE !!FLUDROCORTISONE !!PHENFORMIN !TUREA Doses !TDOGS: As a diagnostic agent after the water deprivation test (WDT); monitor carefully. The WDT is considered contraindicated in animals that are dehydrated or have known renal disease and is used to characterize whether DI is central or nephrogenic in ori-gin. Refer to a current small animal internal medicine text for further information. a) Exogenous vasopressin test: After WDT, empty bladder and start IV catheter and slowly reintroduce water. Give aque-ous vasopressin in D 5W IV at a dose of 2. 5 m U/kg over one hour. T o make one liter of a 5 m U/m L solution add 5 Units of vasopressin to one liter of D 5W. Empty bladder and col-lect urine at 30 minutes, 60 minutes, and 90 minutes. If urine specific gravity >1. 1015 = ADH-responsive DI; if <1. 015 = either nephrogenic DI or medullary washout effect. (Nichols and Miller 1988) For adjunctive treatment of shock: a) Dogs with persistent hypotension after optimal fluid thera-py; Vasopressin (1-4 micro Units/kg/minute) and/or norepi-nephrine (0. 1-2 mcg/kg/minute). Goal of pressor therapy is to maintain mean arterial blood pressure between 70-90 mm Hg. (Hansen 2007a) For treatment of central diabetes insipidus: Note : Because vaso-pressin tannate in oil is no longer commercially available; most clinicians are using desmopressin (DDA VP) for treating central DI. Refer to that monograph for more information. !TCATS: As a diagnostic agent after the water deprivation test (WDT): The WDT is generally considered contraindicated in animals that are dehydrated or have known renal disease and is used to characterize whether DI is central or nephrogenic in origin. a) Immediately after the end-point of the WDT, give aqueous vasopressin 0. 5 U/kg IM; continue to withhold food and water. At 30, 60, and 120 minutes after vasopressin, empty bladder and determine specific gravity (osmolality). Upon completion, the cat is gradually allowed access to water. In-ability to concentrate urine during the water deprivation test followed by a rise in urine specific gravity above 1. 025 after vasopressin is indicative of central DI. (Peterson and Ran-dolph 1989) For treatment of central diabetes insipidus: Note : Because vaso-pressin tannate in oil is no longer commercially available; most

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922 VECURONIUM BROMIDE clinicians are using desmopressin (DDA VP) for treating central DI. Refer to that monograph for more information. Monitoring T ! Urine output/frequency T ! Water consumption T ! Urine specific gravity &/or osmolality Chemistry/Synonyms A hypothalamic hormone stored in the posterior pituitary, vaso-pressin is a 9-amino acid polypeptide with a disulfide bond. In most mammals (including dogs and humans), the natural hormone is arginine vasopressin, while in swine the arginine is replaced with lysine. Lysine vasopressin has only about 1/2 the antidiuretic activ-ity of arginine vasopressin. The commercially available vasopressin products may be a combination of arginine or lysine vasopressin derived from natural sources or synthetically prepared. The prod-ucts are standardized by their pressor activity in rats [USP posterior Pituitary (pressor) Units]; their antidiuretic activity can be variable. Commercially available vasopressin has little, if any, oxytocic activ-ity at usual doses. Vasopressin injection occurs as a clear, colorless or practically colorless liquid with a faint, characteristic odor. Vasopressin is sol-uble in water. Vasopressin may also be known as: ADH, antidiuretic hor-mone, 8-arginine vasopressin, beta-hypophamine, Neo-Lidocaton®, Pitressin® or Pressyn®. Storage/Stability/Compatibility Vasopressin (aqueous) injection should be stored at room tempera-ture; avoid freezing. If the aqueous injection is to be administered as an intravenous or intra-arterial infusion, it may be diluted in either D 5W or nor-mal saline. For infusion use in humans, it is usually diluted to a concentration of 0. 1-1 Unit/m L. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Vasopressin Injection: 20 pressor Units/m L in 0. 5 m L, 1 m L and 10 m L vials; and 1 m L ampules; Pitressin® (Monarch); generic; (Rx) Vasopressin Tannate Sterile Suspension in oil is no longer commer-cially available. VECURONIUM BROMIDE (vek-yew-roe-nee-um) Norcuron® NONDEPOLARIZING NEUROMUSCULAR BLOCKER Prescriber Highlights TT Nondepolarizing neuromuscular blocking agent TT Contraindications: Hypersensitive to it. Caution: Severe renal dysfunction, hepatic, or biliary disease; extreme caution: myasthenia gravis TT Adverse Effects: None, other than pharmacologic actions TT No analgesia or anesthetic effects Uses/Indications Vecuronium is indicated as an adjunct to general anesthesia to pro-duce muscle relaxation during surgical procedures or mechanical ventilation and to facilitate endotracheal intubation. It causes very minimal cardiac effects and generally does not cause the release of histamine. Pharmacology/Actions Vecuronium is a nondepolarizing neuromuscular blocking agent and acts by competitively binding at cholinergic receptor sites at the motor endplate, thereby inhibiting the effects of acetylcholine. The potency of vecuronium when compared to pancuronium (on a weight basis) has been described as being equipotent to up to 3 times as potent. Pharmacokinetics The onset of neuromuscular blockade after IV injection is depen-dent upon the dose administered. In dogs administered 0. 1 mg/ kg IV, full neuromuscular block occurs within 2 minutes and the duration of action at this dose is approximately 25 minutes (also receiving halothane anesthesia). Vecuronium has a shorter duration of action than pancuronium (approx. 1/3-1/2 as long), but is very similar to that of atracurium. Vecuronium is partially metabolized; it and its metabolites are excreted into the bile and urine. Prolonged recovery times may re-sult in patients with significant renal or hepatic disease. Contraindications/Precautions/Warnings Vecuronium is contraindicated in patients hypersensitive to it. It should be used with caution in patients with severe renal dysfunc-tion. Lower doses may be necessary in patients with hepatic or bil-iary disease. Vecuronium has no analgesic or sedative/anesthetic ac-tions. In patients with myasthenia gravis, neuromuscular blocking agents should be used with extreme caution, if at all. One case of successful use in a dog with myasthenia gravis has been reported. Adverse Effects In human studies and one limited dog study, adverse effects other than what would be seen pharmacologically (skeletal muscle weak-ness to profound, prolonged musculoskeletal paralysis) have not 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 No cases of vecuronium overdosage have yet been reported (hu-man or veterinary). Should an inadvertent overdose occur, treat conservatively (mechanical ventilation, O 2, fluids, etc. ). Reversal of blockade might be accomplished by administering an anticholin-esterase agent (edrophonium, physostigmine, or neostigmine) with an anticholinergic (atropine or glycopyrrolate). A suggested dose for neostigmine is 0. 06 mg/kg IV after atropine 0. 02 mg/kg IV.

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VERAPAMIL HCL 923 TDrug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving vecuronium and may be of significance in veterinary patients: T ! NON-DEPOLARIZING MUSCLE RELAXANT DRUGS, OTHER : May have a synergistic effect if used with vecuronium T ! SUCCINYLCHOLINE : May speed the onset of action and enhance the neuromuscular blocking actions of vecuronium; do not give vecuronium until succinylcholine effects have subsided The following agents may enhance or prolong the neuromuscular blocking activity of vecuronium: ! !AMINOGLYCOSIDES ! !ANESTHETICS (halothane, isoflurane, sevoflurane ) ! !CLINDAMYCIN, LINCOMYCIN ! !DANTROLENE ! !MAGNESIUM SALTS ! !PIPERACILLIN, MEZLOCILLIN ! !QUINIDINE ! !TETRACYCLINES T ! VERAPAMIL Doses T ! DOGS: a) 0. 1 mg/kg IV initially (after meperidine and/or acepromazine pre-op 30 minutes before); may give subsequent incremental doses of 0. 04 mg/kg IV. Duration of action after initial dose averages 25 minutes. (Jones and Seymour 1985) b) 10-20 mcg/kg IV (Morgan 2003) c) If using CRI propofol-fentanyl anesthesia: CRI maintenance infusion rate of vecuronium at 0. 2 mg/kg/hr; If using CRI fentanyl-isoflurane or fentanyl-sevoflurane an-esthesia: CRI maintenance infusion rate of vecuronium at 0. 1 mg/kg/hr. (Nagahama, Nishimura et al. 2006) T ! CATS: a) 20-40 mcg/kg (0. 02-0. 04 mg/kg) IV (Morgan 2003) Monitoring T ! Level of neuromuscular relaxation Client Information T ! his drug should only be used by professionals familiar with its use Chemistry/Synonyms Structurally similar to pancuronium, vecuronium bromide is a syn-thetic, nondepolarizing neuromuscular blocking agent. It contains the steroid (androstane) nucleus, but is devoid of steroid activity. It occurs as white to off-white, or slightly pink crystals or crystalline powder. In aqueous solution, it has a p K a of 8. 97, and the commer-cial injection has a p H of 4 after reconstitution. 9 mg are soluble in 1 m L of water; 23 mg are soluble in 1 m L of alcohol. Vecuronium Bromide may also be known as: Org-NC-45, Curlem®, Norcuron®, Rivecrum®, Vecural®, or Vecuron®. Storage/Stability/Compatibility The commercially available powder for injection should be stored at room temperature and protected from light. After reconstitution with sterile water for injection, vecuronium bromide is stable for 24 hours at either 2-8°C or at room temperature (less than 30°C) if stored in the original container. As it contains no preservative, un-used portions should be discarded after reconstitution. The drug is stable for 48 hours at room temperature or refrigerated when stored in plastic or glass syringes, but the manufacturer recommends that it be used within 24 hours. Vecuronium bromide has been shown to be physically compat-ible with D 5W, normal saline, D 5 in normal saline, and lactated Ringer's. It should not be mixed with alkaline solutions (e. g., thiobarbiturates). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Vecuronium Bromide Powder for Injection: 10 mg and 20 mg; in 10 m L and 20 m L vials, with and without diluent; Norcuron® (Or-ganon); (Rx) VERAPAMIL HCL (ver-ap-a-mill) Calan®, Isoptin®, Verelan® CALCIUM-CHANNEL BLOCKER Prescriber Highlights TT Calcium channel blocking agent used for supraventricular tachycardias in dogs & cats TT Contraindications: Cardiogenic shock or severe CHF (unless secondary to a supraventricular tachycardia), hypotension, sick sinus syndrome, 2nd or 3rd degree AV block, digoxin intoxication, or hypersensitive to vera-pamil. IV is contraindicated within a few hours of IV beta-adrenergic blockers. TT Caution: Heart failure, hypertrophic cardiomyopathy, & hepatic or renal impairment. Use very cautiously in patients with atrial fibrillation & Wolff-Parkinson-White (WPW) syndrome. TT Adverse Effects: Hypotension, bradycardia, tachycardia, exacerbation of CHF, peripheral edema, AV block, pulmo-nary edema, nausea, constipation, dizziness, headache, or fatigue TT Drug Interactions Uses/Indications Veterinary experience with this agent is somewhat limited, but in dogs and cats verapamil may be useful for supraventricular tachy-cardias and, possibly, treatment of atrial flutter or fibrillation. Pharmacology/Actions A slow-channel calcium blocking agent, verapamil is classified as a class IV antiarrhythmic drug. Verapamil exerts its actions by block-ing the transmembrane influx of extracellular calcium ions across membranes of vascular smooth muscle cells and myocardial cells. The result of this blocking is to inhibit the contractile mechanisms of vascular and cardiac smooth muscle. Verapamil has inhibitory effects on the cardiac conduction system and these effects produce its antiarrhythmic properties. Electrophysiologic effects include in-creased effective refractory period of the A V node, decreased auto-maticity and substantially decreased A V node conduction. On ECG, heart rate and RR intervals can be increased or decreased; PR and A-H intervals are increased. Verapamil has negative effects on myo-cardial contractility and decreases peripheral vascular resistance.

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924 VERAPAMIL HCL Pharmacokinetics In humans, about 90% of a dose of verapamil is rapidly absorbed after oral administration, but because of a high first-pass effect, only about 20-30% is available to the systemic circulation. Patients with significant hepatic dysfunction may have considerably higher per-centages of the drug systemically bioavailable. Food will decrease the rate and extent of absorption of the sustained-release tablets, but less so with the conventional tablets. Verapamil's volume of distribution is between 4. 5-7 L/kg in hu-mans and has been reported to be approximately 4. 5 L/kg in dogs. In humans, approximately 90% of the drug in the serum is bound to plasma proteins. Verapamil crosses the placenta and milk levels may approach those in the plasma. Verapamil is metabolized in the liver to at least 12 separate me-tabolites, with norverapamil being the most predominant. The majority of the amounts of these metabolites are excreted into the urine. Only 3-4% is excreted unchanged in the urine. In humans, the half-life of the drug is 2-8 hours after a single IV dose, but it can increase after 1-2 days of oral therapy (presumably due to a saturable process of the hepatic enzymes). Serum half-lives of 0. 8 hours and 2. 5 hours have been reported in the dog. Contraindications/Precautions/Warnings Verapamil is contraindicated in patients with cardiogenic shock or severe CHF (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), hypotension (<90 mm Hg sys-tolic), sick sinus syndrome, 2nd or 3rd degree A V block, digoxin intoxication, or hypersensitive to verapamil. IV verapamil is contraindicated within a few hours of IV beta-adrenergic blocking agents (e. g., propranolol) as they both can de-press myocardial contractility and A V node conduction. Use of this combination in patients with wide complex ventricular tachycardia (QRS >0. 11 seconds) can cause rapid hemodynamic deterioration and ventricular fibrillation. Verapamil should be used with caution in patients with heart failure, hypertrophic cardiomyopathy, and hepatic or renal impair-ment. T oxicity may be potentiated in patients with hepatic dys-function. It should be used very cautiously in patients with atrial fibrillation and Wolff-Parkinson-White (WPW) syndrome as fatal arrhythmias may result. Because verapamil may increase blood glucose in dogs, it should be used with caution in diabetic animals. Verapamil is potentially a neurotoxic substrate of P-glycoprotein; use with caution in those herding breeds (e. g., Collies) that may have the gene mutation that causes a nonfunctional protein. Adverse Effects The following adverse reactions may occur: hypotension, bradycar-dia, tachycardia, exacerbation of CHF, peripheral edema, A V block, pulmonary edema, nausea, constipation, dizziness, headache or fatigue. Reproductive/Nursing Safety Oral verapamil in rats with doses 1. 5-6 times the human dose was embryocidal and retarded fetal growth and development, probably due to reduced weight gains in dams. Verapamil crosses the pla-centa and can be detected in umbilical vein blood at delivery. 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. ) Verapamil is excreted in milk. Consider discontinuing nursing if the dam requires verapamil therapy. Overdosage/Acute Toxicity Clinical signs of overdosage may include bradycardia, hypoten-sion, hyperglycemia, junctional rhythms, and 2nd or 3rd degree A V block. If overdose is secondary to a recent oral ingestion, emptying the gut and charcoal administration may be considered. Treatment is generally supportive in nature; vigorously monitor cardiac and re-spiratory function. Intravenous calcium salts (1 m L of 10% solu-tion per 10 kgs of body weight) have been suggested to treat the negative inotropic clinical signs, but may not adequately treat clini-cal signs of heart block. Use of fluids and pressor agents (e. g., do-pamine, norepinephrine, etc. ) may be utilized to treat hypotensive clinical signs. The A V block and/or bradycardia can be treated with isoproterenol, norepinephrine, atropine, or cardiac pacing. Patients that develop a rapid ventricular rate after verapamil due to ante-grade conduction in flutter/fibrillation with WPW syndrome, have been treated with D. C. cardioversion, lidocaine, or procainamide. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving verapamil and may be of significance in veterinary patients: !TACE INHIBITORS : May cause additive hypotensive effects !TALPHA-ADRENERGIC BLOCKERS (e. g., prazosin ): May cause additive hypotensive effects !TBETA-ADRENERGIC BLOCKERS (e. g., propranolol ): May cause additive negative cardiac inotrope and chronotrope effects !TDOXORUBICIN : Verapamil may increase concentrations !TCOPP CHEMOTHERAPY (cyclophosphamide, vincristine, procarbazine, prednisone ): May decrease oral absorption of verapamil !TCYCLOSPORINE : Verapamil may increase levels !TDANTROLENE : Cardiovascular collapse reported in animals when used with verapamil !TDIGOXIN : Verapamil may increase the blood levels of digoxin; monitoring of digoxin levels recommended !TDISOPYRAMIDE : May cause additive effects; impair left ventricular function; use together within 24-48 hours not recommended !TDIURETICS : May cause additive hypotensive effects !TERYTHROMYCIN, CLARITHROMYCIN : May increase verapamil levels !TFLECAINIDE : Possible additive effects; use is together with vera-pamil is to be avoided in humans !TNEUROMUSCULAR B LOCKERS : Neuromuscular blocking effects of nondepolarizing muscle relaxants may be enhanced by verapamil !TPHENOBARBITAL : May reduce verapamil levels !TQUINIDINE : Additive alpha-adrenergic blocking activity; increased hypotensive effect; verapamil can block quinidine's A V conduc-tive effects and increase quinidine levels !TRIFAMPIN : May reduce verapamil levels !TTHEOPHYLLINE : Verapamil may increase serum levels of theophyl-line and lead to toxicity !TVINCRISTINE : Calcium channel blockers may increase intracellular vincristine by inhibiting the drug's outflow from the cell Laboratory Considerations !TVerapamil may elevate blood glucose in dogs and confuse blood glucose determinations

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VINBLASTINE SULFATE 925 TDoses T ! DOGS: a) Initial dose of 0. 05 mg/kg IV slowly, can repeat every 5 min-utes up to a total dose of 0. 15-0. 2 mg/kg; Oral Dose: 0. 5-2 mg/kg PO q8h (Ware 2000) b) For treatment of hypertension: 1-5 mg/kg PO q8h (Brovida 2002) c) 0. 05-0. 15 mg/kg slow IV to effect (Fox 2003a) d) 1-5 mg/kg PO three times daily; 0. 05-0. 25 mg/kg IV slowly (Kramer 2003c) e) For the acute termination of supraventricular tachycardia: Initial dose of 0. 05 mg/kg should be administered over 1-2 minutes while ECG is monitored; if not effective, may repeat in 5-10 minutes. If arrhythmia still not terminated, may give one last dose of 0. 05 mg/kg (total = 0. 15 mg/kg). Effect may persist for 30 minutes or less. For longer control, may give as a CRI at 2-10 mcg/kg/minute. (Kittleson 2006c) T ! CATS: a) Initial dose of 0. 025 mg/kg IV slowly, can repeat every 5 min-utes up to a total dose of 0. 15-0. 2 mg/kg; Oral Dose: 0. 5-1 mg/kg PO q8h (Ware 2000) T ! HORSES: (Note: ARCI UCGFS Class 4 Drug) a) T o control ventricular rate in atrial fibrillation: 0. 025-0. 05 mg/kg IV q 30 minutes; give less than 0. 2 mg/kg total dose (Reimer 2002) Monitoring T ! ECG T ! Clinical signs of toxicity (see Adverse Effects); T ! Blood pressure, during acute IV therapy T ! Serum concentration, if efficacy or toxicity warrant (100-300 ng/m L is considered therapeutic) Client Information cillin sodium, methylprednisolone sodium succinate, metoclopr-amide HCl, morphine sulfate, multivitamin infusion, nitroglycerin, norepinephrine bitartrate, oxytocin, pancuronium Br, penicillin G potassium/sodium, pentobarbital sodium, phenobarbital sodium, phentolamine mesylate, phenytoin sodium, potassium chloride/ phosphate, procainamide HCl, propranolol HCl, protamine sulfate, quinidine gluconate, sodium bicarbonate, sodium nitroprusside, ti-carcillin disodium, tobramycin sulfate, vasopressin, and vitamin B complex with C. The following drugs have been reported to be physically incom-patible with verapamil: albumin injection, amphotericin B, hydrala-zine HCl, nafcillin sodium, and trimethoprim/sulfamethoxazole. Compatibility is dependent upon factors such as p H, concentra-tion, temperature, and diluent used; consult specialized references for more specific information. Verapamil may also be known as: CP-16533-1, D-365, iprover-atril hydrochloride, verapamili hydrochloridum; many trade names are available. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Verapamil HCl Tablets: 40 mg, 80 mg & 120 mg; Calan® (Searle); generic; (Rx) Verapamil HCl Sustained/Extended-Release Tablets and Capsules: 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg and 360 mg; Calan® SR & Covera-HS® (Searle); Isoptin® SR (Abbott); Verelan® and Verelan® PM (Schwarz Pharma); generic; (Rx) Verapamil HCl for Injection: 2. 5 mg/m L in 2 m L, and 4 m L vials, amps and syringes, 2 m L fill in single-use Carpuject syringe; generic; (Rx) T ! o be effective, the animal must receive all doses as prescribed T ! If animal becomes lethargic or becomes exercise intolerant, be-gins wheezing, has shortness of breath or cough, or develops a change in behavior or attitude, notify veterinarian. Chemistry/Synonyms A calcium channel blocking agent, verapamil HCl occurs as a bitter-tasting, nearly white, crystalline powder. It is soluble in water and the injectable product has a p H of 4-6. 5. Verapamil HCl tablets should be stored at room temperature (15-30°C); the injectable product should be stored at room tem-perature (15-30°C) and protected from light and freezing. Verapamil HCl for injection is physically compatible when mixed with all commonly used intravenous solutions. However, a crystal-line precipitate may form if verapamil is added to an infusion line with 0. 45% sodium chloride with sodium bicarbonate running. Verapamil is reported to be physically compatible with the following drugs: amikacin sulfate, aminophylline, ampicillin sodium, ascor-bic acid, atropine sulfate, bretylium tosylate, calcium chloride/ gluconate, carbenicillin disodium, cefamandole naftate, cefazolin sodium, cefotaxime sodium, cefoxitin sodium, cephapirin sodium, chloramphenicol sodium succinate, cimetidine HCl, clindamycin phosphate, dexamethasone sodium phosphate, diazepam, digoxin, dobutamine HCl (slight discoloration due to dobutamine oxida-tion), dopamine HCl, epinephrine HCl, furosemide, gentamicin sulfate, heparin sodium, hydrocortisone sodium phosphate, hydro-morphone HCl, insulin, isoproterenol, lidocaine HCl, magnesium sulfate, mannitol, meperidine HCl, metaraminol bitartrate, methi-VINBLASTINE SULFATE (vin-blas-teen) Velban® ANTINEOPLA STIC Prescriber Highlights TT A Vinca alkaloid antineoplastic used for a variety of tu-mors in dogs (& sometimes cats) TT Contraindications: Preexisting leukopenia or granulocy-topenia (unless a result of the disease being treated) or active bacterial infection; reduce dose if hepatic disease TT Adverse Effects: Gastroenterocolitis (nausea/vomiting), myelosuppression (more so than with vincristine); may also cause constipation, alopecia, stomatitis, ileus, inap-propriate ADH secretion, jaw & muscle pain, & loss of deep tendon reflexes TT CATS can develop neurotoxicity causing constipation or paralytic ileus & aggravating anorexia; can also develop reversible axon swelling & paranodal demyelination TT Potentially teratogenic TT Avoid extravasation; wear gloves & protective clothing when preparing or administering TT Drug Interactions

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926 VINBLASTINE SULFATE Uses/Indications Vinblastine may be employed in the treatment of lymphomas, car-cinomas, mastocytomas, and splenic tumors in small animals. It is more effective than vincristine in the treatment of canine mast cell tumors. Pharmacology/Actions Vinblastine apparently binds to microtubular proteins (tubulin) in the mitotic spindle, thereby preventing cell division during meta-phase. It also interferes with amino acid metabolism by inhibiting glutamic acid utilization and preventing purine synthesis, citric acid cycle, and urea formation. Pharmacokinetics Vinblastine is administered IV. After injection, it is rapidly distrib-uted to tissues. In humans, approximately 75% is bound to tissue proteins and the drug does not appreciably enter the CNS. Vinblastine is extensively metabolized by the liver and is primar-ily excreted in the bile/feces; lesser amounts are eliminated in the urine. Contraindications/Precautions/Warnings Vinblastine is contraindicated in patients with preexisting leukope-nia or granulocytopenia (unless a result of the disease being treat-ed), or active bacterial infection. Doses of vinblastine should be reduced in patients with hepatic disease. A 50% reduction in dose should be considered if serum bilirubin levels are greater than 2 mg/dl. Because vinblastine is potentially a neurotoxic substrate of P-glycoprotein, it should be used with caution in those herding breeds (e. g., Collies) that may have the gene mutation that causes a nonfunctional protein. As vinblastine may be a skin irritant, gloves and protective cloth-ing should be worn when preparing or administering the medica-tion. If skin/mucous membrane exposure occurs, thoroughly wash area with soap and water. Adverse Effects Vinblastine can cause gastroenterocolitis (nausea/vomiting) which generally lasts less than 24-hours. It can be myelosuppressive at usual dosages (nadir at 4-9 days after treatment; recovery at 7-14 days). Vinblastine is considered more myelosuppressive than is vincristine. Vinblastine may not possess the degree of peripheral neurotoxic effects seen with vincristine, but at high doses, these effects may be seen. Additionally, vinblastine may cause constipation, alope-cia, stomatitis, ileus, inappropriate ADH secretion, jaw and muscle pain, and loss of deep tendon reflexes. Cats can develop neurotoxicity that can be associated with con-stipation or paralytic ileus thereby aggravating anorexia. They may develop reversible axon swelling and paranodal demyelination. Extravasation of vinblastine may cause significant tissue irrita-tion and cellulitis. Because of the vesicant action of this drug, it is recommended to use a different needle for injecting the drug than the one used to withdraw the drug from the vial. Should clinical signs of extravasation be noted, discontinue infusion immediately at that site and apply moderate heat to the area to help disperse the drug. Injections of hyaluronidase have also been suggested to help diffuse the drug. Reproductive/Nursing Safety Little is known about the effects of vinblastine on developing fe-tuses, but it is believed that the drug possesses some teratogenic and embryotoxic properties. It may also cause aspermia in males. 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. ) It is not known whether vinblastine is excreted in milk. Because of the potential for serious adverse reactions in nursing offspring, consider using milk replacer if dams are being given this drug. Overdosage/Acute Toxicity In dogs, the lethal dose for vinblastine has been reported as 0. 2 mg/ kg. Effects of an overdosage of vinblastine are exacerbations of the adverse effects outlined above. Additionally, neurotoxic effects sim-ilar to those associated with vincristine may also be noted. In humans, cardiovascular and hematologic monitoring are per-formed after an overdose. Treatment can include anticonvulsants, and prevention of ileus. Additionally, an attempt is made to prevent the effects associated with the syndrome of inappropriate antidi-uretic hormone (SIADH) with fluid restriction and loop diuretics to maintain serum osmolality. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving vinblastine and may be of significance in veterinary patients: !TOTOTOXIC DRUGS (e. g., cisplatin, carboplatin ): May cause additive risk for ototoxicity Caution is advised if using other drugs that can inhibit p-glycopro-tein particularly in those dogs at risk for MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet, etc. “white feet”), unless tested “normal”. Drugs and drug classes in-volved include: !!AMIODARONE !!AZOLE ANTIFUNGALS (e. g., ketoconazole ) !!CARV EDILOL !!CYCLOSPORINE !!DILTIAZEM !!ERYTHROMYCIN; CLARITHROMYCIN !!QUINIDINE !!SPIRONOLACTONE !TTAMOXIFEN !!VERAPAMIL Laboratory Considerations !TVinblastine may significantly increase both blood and urine con-centrations of uric acid Doses For more information on using vinblastine as part of chemotherapy protocols, refer to the protocols found in the appendix or other dos-ages/protocols found in numerous references, including: 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). !TDOGS: For susceptible neoplastic diseases: a) 2 mg/m2 IV every 7-14 days (O'Keefe and Harris 1990), (Thompson 1989a) b) For mast cell tumors after surgical removal: vinblastine at 2 mg/m2 IV, weekly for four weeks then every two weeks for

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VINCRISTINE SULFATE 927 Teight weeks. Prednisolone is given concurrently starting at 2 mg/kg/day, tapering to 0. 5 mg/kg day. (Davies, Wyatt et al. 2002) c) For lymphoma and mastocytoma: 2 mg/m2 weekly. For lym-phosarcoma and various carcinomas: 2. 5 mg/m2 IV weekly (Mac Ewen and Rosenthal 1989), (Rosenthal 1985) T ! CATS: For susceptible neoplastic diseases: a) For lymphosarcoma and mast cell neoplasms: 2 mg/m2 IV every 7-14 days (Couto 1989b) b) 2 mg/m2 slow IV every 7-14 days (Golden and Langston 1988) Monitoring T ! Efficacy T ! oxicity (complete blood counts with platelets; liver function tests prior to therapy and repeated as necessary; serum uric acid) Client Information T ! Clients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality T ! Contact the veterinarian if the patient exhibits any symptoms of profound depression, abnormal bleeding (including bloody diar-rhea) and/or bruising Chemistry/Synonyms Commonly referred to as a Vinca alkaloid, vinblastine sulfate is isolated from the plant Cantharanthus roseus (Vinca rosea Linn) and occurs as a white or slightly yellow, hygroscopic, amorphous or crystalline powder that is freely soluble in water. The commercially available injection has a p H of 3-5. 5. Vinblastine may also be known as: 29060-LE, NSC-49842, sulf-ato de vimblastina, vinblastini sulfas, vincaleukoblastine sulphate, VBL, Alkaban®, Blastovin®, Cellblastin®, Cytoblastin®, Ifabla®, Lemblastine®, Periblastine®, Serovin®, Solblastin®, Velban®, Velbe ®, Velsar®, or Xintoprost®. Storage/Stability/Compatibility The sterile powder for injection, solution for injection and reconsti-tuted powder for injection should all be protected from light. The powder for injection and injection should be stored in the refrig-erator (2-8°C). The intact powder for injection is stable at room temperature for at least one month. After reconstituting with bac-teriostatic saline, the powder for injection is stable for 30 days if refrigerated. Vinblastine sulfate is reportedly physically compatible with the following intravenous solutions and drugs: D 5W and bleomycin sulfate. In syringes or at Y-sites with: bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, fluorouracil, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, and vin-cristine sulfate. Vinblastine sulfate compatibility information conflicts or is depen-dent on diluent or concentration factors with the following drugs or solutions: doxorubicin HCl and heparin sodium (in syringes). Vinblastine sulfate is reportedly physically incompatible with furosemide. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Vinblastine Sulfate Injection: 1 mg/m L in 10 m L and 25 m L vials; generic; (Rx) Vinblastine Powder for Injection: 10 mg in vials; Velban® (Lilly); ge-neric; (Rx) VINCRISTINE SULFATE (vin-kris-teen) Oncovin® ANTINEOPLA STIC Prescriber Highlights TT A Vinca alkaloid antineoplastic used for a variety of tu-mors in dogs & cats (primarily lymphoid & hematopoietic neoplasms); also used for the treatment of immune-mediated thrombocytopenia TT Caution: Hepatic disease, leukopenia, infection, or pre-existing neuromuscular disease; reduce dose if hepatic disease TT Adverse Effects: Much less myelosuppressive than vin-blastine, but may cause more peripheral neurotoxic effects; neuropathic clinical signs can include propriocep-tive deficits, spinal hyporeflexia, or paralytic ileus with resulting constipation; CATS can develop neurotoxicity causing constipation or paralytic ileus & aggravating an-orexia; can also develop reversible axon swelling & para-nodal demyelination TT Potentially teratogenic TT Avoid extravasation; wear gloves & protective clothing when preparing or administering TT Drug Interactions Uses/Indications Vincristine is used as an antineoplastic primarily in combination drug protocols in dogs and cats in the treatment of lymphoid and hematopoietic neoplasms. In dogs, it may be used alone in the ther-apy of transmissible venereal neoplasms. Because vincristine can induce thrombocytosis (at low doses) and has some immunosuppressant activity, it may also be employed in the treatment of immune-mediated thrombocytopenia. Pharmacology/Actions Vincristine apparently binds to microtubular proteins (tubulin) in the mitotic spindle, thereby preventing cell division during meta-phase. It also interferes with amino acid metabolism by inhibiting glutamic acid utilization and preventing purine synthesis, citric acid cycle and urea formation. Tumor resistance to one Vinca alka-loid does not imply resistance to another. Vincristine can induce thrombocytosis (mechanism unknown) and has some immunosuppressant activity. Pharmacokinetics Vincristine is administered IV as it is unpredictably absorbed from the GI tract. After injection it is rapidly distributed to tissues. In humans, approximately 75% is bound to tissue proteins and the drug does not appreciably enter the CNS.

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928 VINCRISTINE SULFATE Vincristine is extensively metabolized, presumably by the liver and primarily excreted in the bile/feces; lesser amounts are elimi-nated in the urine. The elimination half-life in dogs is reportedly biphasic with an alpha half-life of 13 minutes and a beta half-life of 75 minutes. Contraindications/Precautions/Warnings Vincristine should be used with caution in patients with hepatic dis-ease, leukopenia, infection, or preexisting neuromuscular disease. Doses of vincristine should be reduced in patients with hepatic disease. A 50% reduction in dose should be considered if serum bilirubin levels are greater than 2 mg/dl. Because vincristine is potentially a neurotoxic substrate of P-glycoprotein, it should be used with caution in those herding breeds (e. g., Collies) that may have the gene mutation that causes a nonfunctional protein As vincristine may be a skin irritant, gloves and protective cloth-ing should be worn when preparing or administering the medica-tion. If skin/mucous membrane exposure occurs, thoroughly wash area with soap and water. Adverse Effects Although structurally related to and having a similar mechanism of action as vinblastine, vincristine has a different adverse reaction profile. Vincristine is much less myelosuppressive (mild leukope-nia) at usual doses than is vinblastine, but may cause more pe-ripheral neurotoxic effects. Neuropathic clinical signs may include proprioceptive deficits, spinal hyporeflexia, or paralytic ileus with resulting constipation. In humans, vincristine commonly causes mild sensory impairment and peripheral paresthesias. These may also occur in animals, but are not usually noted due to difficulty in detection. Cats, however, can develop neurotoxicity that can be associated with constipation or paralytic ileus thereby aggravating anorexia. They can develop reversible axon swelling and paranodal demyelination. Additionally, in small animals, vincristine may cause impaired platelet aggregation, increased liver enzymes, inappropriate ADH secretion, jaw pain, alopecia, stomatitis, or seizures. Extravasation injuries associated with perivascular injection of vincristine can range from irritation to necrosis and tissue slough-ing. Because of the vesicant action of this drug, it is recommended to use a different needle for injecting the drug than the one used to withdraw it from the vial. Recommendations of therapy for ex-travasation include discontinuing the infusion immediately at that site and applying moderate heat to the area to help disperse the drug. Injections of hyaluronidase have been suggested to help dif-fuse the drug. Others have suggested applying ice to the area to limit the drug's diffusion and minimize the area affected. T opical dim-ethyl sulfoxide (DMSO) has also been recommended by some to treat the area involved. Reproductive/Nursing Safety Little is known about the effects of vincristine on developing fe-tuses, but it is believed that the drug possesses some teratogenic and embryotoxic properties. It may also cause aspermia in males. 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 accept-able despite its potential risks. ) 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. ) It is not known whether this drug is excreted in milk. Because of the potential for serious adverse reactions in nursing offspring, consider using milk replacer if dams are being given this drug. Overdosage/Acute Toxicity In dogs, it is reported that the maximally tolerated dose of vincris-tine is 0. 06 mg/kg every 7 days for 6 weeks. Animals receiving this dose showed signs of slight anemia, leukopenia, increased liver en-zymes, and neuronal shrinkage in the peripheral and central ner-vous systems. In cats, the lethal dose of vincristine is reportedly 0. 1 mg/kg. Cats receiving toxic doses showed clinical signs of weight loss, sei-zures, leukopenia, and general debilitation. In humans, cardiovascular and hematologic monitoring are per-formed after an overdose. Treatment can include anticonvulsants, and prevention of ileus. Additionally, an attempt is made to prevent the effects associated with the syndrome of inappropriate antidi-uretic hormone (SIADH) with fluid restriction and loop diuretics to maintain serum osmolality. There have been some reports of leucovorin calcium being used to treat vincristine overdoses in hu-mans, but efficacy of this treatment has not yet been confirmed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving vincristine and may be of significance in veterinary patients: !TASPARAGINASE : Additive neurotoxicity may occur; is appar-ently less common when asparaginase is administered after vincristine !TMITOMYCIN : In humans who have previously or simultaneously received mitomycin-C with Vinca alkaloids, severe bronchos-pasm has occurred Caution is advised if using other drugs that can inhibit p-glycopro-tein particularly in those dogs at risk for MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet, etc. “white feet”), unless tested “normal”. Drugs and drug classes in-volved include: !!AMIODARONE !!AZOLE ANTIFUNGALS (e. g., ketoconazole ) !!CARV EDILOL !!CYCLOSPORINE !!DILTIAZEM !!ERYTHROMYCIN; CLARITHROMYCIN !!QUINIDINE !!SPIRONOLACTONE !!TAMOXIFEN !!VERAPAMIL Laboratory Considerations !TVincristine may significantly increase both blood and urine con-centrations of uric acid Doses For more information on using vincristine as part of chemother-apy protocols such as COP, VELCAP, etc, refer to the protocols found in the appendix or other dosages/protocols found in numer-ous references, including: 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).

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VITAMIN E/SELENIUM 929 TT ! DOGS: For neoplastic diseases (usually used in combination protocols with other drugs; see the appendix for sample protocols): a) 0. 5-0. 75 mg/m2 IV every 7-14 days (O'Keefe and Harris 1990) b) 0. 5 mg/m2 every 7-14 days (Coppoc 1988) c) 0. 5 mg/m2 IV weekly (Mac Ewen and Rosenthal 1989) d) For transmissible venereal tumor: 0. 025 mg/kg (maximum dose 1 mg) IV once weekly. Generally requires 3-6 weeks of therapy. Usually tumor regression noted within 2 weeks of initial treatment. (Herron 1988) e) For transmissible venereal tumor: 0. 5 mg/m2 (maximum dose 1 mg) IV every 7 days until there is no evidence of dis-ease. Generally requires 4-6 weeks of therapy. (Rosenthal 1985) For immune-mediated thrombocytopenia: a) Used only when other therapies are ineffective and bone marrow aspirate demonstrates adequate megakaryocytopoi-esis: 0. 02 mg/kg IV once weekly (Feldman 1989) b) If refractory to prednisone (3-5 days), give vincristine at 0. 5-0. 7 mg/m2 IV bolus or as an infusion over 4-6 hours (Trepanier 1999) c) 0. 02 mg/kg IV once; generally single use (Cohn 2004) T ! CATS: For neoplastic diseases (usually used in combination proto-cols with other drugs; see the appendix for additional sample protocols): a) 0. 5-0. 75 mg/m2 IV once a week (Couto 1989b) b) For feline lymphoma: A neutrophil count over 4,500 cells/UL is required. Cats should be well hydrated before treatment and fluid therapy should be continued for 24-36 hours. On day 1 give vincristine at 0. 5 mg/m2 IV and cyclophosphamide at 250 mg/m2 IV or orally. These drugs may be administered by slow IV push. If no adverse reactions and neutrophil count is over 4,500, may repeat on day 21. On day 42, premedicate with diphenhydramine (2. 2. mg/kg SC) and give doxorubi-cin at 1 mg/kg IV over 20 minutes into the injection port of an IV drip set. This regimen is repeated until a total of six cycles have been administered. If cat is in complete remission at the end of the of the 6 cycles, consider stopping therapy. Treatment is delayed if neutropenia of thrombocytopenia occur. If hemorrhagic cystitis occurs, discontinue cyclophos-phamide. Monitor renal function throughout therapy. (Leg-endre 2003) Monitoring T ! Efficacy (tumor burden reduction or platelet count) T ! oxicity (peripheral neuropathic clinical signs; complete blood counts with platelets; liver function tests prior to therapy and re-peated as necessary; serum uric acid) Client Information T ! Clients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality T ! Clients should contact the veterinarian if the patient exhibits any signs of profound depression, abnormal bleeding (including bloody diarrhea) and/or bruising, severe constipation, or severe peripheral neuropathic signs Chemistry/Synonyms Commonly referred to as a Vinca alkaloid, vincristine sulfate is iso-lated from the plant Cantharanthus roseus (Vinca rosea Linn) and occurs as a white or slightly yellow, hygroscopic, amorphous or crystalline powder that is freely soluble in water and slightly soluble in alcohol. The commercially available injection has a p H of 3-5. 5. Vincristine sulfate has p K as of 5 and 7. 4 Vincristine Sulfate may also be known as: leurocristine sulfate, VCR, LCR compound 37231, leurocristine sulphate, NSC-67574, 22-oxovincaleukoblastine sulphate, sulfato de vincristina, vincris-tini sulfas and Oncovin®; many other trade names are available. Storage/Stability/Compatibility Vincristine sulfate injection should be protected from light and stored in the refrigerator (2-8°C). Vincristine sulfate is reportedly physically compatible with the following intravenous solutions and drugs: D 5W, bleomycin sul-fate, cytarabine, fluorouracil, and methotrexate sodium. In syringes or at Y-sites with: bleomycin sulfate, cisplatin, cyclophosphamide, doxorubicin HCl, droperidol, fluorouracil, heparin sodium, leuco-vorin calcium, methotrexate sodium, metoclopramide HCl, mito-mycin, and vinblastine sulfate. Vincristine sulfate is reportedly physically incompatible with furosemide. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Vincristine Sulfate Injection: 1 mg/m L in 1 m L, 2 m L and 5 m L vials and flip-top vials; Vincasar® PFS (Genesia Sicor); generic; (Rx) VITAMIN E/SELENIUM VITAMIN E (se-lee-nee-um) NUTRITIONAL; FAT SOLUBLE VITAMIN Prescriber Highlights TT Lipid-soluble vitamin (E) with or without selenium used alone for discoid lupus erythematosus, canine demodi-cosis, acanthosis nigricans, hepatic fibrosis, or adjunctive therapy of exocrine pancreatic deficiency or hepatopathy in dogs & cats; used in combination for selenium-tocoph-erol deficiency (white muscle disease) TT Contraindications: Vitamin E/selenium products should only be used in the species for which they are approved TT Selenium overdoses can be extremely toxic TT Adverse Effects: Anaphylactoid reactions; IM injections may cause transient muscle soreness. Selenium OD's can cause depression, ataxia, dyspnea, blindness, diar-rhea, muscle weakness, & a “garlic” odor on the breath Uses/Indications Depending on the actual product and species, vitamin E/selenium is indicated for the treatment or prophylaxis of selenium-tocoph-erol deficiency (STD) syndromes in ewes and lambs (white muscle disease), sows, weanling and baby pigs (hepatic necrosis, mulber-ry heart disease, white muscle disease), calves and breeding cows (white muscle disease), and horses (myositis associated with STD). Vitamin E may be useful as adjunctive treatment of discoid lu-pus erythematosus, canine demodicosis, and acanthosis nigricans

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930 VITAMIN E/SELENIUM in dogs. It may also be of benefit in the adjunctive treatment of he-patic fibrosis or adjunctive therapy of copper-associated hepatopa-thy in dogs. Pharmacology/Actions Both vitamin E and selenium are involved with cellular metabolism of sulfur. Vitamin E has antioxidant properties and, with selenium, protects against red blood cell hemolysis and prevents the action of peroxidase on unsaturated bonds in cell membranes. Pharmacokinetics After absorption, vitamin E is transported in the circulatory system via beta-lipoproteins. It is distributed to all tissues and stored in adipose tissue. Vitamin E is only marginally transported across the placenta. Vitamin E is metabolized in the liver and excreted primar-ily into the bile. Pharmacokinetic parameters for selenium were not located. Contraindications/Precautions/Warnings Vitamin E/selenium products should only be used in the species for which they are approved. Because selenium can be extremely toxic, the promiscuous use of these products cannot be condoned. Give slowly when administering intravenously to horses. Adverse Effects Anaphylactoid reactions have been reported. Intramuscular in-jections may be associated with transient muscle soreness. Other adverse effects are generally associated with overdoses of selenium (see below). Overdosage/Acute Toxicity Selenium is quite toxic in overdose quantities, but has a fairly wide safety margin. Cattle have tolerated chronic doses of 0. 6 mg/kg/day with no adverse effects (approximate therapeutic dose is 0. 06 mg/ kg). Clinical signs of selenium toxicity include depression, ataxia, dyspnea, blindness, diarrhea, muscle weakness, and a “garlic” odor on the breath. Horses suffering from selenium toxicity may become blind, paralyzed, slough their hooves, and lose hair from the tail and mane. Dogs may exhibit clinical signs of anorexia, vomiting, and diarrhea at high dosages. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving vitamin E/selenium and may be of significance in veterinary patients: !TIRON : Large doses of vitamin E may delay the hematologic re-sponse to iron therapy in patients with iron deficiency anemia. !TMINERAL OIL : May reduce the absorption of orally administered vitamin E !TVITAMIN A : Absorption, utilization and storage may be enhanced by vitamin E Doses (Vitamin E alone): For doses of vitamin E/selenium products see the Dosage Form section !TDOGS: For adjunctive treatment of discoid lupus erythematosus, canine demodicosis or acanthosis nigricans: a) 200-400 IU PO three times daily; variable efficacy, but rela-tively innocuous at these dosages (White 2000) For adjunctive treatment of hepatic fibrosis: a) 100-400 IU q12h PO (Rutgers 2000) For adjunctive treatment of copper-associated hepatopathy: a) 400-600 IU PO per day (Johnson 2000) For treatment of tocopherol deficiency associated with exocrine pancreatic disease: a) 100-400 IU PO once daily for one month then every 1-2 weeks as needed (Williams 2000) !TCATS: For treatment of tocopherol deficiency associated with exocrine pancreatic disease: a) 30 IU PO once daily for one month then every 1-2 weeks as needed (Williams 2000) For adjunctive treatment of hepatic lipidosis: a) 10 IU/kg once PO once daily) (Scherk and Center 2005) !THORSES: For adjunctive treatment of ionophore (monensin) toxicity: a) 4-12 Units/kg PO once daily (Mogg 1999) For adjunctive therapy for EPM: a) 8000-9000 IU PO per day (Dowling 1999) For adjunctive therapy for metabolic syndrome: a) 10,000 IU PO once daily (Johnson 2003b) For adjunctive treatment of perinatal asphyxia syndrome (hy-poxic ischemic encephalopathy): a) Foals: 4,000 IU PO once daily; Mares: 10,000 IU PO once daily (Slovis 2003b) Monitoring !TClinical efficacy !TBlood selenium levels (when using the combination prod-uct). Normal values for selenium have been reported as: >1. 14 micromol/L in calves, >0. 63 micromol/L in cattle, >1. 26 micromol/L in sheep, and >0. 6 micromol/L in pigs. Values in-dicating deficiency are: <0. 40 micromol/L in cattle, <0. 60 micromol/L in sheep, and <0. 20 micromol/L in pigs. Intermedi-ate values may result in suboptimal production !TOptionally, glutathione peroxidase activity may be monitored Chemistry/Synonyms Vitamin E is a lipid soluble vitamin that can be found in either liq-uid or solid forms. The liquid forms occur as clear, yellow to brown-ish red, viscous oils that are insoluble in water, soluble in alcohol and miscible with vegetable oils. Solid forms occur as white to tan-white granular powders that disperse in water to form cloudy sus-pensions. Vitamin E may also be known as alpha tocopherol. Selenium in commercially available veterinary injections is found as sodium selenite. Each mg of sodium selenite contains ap-proximately 460 micrograms (46%) of selenium. Storage/Stability Vitamin E/Selenium for injection should be stored at temperatures less than 25°C (77°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Vitamin E (Alone) Injection Vitamin E Injection: 300 mg/m L in 250 m L vials; Emulsivit® E-300 (Vedco); Vital E®-300 (Schering-Plough); (OTC or Rx) Vitamin E/Selenium Oral Equ-Se E® (Vet-A-Mix) (one teaspoonful contains 1 mg selenium and 220 IU vitamin E) and Equ-Se5E® (one teaspoonful contains 1 mg se-lenium and approximately 1100 IU vitamin E); (Vet-a-Mix); (OTC) Approved for oral use in horses.

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VORICONAZOLE 931 Other top dress equine products containing Vitamin E and Selenium include: Vitamin E and Selenium Powder (Farnam, Horse Health), Vitamin E and Selenium Crumbles® (Horse Health) Vitamin E/Selenium Injection Mu-Se® (Schering); (Rx): Each m L contains: selenium 5 mg (as so-dium selenite); Vitamin E 68 IU; 100 m L vial for injection. Approved for use in non-lactating dairy cattle and beef cattle. Slaughter with-drawal (at labeled doses) = 30 days. Dose: For weanling calves: 1 m L per 200 lbs. body weight IM or SC. For breeding beef cows: 1 m L per 200 lbs. body weight during middle third of pregnancy and 30 days before calving IM or SC. Bo-Se® (Schering); (Rx): Each m L contains selenium 1 mg (as sodium selenite) and Vitamin E 68 IU; 100 m L vial for injection. Approved for use in calves, swine and sheep. Slaughter withdrawal (at labeled doses) = 30 days (calves); 14 days (lambs, ewes, sows, and pigs). Dose: Calves: 2. 5-3. 75 m L/100 lbs body weight (depending on severity of condition and geographical area) IM or SC. Lambs (2 weeks of age or older): 1 m L per 40 lbs. body weight IM or SC (1 m L minimum). Ewes: 2. 5 m L/100 lbs. body weight IM or SC. Sows and weanling pigs: 1 m L/40 lbs. body weight IM or SC (1 m L minimum). Do not use on newborn pigs. L-Se® (Schering); (Rx): Each m L contains: selenium 0. 25 mg (as so-dium selenite) and Vitamin E 68 IU in 30 m L vials. Approved for use in lambs and baby pigs. Slaughter withdrawal (at labeled doses) = 14 days. Dose: Lambs: 1 m L SC or IM in newborns and 4 m L SC or IM in lambs 2 weeks of age or older; Baby Pigs: 1 m L SC or IM. E-Se® (Schering); (Rx): Each m L contains selenium 2. 5 mg (as so-dium selenite) and Vitamin E 68 IU in 100 m L vials. Approved for use in horses. Dose: Equine: 1 m L/100 lbs. body weight slow IV or deep IM (in 2 or more sites; gluteal or cervical muscles). May be repeated at 5-10 day intervals. Seletoc® (Schering); (Rx): Each m L contains selenium 1 mg (as so-dium selenite) and Vitamin E 68 IU in 10 m L vials. Approved for use in dogs. Dose: Dogs: Initially, 1 m L per 20 pounds of body weight (minimum 0. 25 m L; maximum 5 m L) SC, or IM in divided doses in 2 or more sites. Repeat dose at 3 day intervals until satisfactory results then switch to maintenance dose. If no response in 14 days reevalu-ate. Maintenance dose: 1 m L per 40 lbs body weight (minimum 0. 25 m L) repeat at 3-7 day intervals (or longer) to maintain. HUMAN-LABELED PRODUCTS: Vitamin E Tablets: 100 IU, 200 IU, 400 IU, 500 IU & 800 IU; generic (various; OTC) Vitamin E Capsules: 100 IU, 200 IU, 400 IU & 1000 IU; Mixed E 400 Softgels® & d'ALPHA E 1000 Softgels® (Naturally); Vita-Plus E® (Scot-Tussin); generic; (OTC) Vitamin E Drops: 15 IU/0. 3 m L in 12 m L & 30 m L; Aquasol E® (Mayne Pharma); Aquavit-E® (Cypress); (OTC) Vitamin E Liquid: 15 IU/30 m L in 30 m L, 60 m L & 120 m L; 798 IU/30 m L in 473 m L; Vitamin E (Freeda); Nutr-E-Sol® (Advanced Nutri-tional T echnology); (OTC) T opicals are available. There are no approved vitamin E/selenium products, but there are many products that contain either vitamin E (alone, or in combination with other vitamins ± minerals) or sele-nium (as an injection alone or in combination with other trace ele-ments) available. VORICONAZOLE (vor-ih-koh-nah-zohl) Vfend® SECOND GENERATION TRIAZOLE ANTIFUNGAL Prescriber Highlights TT Broad-spectrum oral/parenteral triazole antifungal TT Very little clinical experience thus far in veterinary medi-cine; extremely expensive TT Like other compounds in this class, there are many po-tential drug interactions Uses/Indications Voriconazole may be a useful treatment for a variety of fungal in-fections in veterinary patients, particularly against Blastomyces, Cryptococcus, and Aspergillus. It has high oral bioavailability in a variety of species and can cross into the CNS. Currently available human dosage forms are extremely expensive, however, and little clinical experience has occurred using voriconazole in veterinary patients. There is considerable interest in using voriconazole for treating aspergillosis in pet birds as their relative small size may allow the drug to be affordable; additional research must be per-formed before dosing regimens are available. Pharmacology/Actions Voriconazole a synthetic derivative of fluconazole, has broad-spectrum antifungal activity against a variety of organisms, includ-ing Candida, Aspergillus, Trichosporon, Histoplasma, Cryptococcus, Blastomyces, and Fusarium species. Like the other azole/triazole an-tifungals it inhibits cytochrome P-450-dependent 14-alpha-sterol demethylase which is required for ergosterol biosynthesis in fungal cell walls. Unlike fluconazole, voriconazole also inhibits 24-methyl-ene dehydrolanosterol demethylation in molds such as Aspergillus giving it more activity against these fungi. Pharmacokinetics In dogs, voriconazole is rapidly and essentially completely absorbed after oral administration. Peak levels occur about 3 hours after oral dosing. Voriconazole is only moderately (51%) bound to canine plasma proteins and volume of distribution is about 1. 3 L/kg. It is metabolized in the liver to a variety of metabolites with the N-oxide metabolite being the primary circulating metabolite. This metabo-lite has only weak (<100X as active as the parent) antifungal activity. The elimination pharmacokinetics of voriconazole in dogs is very complex. Both dose-dependent non-linear elimination and auto-induced metabolism after multiple dosages are seen complicating any dosage regimen scenarios; dosages may need to be increased over time. Auto-induction of metabolism apparently does not oc-cur in humans, rabbits or guinea pigs. In horses, voriconazole is well absorbed after oral administra-tion with peak levels occurring at approximately 3 hours post-dose. Voriconazole has low protein binding (31%); volume of distribu-tion is about 1. 35 L/kg. Elimination half-life is quite long—approx-imately 13 hours after oral dosing. It is not known if voriconazole self-induces hepatic metabolism after multiple doses in the horse. Contraindications/Precautions/Warnings Voriconazole is contraindicated in patients hypersensitive to it oth-er azole antifungals. It should be given with caution to patients with hepatic dysfunction, or proarrhythmic conditions.

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932 VORICONAZOLE The intravenous product contains 3200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD) per vial. This compound can accumulate in patients with decreased renal function. Adverse Effects Accurate adverse effect profiles are unknown for veterinary species. Liver enlargement and up to a 2-3 fold increase in cytochrome P450 hepatic microsomal enzyme concentrations were noted in dogs orally dosed for 30 days. This may significantly impact the metabolism of other drugs that are hepatically metabolized (See Drug Interactions). In humans, commonly encountered adverse effects include visu-al disturbances (blurring, spots, wavy lines) usually within 30 min-utes of dosing or if higher drug concentrations are attained, and rashes (usually mild to moderate in severity). Less frequent adverse effects include gastrointestinal effects (nausea, vomiting, diarrhea), hepatotoxicity (jaundice, abnormal liver function tests), hyperten-sion/hypotension, tachycardia, peripheral edema, hypokalemia, and hypomagnesemia. Rarely, eye hemorrhage, anemia, leukope-nia, thrombocytopenia, pancytopenia, QT prolongation, torsade de pointes, and nephrotoxicity have been reported. Reproductive/Nursing Safety Voriconazole was teratogenic in rats at low dosages (10 mg/kg) and embryotoxic in rabbits at higher dosages (100 mg/kg). In humans, the FDA categorizes voriconazole as category D for use during preg-nancy (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. ) Weigh the risks of treatment versus the benefits when considering use in pregnant patients. It is unknown if voriconazole enters milk. Overdosage/Acute Toxicity The minimum lethal dose in rats and mice was 300 mg/kg (4-7X maintenance dose). T oxic effects included increased salivation, my-driasis, ataxia, depression, dyspnea, and seizures. Accidental single overdoses of up to 5X in human pediatric patients caused only brief photophobia. No antidote is known for voriconazole overdoses. Gut emptying should be considered for very large oral overdoses, fol-lowed by close observation and supportive treatment if required. Drug Interactions There are many potential drug interactions involving voriconazole. The following partial listing includes reported or theoretical in-teractions in humans receiving voriconazole that may also be of significance in veterinary patients. Because, in dogs, voriconazole induces hepatic microsomal enzymes (in humans it does not) ad-ditional interactions and further clarification may be reported as clinical use increases in veterinary patients. !TANTIDIABETIC AGENTS (sulfonylureas ): Voriconazole may increase serum concentrations of these drugs and increase risk for hypoglycemia !TBARBITURATES (phenobarbital ): Decreased voriconazole concentra-tions; use together contraindicated !TBENZODIAZEPINES : Voriconazole may increase benzodiazepine concentrations !TCALCIUM-CHANNEL BLOCKERS (amlodipine, diltiazem, verapamil ): Voriconazole may increase serum concentrations, dosage adjust-ment may be required !TCARBAMAZEPINE : Decreased voriconazole concentrations; use to-gether contraindicated !TCISAPRIDE : Potential for serious cardiac arrhythmias; use is contraindicated !TCORTICOSTEROIDS (prednisolone ): Potentially increased AUC for prednisolone !TIMMUNOSUPPRESSIVE AGENTS (systemic : cyclosporine, tacrolimus ): Increased cyclosporine and tacrolimus concentrations; decrease cyclosporine dosage by 50% when starting voriconazole; decrease tacrolimus dosage by 33% when starting voriconazole !TMETHADONE : Voriconazole may increase plasma concentrations of R-methadone; monitor for methadone toxicity and adjust dosage if necessary !TPHENYTOIN : Can decrease voriconazole concentrations and vori-conazole can increase phenytoin concentrations; monitoring and dosage adjustment may be required !TPIMOZIDE : Potential for serious cardiac arrhythmias; use is contraindicated !TPROTON-PUMP INHIBITORS (omeprazole ): Voriconazole may increase omeprazole (and potentially other PPI's) concentrations !TQUINIDINE : Potential for serious cardiac arrhythmias; use is contraindicated !TRIFAMPIN, RIFABUTIN : Decreased voriconazole concentrations; use together contraindicated !TVINCA ALKALOIDS (vincristine, vinblastine ): Possible increased Vinca alkaloid concentrations; monitor for toxicity !TWARFARIN : Voriconazole may potentiate warfarin's effects Laboratory Considerations No specific concerns were noted; see Monitoring for additional information. Doses At the time of writing (March 2007) there is little data or clinical ex-perience with voriconazole to support science-or experience-based dosing regimens for systemic use in veterinary species, particularly in small animals. The drug's pharmacokinetic profile can vary con-siderably across species and in some species (dogs) the drug induc-es hepatic microsomal enzymes that increase its own metabolism. A single-dose pharmacokinetic study in horses (Davis, Salmon et al. 2006) gives support to a dose of 4 mg/kg PO once daily for sus-ceptible fungi with an MIC ≤1 mcg/m L, but it is unknown if this dose will be adequate after repeated dosing. One respected refer-ence (Greene, Hartmannn et al. 2006), has listed a dose for treat-ing fungal infections in dogs extrapolated from the human dose: Loading dose: 6 mg/kg IV or PO q12h for days, then 3-4 mg/kg PO q12h for a duration as necessary. Monitoring !TEfficacy !TLiver function tests, serum electrolytes Client Information !TInform clients of the investigational nature of using this drug in veterinary species and the associated expense !TGive at least one hour before or one hour after feeding !TBecause experience with this medication has been limited, report any possible adverse effects to the veterinarian immediately, in-cluding itching/rash, yellowing of whites of the eyes, reduced ap-petite, etc. Chemistry/Synonyms A triazole antifungal, voriconazole occurs as a white to light colored powder with a molecular weight of 349. 3. Aqueous solubility is 0. 7 mg/m L. Voriconazole may also be known as UK-109496, voriconazol, voraconazolum, or Vfend®.

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WARFARIN SODIUM 933 Storage/Stability/Compatibility Voriconazole tablets should be stored at 15-30°C. The unreconstituted powder for oral suspension should be stored in the refrigerator (2-8°C); it has a shelf-life of approxi-mately 18 months. Once reconstituted, it should be stored in tightly closed containers at room temperature (15-30°C); do not refriger-ate or freeze. After reconstitution, the suspension is stable for 14 days. The suspension should be shaken well for 10 seconds prior to each administered dose. The powder for injection should be stored at room temperature (15-30°C). After reconstituting with 19 m L of sterile water for in-jection, the manufacturer recommends using immediately; how-ever, chemical and physical stability remain for up to 24 hours if stored in the refrigerator (2-8°C). Discard solution if it is not clear or particles are visible. The injectable solution must be further diluted to a concentra-tion of 5mg/m L or less for administration over 1-2 hours. Suitable diluents for IV infusion include (partial list): NS, LRS, D5LRS, and D5W. Voriconazole is not compatible with simultaneous infusion with blood products. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Voriconazole Tablets: 50 mg, 200 mg; Vfend® (Pfizer); (Rx) Voriconazole Powder for Oral Suspension: 45 g (40 mg/m L after re-constitution; orange flavor in 100 m L bottles; Vfend® (Pfizer); (Rx) Voriconazole Powder for Injection, Lyophilized: 200 mg/vial (single use); Vfend I. V. ® (Pfizer); (Rx). Also contains 3200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD) per vial (See Warnings) to solubolize the drug for IV administration. WARFARIN SODIUM (war-far-in) Coumadin® ANTICOAGULANT Prescriber Highlights TT Coumarin derivative anticoagulant used primarily for long-term treatment (or prevention of recurrence) of thrombotic conditions, primarily in cats, dogs, or horses TT Contraindications: Preexistent hemorrhage, pregnancy, those undergoing or contemplating eye or CNS surgery, major regional lumbar block anesthesia, surgery of large, open surfaces, active bleeding from the GI, respiratory, or GU tract; aneurysm, acute nephritis, cerebrovascular hemorrhage, blood dyscrasias, uncontrolled or malignant hypertension, hepatic insufficiency, pericardial effusion, & visceral carcinomas TT Adverse Effects: Dose-related hemorrhage TT Teratogenic; contraindicated in pregnancy TT Must actively monitor coagulation status TT Drug Interactions Uses/Indications In veterinary medicine, warfarin is used primarily for the oral, long-term treatment (or prevention of recurrence) of thrombotic conditions, primarily in cats, dogs, or horses. Use of warfarin in veterinary species is somewhat controversial and due to unproven benefit in reducing mortality, increased expense associated with monitoring, and potential for serious effects (bleeding), many do not recommend its use. Pharmacology/Actions Warfarin acts indirectly as an anticoagulant (it has no direct an-ticoagulant effect) by interfering with the action of vitamin K 1 in the synthesis of the coagulation factors II, VII, IX, and X. Sufficient amounts of vitamin K 1 can override this effect. Warfarin is ad-ministered as a racemic mixture of S (+) and R (-) warfarin. The S enantiomer is a significantly more potent vitamin K antagonist than the R enantiomer in species studied. Pharmacokinetics Warfarin is administered as a racemic mixture of S (+) and R (-) warfarin. Warfarin is rapidly and completely absorbed in humans after oral administration. In cats, warfarin is also rapidly absorbed after oral administration. After absorption, warfarin is highly bound to plasma proteins in humans, with approximately 99% of the drug bound. In cats, more than 96% of the drug is protein bound. It is reported that there are wide species variations with regard to protein binding; horses have a higher free (unbound) fraction of the drug than do rats, sheep or swine. Only free (unbound) warfarin is active. While other coumarin and indanedione anticoagulants are distributed in milk, warfarin does not enter milk in humans. Warfarin is principally metabolized in the liver to inactive me-tabolites that are excreted in urine and bile (and then reabsorbed and excreted in the urine). The plasma half-life of warfarin may be several hours to several days, depending on the patient (and spe-cies?). In cats, the terminal half-life of the S enantiomer is approxi-mately 23-28 hours and the R enantiomer approximately 11-18 hours. Contraindications/Precautions/Warnings Warfarin is contraindicated in patients with preexistent hemor-rhagic tendencies or diseases, those undergoing or contemplating eye or CNS surgery, major regional lumbar block anesthesia, or sur-gery of large, open surfaces. It should not be used in patients with active bleeding from the GI, respiratory, or GU tract. Other con-traindications include: aneurysm, acute nephritis, cerebrovascular hemorrhage, blood dyscrasias, uncontrolled or malignant hyper-tension, hepatic insufficiency, pericardial effusion, pregnancy, and visceral carcinomas. Adverse Effects The principal adverse effect of warfarin use is dose-related hemor-rhage, which may manifest with clinical signs of anemia, throm-bocytopenia, weakness, hematomas and ecchymoses, epistaxis, hematemesis, hematuria, melena, hematochezia, hemathrosis, he-mothorax, intracranial and/or pericardial hemorrhage, and death. Reproductive/Nursing Safety Warfarin is embryotoxic, can cause congenital malformations and considered contraindicated during pregnancy. If anticoagulant therapy is required during pregnancy, most clinicians recommend using low-dose heparin. In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or hu-mans demonstrate fetal abnormalities or adverse reaction; reports in-dicate evidence of fetal risk. The risk of use in pregnant women clearly

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934 WARFARIN SODIUM outweighs any possible benefit. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: D (Contraindicated. These drugs have been shown to cause congenital malformations or embryotoxicity. ) Based on very limited published data, warfarin has not been de-tected in the breast milk of humans treated, but there are reports of some breast-fed infants whose mothers were treated having pro-longed prothrombin times. Use with caution in nursing patients. Overdosage/Acute Toxicity Acute overdosages of warfarin may result in life-threatening hem-orrhage. In dogs and cats, single doses of 5-50 mg/kg have been as-sociated with toxicity. It must be remembered that a lag time of 2-5 days may occur before signs of toxicity occur, and animals must be monitored and treated accordingly. Cumulative toxic doses of warfarin have been reported as 1-5 mg/kg for 5-15 days in dogs and 1 mg/kg for 7 days in cats. If overdosage is detected early, prevent absorption from the gut using standard protocols. If clinical signs are noted, they should be treated with blood products and vitamin K 1 (phytonadione). Refer to the phytonadione monograph for more information. Drug Interactions Drug interactions with warfarin are perhaps the most important in human medicine. The following drug interactions have either been reported or are theoretical in humans or animals receiving warfarin and may be of significance in veterinary patients: A multitude of drugs have been documented or theorized to interact with warfarin. The following drugs or drug classes may increase the anticoagulant response of warfarin (not necessarily complete): !!ACETAMINOPHEN !!ALLOPURINOL !!AMIODARONE !!ANABOLIC STEROIDS !!AZITHROMYCIN !!CHLORAMPHENICOL !!CIMETIDINE !!CISAPRIDE !!CO-TRIMOXAZOLE (trimethoprim/sulfa ) !!DANAZOL !!DIAZOXIDE !!ERYTHROMYCIN !!ETHACRYNIC ACID !!FLUOROQUINOLONES !!FLUOXETINE !!HEPARIN !!METRONIDAZOLE !!NSAIDS !!PENTOXIFYLLINE !!PROPYLTHIOURACIL !!QUINIDINE !!SALICYLATES !!SERTRALINE !!SULFONAMIDES !!THYROID MEDICATIONS !!ZAFIRLUKAST The following drugs or drug classes may decrease the anticoagulant response of warfarin (not necessarily complete): !!BARBITURATES (phenobarbital, etc. ) !!CORTICOSTEROIDS !!ESTROGENS !!GRISEOFULV IN !!MERCAPTOPURINE !!RIFAMPIN !!SPIRONOLACTONE !!SUCRALFATE !!VITAMIN K Should concurrent use of any of the above drugs with warfarin be necessary, enhanced monitoring is required. Refer to other refer-ences on drug interactions for more specific information. Laboratory Considerations !TWarfarin may cause falsely decreased theophylline values if using the Schack and Waxler ultraviolet method of assay Doses !TDOGS: For adjunctive therapy of thromboemboli: a) 0. 22 mg/kg PO q12h; target dosage to prolong PT by 1. 25-1. 5 times the pretreatment value (Brooks 2000) b) For pulmonary thromboembolism: 0. 2 mg/kg PO once daily then 0. 05-0. 1 mg/kg PO once daily. Adjust dosage to increase PT to 1. 5-2. 5 times baseline. Heparin may be stopped once appropriate warfarin dosage is established. If PT exceeds 2. 5 times baseline, reduce dose. If bleeding develops, stop dose and institute blood or phytonadione therapy as appropriate. (Roudebush 1985) c) For prophylactic use in patients with glomerular disease and severe proteinuria: Initially, 0. 22 mg/kg, PO once daily. Mon-itor PT and adjust dose so that PT is maintained at 1. 5 times normal. (Grauer and Di Bartola 2000) !TCATS: For adjunctive therapy of thromboembolism: a) For feline aortic thromboembolism: 0. 06-0. 1 mg/kg once daily PO. Evaluate using PT, a PTT, or preferably PIVKA (pro-teins induced by vitamin K antagonists) daily during initial titration (3 days), then every other day (2 times) and weekly thereafter until stable. New steady state may require one week after dosage adjustments. Long-term therapy should be monitored at least once monthly. (Pion and Kittleson 1989) b) For chronic management/prevention of recurrence: 0. 1-0. 2 mg/kg PO once daily. Adjust dosage to prolong PT to 2-2. 5 times normal. Collect blood sample 8 hours after dosing. Requires 48-72 hours to achieve effective anticoagulation. Monitor PT weekly for 1 month, then at monthly intervals. Also determine hematocrit with each PT. (Harpster 1988) c) For thromboembolism: 0. 5 mg per cat PO once daily; target dosage to prolong PT by 1. 25-1. 5 times the pretreatment value (Brooks 2000) d) For long-term thromboprophylaxis: Initially warfarin at 0. 06-0. 09 mg/kg per day PO. Due to unequal drug distribu-tion, tablets should be crushed and mixed well. PT, adjusted to international normalized ratio (INR) is used to monitor therapy, but may not be applicable to cats. Overlap heparin and warfarin therapy by at least 4-5 days. Reevaluate antico-agulation status with any change in concurrent drug therapy. (Smith 2004)

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XYLAZINE HCL 935 e) Initially, 0. 25-0. 5 mg (total dose) per cat PO once daily. Ad-just dosage to prolong PT to twice normal value, or INR to be between 2-3. Overlap therapy with heparin. (Fox 2007a) T ! HORSES: (Note : ARCI UCGFS Class 5 Drug) As an anticoagulant: a) For adjunctive treatment of laminitis: 0. 0198 mg/kg PO once daily; monitor OSPT (one-step prothrombin time) until prolonged 2-4 seconds beyond baseline (Brumbaugh, Lopez et al. 1999) b) Initially, 0. 018 mg/kg PO once daily and increase dose by 20% every day until baseline PT is doubled. Final dose rates may be from 0. 012 mg/kg to 0. 57 mg/kg daily. (Vrins, Carl-son, and Feldman 1983) Monitoring Note : The frequency of monitoring is controversial, and is dependent on several factors including dose, patient's condition, concomitant problems, etc. See the Dosage section above for more information. T ! While Prothrombin Times (PT) or International Normalized Ra-tio (INR) are most commonly used to monitor warfarin, PIVKA (proteins induced by vitamin K antagonists) has been suggested as being more sensitive. PT's are usually recommended to be 1. 5-2X normal and INR's to be between 2-3. T ! Platelet counts and hematocrit (PCV) should be done periodically T ! Occult blood in stool and urine; other observations for bleeding T ! Clinical efficacy Client Information T ! Clients must be counseled on both the importance of adminis-tering the drug as directed T ! Immediately report any signs or symptoms of bleeding Chemistry/Synonyms A coumarin derivative, warfarin sodium occurs as a slightly bitter tasting, white, amorphous or crystalline powder. It is very soluble in water and freely soluble in alcohol. The commercially available products contain a racemic mixture of the two optical isomers. Warfarin Sodium may also be known as: sodium warfarin, war-farinum natricum, Coumadin®, Jantoven®, or Panwarfin®; there are many other trade names internationally. Storage/Stability Warfarin sodium tablets should be stored in tight, light-resistant containers at temperatures less than 40°C, preferably at room tem-perature. Warfarin sodium powder for injection should be protect-ed from light and used immediately after reconstituting. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 5 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Warfarin Sodium Tablets (scored): 1 mg, 2 mg, 2. 5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7. 5 mg & 10 mg; Coumadin® (Bristol-Myers Squibb), Jantoven® (Upsher-Smith), generic; (Rx) Warfarin Sodium Powder for Injection, lyophilized: 5. 4 mg (2 mg/ m L when reconstituted) preservative-free in 5 mg vials; Coumadin® (Bristol-Myers Squibb); (Rx) A method of suspending warfarin tablets in an oral suspension has been described (Enos 1989). T o make 30 m L of a 0. 25 mg/m L suspen-sion: Crush three 2. 5 mg tablets with a mortar and pestle. Add 10 m L glycerin to form a paste; then 10 m L of water; add sufficient amount of dark corn syrup (Karo®) to obtain a final volume of 30 m L. Warm gently; shake well and use within 30 days. XYLAZINE HCL (zye-la-zeen) Rompun® ALPHA 2-ADRENERGIC AGONIST Prescriber Highlights TT Alpha 2-adrenergic agonist used for its sedative & analge-sic in a variety of species; sometimes used as an emetic in cats TT Contraindications: Animals receiving epinephrine or hav-ing active ventricular arrhythmias. Extreme caution: pre-existing cardiac dysfunction, hypotension or shock, respi-ratory dysfunction, severe hepatic or renal insufficiency, preexisting seizure disorders, or if severely debilitated. Should generally not be used in the last trimester of pregnancy, particularly in cattle. Do not give to ruminants that are debilitated, dehydrated, or with urinary tract obstruction. Horses may kick after a stimulatory event (usually auditory); use caution. Avoid intra-arterial injec-tion; may cause severe seizures & collapse. Caution in patients treated for intestinal impactions. Use cautiously in horses during the vasoconstrictive development phase of laminitis. TT Adverse Effects: CATS: emesis, muscle tremors, bradycar-dia with partial A-V block, reduced respiratory rate, move-ment in response to sharp auditory stimuli, & increased urination. TT Adverse Effects: DOGS: Muscle tremors, bradycardia with partial A-V block, reduced respiratory rate, movement in response to sharp auditory stimuli, emesis, bloat from aerophagia which may require decompression. TT Adverse Effects: HORSES: Muscle tremors, bradycardia with partial A-V block, reduced respiratory rate, move-ment in response to sharp auditory stimuli, sweating, increased intracranial pressure, or decreased mucociliary clearance. TT Adverse Effects: CATTLE: Salivation, ruminal atony, bloat-ing, regurgitation, hypothermia, diarrhea, bradycardia, premature parturition, & ataxia. TT Yohimbine, atipamezole, & tolazoline may be used alone or in combination to reverse effects or speed recovery times TT Dosages between species can be very different; be cer-tain of product concentration when drawing up into sy-ringe, especially if treating ruminants TT Drug Interactions

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936 XYLAZINE HCL Uses/Indications Xylazine is approved for use in dogs, cats, horses, deer, and elk. It is indicated in dogs, cats, and horses to produce a state of sedation with a shorter period of analgesia, and as a preanesthetic before lo-cal or general anesthesia. Because of the emetic action of xylazine in cats, it is occasionally used to induce vomiting after ingesting toxins. Pharmacology/Actions A potent alpha 2-adrenergic agonist, xylazine is classified as a seda-tive/analgesic with muscle relaxant properties. Although xylazine possesses several of the same pharmacologic actions as morphine, it does not cause CNS excitation in cats, horses or cattle, but causes sedation and CNS depression. In horses, the visceral analgesia pro-duced has been demonstrated to be superior to that produced by meperidine, butorphanol or pentazocine. Xylazine causes skeletal muscle relaxation through central medi-ated pathways. Emesis is often seen in cats, and occasionally in dogs receiving xylazine. While thought to be centrally mediated, neither dopaminergic blockers (e. g., phenothiazines) nor alpha-blockers (yohimbine, tolazoline) block the emetic effect. Xylazine does not cause emesis in horses, cattle, sheep or goats. Xylazine depresses thermoregulatory mechanisms and either hypothermia or hyper-thermia is a possibility depending on ambient air temperatures. Effects on the cardiovascular system include an initial increase in total peripheral resistance with increased blood pressure fol-lowed by a longer period of lowered blood pressures (below base-line). A bradycardic effect can be seen with some animals develop-ing a second-degree heart block or other arrhythmias. An overall decrease in cardiac output of up to 30% may be seen. Xylazine has been demonstrated to enhance the arrhythmogenic effects of epi-nephrine in dogs with or without concurrent halothane. Xylazine's effects on respiratory function are usually clinically insignificant, but at high dosages it can cause respiratory depression with decreased tidal volumes and respiratory rates, and an overall decreased minute volume. Brachycephalic dogs and horses with up-per airway disease may develop dyspnea. Xylazine can increase blood glucose secondary to decreased se-rum levels of insulin; in non-diabetic animals, there appears to be little clinical significance associated with this effect. In horses, sedatory signs include a lowering of the head with relaxed facial muscles and drooping of the lower lip. The retractor muscle is relaxed in male horses, but unlike acepromazine, no re-ports of permanent penile paralysis have been reported. Although, the animal may appear to be thoroughly sedated, auditory stimuli may provoke arousal with kicking and avoidance responses. With regard to the sensitivity of species to xylazine, definite dif-ferences are seen. Ruminants are extremely sensitive to xylazine when compared with horses, dogs, or cats. Ruminants generally require approximately 1/10 th the dosage that is required for hors-es to exhibit the same effect. In cattle (and occasionally cats and horses), polyuria is seen following xylazine administration, prob-ably because of decreased production of vasopressin (anti-diuretic hormone, ADH). Bradycardia and hypersalivation are also seen in cattle and diminished by pretreating with atropine. Because swine require 20-30 times the ruminant dose, it is not routinely used. Pharmacokinetics Absorption is rapid following IM injection, but bioavailabilities are incomplete and variable. Bioavailabilities of 40-48% in horses, 17-73% in sheep, and 52-90% in dogs have been reported after IM administration. In horses, the onset of action following IV dosage occurs within 1-2 minutes with a maximum effect 3-10 minutes after injection. The duration of effect is dose dependent but may last for approxi-mately 1. 5 hours. The serum half-life after a single dose of xylazine is approximately 50 minutes in the horse; recovery times generally take from 2-3 hours. In dogs and cats, the onset of action following an IM or SC dose is approximately 10-15 minutes, and 3-5 minutes following an IV dose. The analgesic effects may persist for only 15-30 minutes, but the sedative actions may last for 1-2 hours depending on the dose given. The serum half-live of xylazine in dogs has been reported as averaging 30 minutes. Complete recovery after dosing may take 2-4 hours in dogs and cats. Xylazine is not detected in milk of lactating dairy cattle at 5 and 21 hours post-dose, but the FDA has not approved its use in dairy cattle and no meat or milk withdrawal times have been specified. Contraindications/Precautions/Warnings Xylazine is contraindicated in animals receiving epinephrine or having active ventricular arrhythmias. It should be used with ex-treme caution in animals with preexisting cardiac dysfunction, hypotension or shock, respiratory dysfunction, severe hepatic or renal insufficiency, preexisting seizure disorders, or if severely de-bilitated. Because it may induce premature parturition, it should generally not be used in the last trimester of pregnancy, particularly in cattle. Be certain of product concentration when drawing up into sy-ringe, especially if treating ruminants. Do not give to ruminants that are dehydrated, debilitated, or with urinary tract obstruction. It is not approved for any species to be consumed for food purposes. Horses have been known to kick after a stimulatory event (usu-ally auditory); use caution. The addition of opioids (e. g., butorpha-nol) may help temper this effect, but may cause increased risks for hypotension or ileus development. Avoid intra-arterial injection; may cause severe seizures and collapse. The manufacturers warn against using xylazine in conjunction with other tranquilizers. Because this drug may inhibit gastrointestinal motility, use with caution in patients treated for intestinal impactions. Use cautiously in horses during the vasoconstrictive development phase of lamini-tis as xylazine has been shown to reduce digital flow of blood for about 8 hours after administration. Adverse Effects Emesis is generally seen within 3-5 minutes after xylazine admin-istration in cats and occasionally in dogs. T o prevent aspiration, do not induce further anesthesia until this time has lapsed. Other ad-verse effects listed in the package insert (Gemini®, Butler) for dogs and cats include: muscle tremors, bradycardia with partial A-V block, reduced respiratory rate, movement in response to sharp au-ditory stimuli, and increased urination in cats. Dogs may develop bloat from aerophagia that may require de-compression. Because of gaseous distention of the stomach, xyla-zine's use before radiography can make test interpretation difficult. Adverse effects listed in the package insert (Ana Sed®, Lloyd) for horses include: muscle tremors, bradycardia with partial A-V block, reduced respiratory rate, movement in response to sharp auditory stimuli, and sweating (rarely profuse). Additionally, horses may develop increased intracranial pressure or decreased mucociliary clearance rates when xylazine is used. Adverse reactions reported in cattle include: salivation, rumi-nal atony, bloating and regurgitation, hypothermia, diarrhea, and bradycardia. Hypersalivation and bradycardia may be alleviated by pretreating with atropine. Large animals may become ataxic following dosing and caution should be observed.

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XYLAZINE HCL 937 Reproductive/Nursing Safety Limited information was located on the safety of xylazine in preg-nancy; apparently, there are no reports of teratogenicity in animals. Xylazine may induce premature parturition in cattle. Xylazine does not appear to be excreted in detectable quantities in cows' milk. Overdosage/Acute Toxicity In the event of an accidental overdosage, cardiac arrhythmias, hy-potension, and profound CNS and respiratory depression may oc-cur. Seizures have also been reported after overdoses. There has been much interest in using alpha-blocking agents as antidotes or reversal agents to xylazine. Y ohimbine, atipamezole, and tolazoline have been suggested for use alone and in combination to reverse the effects of xylazine or speed recovery times. Separate mono-graphs for yohimbine and atipamezole are available with suggested doses, etc. T o treat the respiratory depressant effects of xylazine toxicity, mechanical respiratory support with respiratory stimulants (e. g., doxapram) have been recommended for use. Drug Interactions The manufacturers warn against using xylazine in conjunction with other tranquilizers. !TACEPROMAZINE : The combination use of acepromazine with xyla-zine is generally considered safe, but there is potential for addi-tive hypotensive effects and this combination should be used cau-tiously in animals susceptible to hemodynamic complications. !TCNS DEPRESSANT AGENTS, OTHER (barbiturates, narcotics, anesthet-ics, phenothiazines, etc. ): May cause additive CNS depression if used with xylazine. Dosages of these agents may need to be reduced. !TEPINEPHRINE : The use of epinephrine with or without the concur-rent use of halothane with xylazine may induce the development of ventricular arrhythmias. !TRESERPINE : A case of a horse developing colic-like clinical signs after reserpine and xylazine has been reported. Until more is known about this potential interaction, use of these two agents together should be avoided. Doses !TDOGS: a) 1. 1 mg/kg IV, 1. 1-2. 2 mg/kg IM or SC (Package Insert; Rompun®—Miles) b) 0. 6 mg/kg IV, IM as a sedative (Morgan 1988) c) T o treat a hypoglycemic crises (with IV dextrose): 1. 1 mg/kg IM (Schall 1985) d) For epidural injection: 0. 02-0. 25 mg/kg; dilute with suffi-cient quantity of sterile saline to a volume of 0. 26 m L/kg. Onset of action 20-30 minutes; 2-5 hour duration. Xylazine 0. 02 mg/kg with morphine 0. 1 mg/kg; dilute with sufficient quantity of sterile saline to a volume of 0. 26 m L/kg. Onset of action 30-60 minutes; 10-20 hour duration. As an analgesic: 0. 1-1 mg/kg IV, IM or SC. For post-opera-tive anxiety: 0. 1-0. 5 mg/kg IV, IM or SC (Carroll 1999) !TCATS: a) 1. 1 mg/kg IV, 1. 1-2. 2 mg/kg IM or SC (Package Insert; Rompun®—Miles) b) As an emetic: 0. 44 mg/kg IM (Morgan 1988), (Riviere 1985) c) As an analgesic: 0. 1-1 mg/kg IV, IM or SC. For post-opera-tive anxiety: 0. 1-0. 5 mg/kg IV, IM or SC (Carroll 1999) d) 0. 55 mg/kg IM (Mandsager 1988) !TRABBITS, RODENTS, SMALL MAMMALS: a) Rabbits: For minimally invasive procedures lasting less than 30-45 minutes: 5 mg/kg once SC or IM in combination with ketamine (35 mg/kg). Mice/Rats: General anesthesia 13 mg/kg once IP in combina-tion with ketamine (87 mg/kg). Hamsters/Guinea pigs: General anesthesia 8-10 mg/kg once IP in combination with ketamine (200 mg/kg for hamsters and 60 mg/kg for Guinea pigs) (Huerkamp 1995) !TFERRETS: a) As a sedative/analgesic: Xylazine: 0. 5-2 mg/kg IM or SC. Usually combined with atropine (0. 05 mg/kg) or glycopyrro-late (0. 01 mg/kg IM) or Butorphanol/Xylazine: Butorphanol 0. 2 mg/kg plus Xylazine (2 mg/kg) IM (Finkler 1999) b) Xylazine (2 mg/kg) plus butorphanol (0. 2 mg/kg) IM; T elazol (1. 5 mg/kg) plus xylazine (1. 5 mg/kg) IM; may re-verse xylazine with yohimbine (0. 05 mg/kg IM) T elazol (1. 5 mg/kg) plus xylazine (1. 5 mg/kg) plus butorpha-nol (0. 2 mg/kg) IM; may reverse xylazine with yohimbine (0. 05 mg/kg IM) (Williams 2000) !TBIRDS: a) As a sedative/analgesic: 1-4 mg/kg IM, provides sedation for ketamine anesthesia. Has been used at dosages of up to 10 mg/kg in small psittacines (Clyde and Paul-Murphy 2000) !TCATTLE: Caution : Cattle are extremely sensitive to xylazine's effects; be cer-tain of dose and dosage form. Pretreatment with atropine can decrease bradycardia and hypersalivation. a) 0. 05-0. 15 mg/kg IV; 0. 10-0. 33 mg/kg IM. If administering IM use an 18 or 20 gauge needle at least 1. 5 inches long. In-travenous route may stress cardiovascular function. (Thur-mon and Benson 1986) b) 0. 044-0. 11 mg/kg IV; 0. 22 mg/kg IM (Mandsager 1988) c) 0. 1-0. 3 mg/kg IM; 0. 05-0. 15 mg/kg IV; 0. 05-0. 07 mg/kg epidurally. When used IV/IM, analgesia can be very short-lived (1/2 hour). (Walz 2006b) !THORSES: (Note: ARCI UCGFS Class 3 Drug) a) 1. 1 mg/kg IV; 2. 2 mg/kg IM. Allow animal to rest quietly un-til full effect is reached. (Package Insert; Rompun®—Bayer) b) Sedative/analgesic for colic: 0. 2-0. 5 mg/kg IV (will provide analgesia for 20-30 minutes); or 0. 6-1 mg/kg IM (effects for 1-2 hours). Evaluate heart rate prior to therapy. (Moore 1999) c) For sedation/analgesia: Xylazine 0. 5-1 mg/kg IV or IM with or without butorphanol (0. 02-0. 03 mg/kg) (Taylor 1999) d) Prior to guaifenesin/thiobarbiturate anesthesia: 0. 55 mg/kg IV; Prior to ketamine induction: 1. 1 mg/kg IV; In combi-nation with opioid/tranquilizers (all IV doses): 1) Xylazine 0. 66 mg/kg and meperidine 1. 1 mg/kg; 2) Xylazine 1. 1 mg/ kg and butorphanol 0. 01-0. 02 mg/kg; 3) Xylazine 0. 6 mg/ kg; and acepromazine 0. 02 mg/kg. Note : The manufacturers state that xylazine should not be used in conjunction with tranquilizers (Thurmon and Benson 1987) e) For field anesthesia: Sedate with xylazine (1 mg/kg IV; 2 mg/ kg IM) given 5-10 minutes (longer for IM route) before induction of anesthesia with ketamine (2 mg/kg IV). Horse must be adequately sedated (head to the knees) before giving the ketamine (ketamine can cause muscle rigidity and sei-zures). If adequate sedation does not occur, either: 1) Redose xylazine: up to half the original dose, 2) Add butorphanol (0. 02-. 04 mg/kg IV). Butorphanol can be given with the

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938 YOHIMBINE HCL original xylazine if you suspect that the horse will be difficult to tranquilize (e. g., high-strung Thoroughbreds) or added before the ketamine. This combination will improve induc-tion, increase analgesia and increase recumbency time by about 5-10 minutes. 3) Diazepam (0. 03 mg/kg IV). Mix the diazepam with the ketamine. This combination will improve induction when sedation is marginal, improve muscle re-laxation during anesthesia and prolong anesthesia by about 5-10 minutes. 4) Guaifenesin (5% solution administered IV to effect) can also be used to increase sedation and muscle relaxation. (Mathews 1999) T ! SHEEP & GOATS: Note : Use xylazine with extreme caution in these species. a) 0. 05-0. 1 mg/kg IV; 0. 1-0. 22 mg/kg IM (Thurmon and Ben-son 1986) b) 0. 044-0. 11 mg/kg IV; 0. 22 mg/kg IM (Mandsager 1988) T ! EXOTICS: a) An extensive list of suggested dosages can be found on page 359 of Veterinary Pharmacology and Therapeutics, 6th Ed., Booth, NH and Mc Donald, LE, Eds. 1988; Iowa State Univer-sity Press; Ames, Iowa Monitoring T ! Level of anesthesia/analgesia T ! Respiratory function; cardiovascular status (rate, rhythm, BP if possible) T ! Hydration status if polyuria present Client Information T ! Xylazine should only be used by individuals familiar with its use Chemistry/Synonyms Xylazine HCl is a alpha 2-adrenergic agonist structurally related to clonidine. The p H of the commercially prepared injections is ap-proximately 5. 5. Dosages and bottle concentrations are expressed in terms of the base. Xylazine HCl may also be known as Bay-Va-1470, Rompun®, Ana Sed®, Sedazine®, X-Ject®, or Xyla-Ject®. Storage/Stability/Compatibility Do not store above 30°C (86°F). Xylazine is reportedly physically compatible in the same syringe with several compounds, including: acepromazine, buprenorphine, butorphanol, chloral hydrate, and meperidine. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Xylazine Injection: 20 mg/m L in 20 m L vials or 100 mg/m L in 50 m L vials: Ana Sed® (Lloyd); X-Ject® (Butler); Xyla-Ject® (Phoenix); Sedazine® (Fort Dodge); Tranqui Ved® (Vedco); generic; (Rx); Ap-proved for use (depending on strength and product) in dogs, cats, horses, deer, and elk. While xylazine is not approved for use in cattle in the USA, at labeled doses in Canada it reportedly has been assigned withdrawal times of 3 days for meat and 48 hours for milk. FARAD has reportedly sug-gested a withdrawal of 7 days for meat and 72 hours for milk for extra-label use. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None YOHIMBINE HCL (yo-him-been) Yobine®, Antagonil® ALPHA 2-ADRENERGIC ANTAGONIST Prescriber Highlights TT Alpha 2-adrenergic antagonist used to reverse xylazine & potentially amitraz; may be used prophylactically before amitraz dips TT Contraindications: Hypersensitivity to it. Caution: Renal disease, seizure disorders TT Adverse Effects: Transient apprehension or CNS excite-ment, muscle tremors, salivation, increased respiratory rates, & hyperemic mucous membranes; more likely in small animals TT Drug interactions Uses/Indications Y ohimbine is indicated to reverse the effects of xylazine in dogs, but it is being used clinically in several other species as well. Y ohimbine may be efficacious in reversing some of the toxic ef-fects associated with other agents (e. g., amitraz) and can be used prophylactically before amitraz dips. Pharmacology/Actions Y ohimbine is an alpha 2-adrenergic antagonist that can antagonize the effects of xylazine. Alone, yohimbine increases heart rate, blood pressure, causes CNS stimulation and antidiuresis, and has hyper-insulinemic effects. By blocking central alpha 2-receptors, yohimbine causes sympa-thetic outflow (norepinephrine) to be enhanced. Peripheral alpha 2-receptors are also found in the cardiovascular system, genitourinary system, GI tract, platelets, and adipose tissue. Pharmacokinetics The pharmacokinetics of this drug have been reported in steers, dogs, and horses (Jernigan et al. 1988). The apparent volume of distribution (steady-state) is approximately 5 L/kg in steers, 2-5 L/ kg in horses, and 4. 5 L/kg in dogs. The total body clearance is ap-proximately 70 m L/min/kg in steers, 35 m L/min/kg in horses, and 30 m L/min/kg in dogs. The half-life of the drug is approximately 0. 5-1 hours in steers, 0. 5-1. 5 hours in horses, and 1. 5-2 hours in dogs. Y ohimbine is believed to penetrate the CNS quite readily and, when used to reverse the effects of xylazine, onset of action gener-ally occurs within 3 minutes. The metabolic fate of the drug is not known. Contraindications/Precautions/Warnings Y ohimbine is contraindicated in patients hypersensitive to it. In hu-mans, yohimbine is contraindicated in patients with renal disease. Y ohimbine should be used cautiously in patients with seizure disorders. When used to reverse the effects xylazine, normal pain perception may result. Adverse Effects Y ohimbine may cause transient apprehension or CNS excitement, muscle tremors, salivation, increased respiratory rates, and hyper-emic mucous membranes. Adverse effects appear to be more prob-able in small animals than in large animals.

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ZAFIRLUKAST 939 TReproductive/Nursing Safety Safe use of yohimbine in pregnant animals has not been established. No information on safety during lactation was located. Overdosage/Acute Toxicity Dogs receiving 0. 55 mg/kg (5 times recommended dose) exhibited clinical signs of transient seizures and muscle tremors. There were 51 exposures to yohimbine reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 46 were dogs with 9 showing clinical signs and the remaining 5 cases were cats with 1 showing clinical signs. Common findings in dogs recorded in decreasing frequency included panting, tachycardia, agitation, hypertension and anxiety. Common findings in cats recorded in decreasing frequency includ-ed hyperactivity, tachycardia, tachypnea and tremors. Drug Interactions Little information is available, use with caution with other alpha 2-adrenergic antagonists or other drugs that can cause CNS stimulation. The following drug interaction has been reported in humans receiv-ing yohimbine and may be of significance in veterinary patients: T ! TRICYCLIC ANTIDEPRESSANTS : In humans, yohimbine is not rec-ommended for use with antidepressants or other mood-altering agents; hypertension has been reported with tricyclics Doses T ! DOGS: For xylazine reversal: a) 0. 11 mg/kg IV slowly (Package insert; Yobine®—Lloyd) b) 0. 1 mg/kg IV (Gross and Tranquilli 1989) c) As an antiemetic: 0. 25-0. 5 mg/kg q12h SC or IM (Washabau and Elie 1995) For reversal or prevention of amitraz effects: a) T o reverse centrally mediated bradycardia and hypotension associated with amitraz ingestion: 0. 1 mg/kg IV; repeat as necessary (Manning 2000) b) In cases of toxicity or to prevent a dog from having an acute episode of toxicity associated with demodicosis treatment: Y ohimbine at 0. 11 mg/kg IV or 0. 25 mg/kg IM with atipam-ezole (50 mcg/kg IM). (T orres 2007b) c) For treatment or prevention of side effects associated with amitraz dips: 0. 1 mg/kg IV; may give prior to, or after bathing to prevent effects. (Hillier 2006g) T ! RABBITS, RODENTS, SMALL MAMMALS : T o reverse the effects of xylazine and to partially antagonize the effects of ketamine and acepromazine: a) Rabbits: 0. 2 mg/kg IV as needed b) Mice/Rats: 0. 2 mg/kg IP as needed (Huerkamp 1995) T ! BIRDS: As a reversal agent for alpha2-adrenergic agonists (e. g., xyla-zine): a) 0. 1 mg/kg IV (Clyde and Paul-Murphy 2000) T ! CATTLE: For xylazine reversal: a) 0. 125 mg/kg IV (Gross and Tranquilli 1989) T ! HORSES: (Note: ARCI UCGFS Class 2 Drug) For xylazine reversal: a) 0. 075 mg/kg IV (Gross and Tranquilli 1989) T ! LLAMAS: For xylazine reversal: a) 0. 25 mg/kg IV or IM (Fowler 1989) T ! DEER: For xylazine reversal: a) In wild, exotic and ranched deer: 0. 2-0. 3 mg/kg IV (Package Insert; Antagonil®—Wildlife Labs) Note : Y ohimbine has also been used as a reversal agent in several exotic species. Several dosages are listed in the chapter on Stimu-lants by Booth in Veterinary Pharmacology and Therapeutics, 6th Edition. Booth, NH and Mc Donald, LE Eds., Iowa State Uni-versity Press. Ames. 1988 Monitoring T ! CNS status (arousal level, etc. ) T ! Cardiac rate; rhythm (if indicated), blood pressure (if indicated and practical) T ! Respiratory rate Client Information T ! his agent should be used with direct professional supervision only Chemistry/Synonyms A Rauwolfia or indolealkylamine alkaloid, yohimbine HCl has a molecular weight of 390. 9. It is chemically related to reserpine. Y ohimbine may also be known as: aphrodine hydrochloride, chlorhydrate de quebrachine, corynine hydrochloride, Aphrodyne®, Dayto Himbin®, Pluriviron mono®, Prowess Plain®, Urobine®, Virigen®, Yobine®, Yocon®, Yocoral®, Yohimex®, Yohydrol, Yomax®, or Zumba®. Storage/Stability/Compatibility Y ohimbine injection should be stored at room temperature (15-30°C) and protected from light and heat. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Y ohimbine Sterile Solution for Injection: 2 mg/m L in 20 m L vials; Yobine® (Lloyd); (Rx). Approved for use in dogs. HUMAN-LABELED PRODUCTS: Oral 5. 4 mg tablets are available, but would unlikely to be of veteri-nary benefit. ZAFIRLUKAST (zah-fur-luh-kast) Accolate® LEUKOTRIENE-RECEPTOR ANTAGONIST Prescriber Highlights TT Leukotriene-receptor antagonist used primarily for feline asthma; appears to have very limited efficacy TT Not for treatment of acute bronchospasm TT Well tolerated TT Dose on an empty stomach Uses/Indications While zafirlukast potentially could be useful in treating feline asth-ma, including allowing dose reductions of corticosteroid therapy, its efficacy has been disappointing to this point and most do not recommend its use. Potentially, it could be of benefit in allergy-mediated (where leukotrienes play a role) dermatologic condi-

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940 ZIDOVUDINE (AZT) tions, such as atopy in dogs, but evidence has been that it is not very effective. Pharmacology/Actions Zafirlukast selectively and competitively inhibits leukotriene recep-tors, specifically receptors for leukotriene D 4 and E 4 (LTD 4 and LTE4). Additionally, it competes for receptors with some compo-nents of slow-reacting substance of anaphylaxis (SRS-A). These substances have all been implicated in the inflammatory and bron-choconstrictive aspects of bronchial asthma. Pharmacokinetics No specific veterinary data was located. In humans, zafirlukast is rapidly absorbed after oral administration. Food may impair the absorption of the drug, therefore, give on an empty stomach. Peak plasma levels occur about 3 hours after dosing. Zafirlukast is highly bound to plasma proteins (>99%). The drug is extensively metabo-lized; less than 10% of a dose is excreted in the urine, the rest in the feces. Half lives in humans average about 10 hours. Contraindications/Precautions/Warnings Zafirlukast is contraindicated in patients hypersensitive to it. Zafirlukast is not indicated for, and is ineffective for treating bronchospasm associated with acute asthma attacks. Patients with significantly decreased hepatic function may have reduced clearances (and increased plasma levels) of zafirlukast. Adverse Effects Veterinary experience is very limited and no adverse effects have been reported thus far. In humans, the adverse effect profile seems to be minimal; headache was noted most often, but incidence is not much different than placebo. 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. ) Zafirlukast is excreted in milk, but it is probably safe to adminis-ter to nursing veterinary patients. Overdosage/Acute Toxicity In dogs, doses of up to 500 mg/kg were tolerated without mortality. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving zafirlukast and may be of significance in veterinary patients: ! !ASPIRIN : May significantly increase zafirlukast plasma levels ! !ERYTHROMYCIN : May decrease the bioavailability of zafirlukast ! !THEOPHYLLINE : May decrease plasma levels of zafirlukast T ! WARFARIN : Zafirlukast may significantly increase the prothrom-bin time of patients taking warfarin. Laboratory Considerations None were noted Doses T ! DOGS: a) For adjunctive treatment of atopic dermatitis: 20 mg (total dose) PO twice daily; only moderate success (Foil 2003a) T ! CATS: a) For adjunctive treatment of feline bronchial asthma: 1-2 mg/kg PO once to twice daily (Noone 1999) Monitoring T ! Clinical efficacy Client Information T ! Preferably give on an empty stomach. T ! Give this medication even if animal appears well; do not use to treat acute asthma clinical signs. T ! Because experience in veterinary medicine is minimal, report any untoward effects to the veterinarian. Chemistry/Synonyms A leukotriene-receptor antagonist, zafirlukast occurs as a white to pale yellow, fine amorphous powder. It is practically insoluble in water. Zafirlukast may also be known as: ICI-204219, Accolate®, Accoleit®, Aeronix®, Azimax®, Olmoran®, Resma®, Vanticon®, Zafarismal®, Zafirst®, or Zuvair®. Storage/Stability Zafirlukast tablets should be stored at room temperature and protected from light and moisture. The manufacturer states that the tablets should be dispensed only in the original, unopened container. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Zafirlukast Tablets (film-coated): 10 mg & 20 mg; Accolate® (Astra-Zeneca); (Rx) ZIDOVUDINE (AZT) (zid-o-vew-den) Retrovir® ANTIRETROVIRAL Prescriber Highlights TT Antiretroviral agent that may be useful for adjunctive treatment of Fe LV or FIV in cats TT Limited experience TT Use with caution if renal, hepatic, or bone marrow dys-function present TT Anemia (non-regenerative) most common adverse effect in cats

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ZIDOVUDINE (AZT) 941 Uses/Indications In veterinary medicine, zidovudine may be useful for treating fe-line immunodeficiency virus (FIV) or feline leukemia virus (Fe LV). While zidovudine can reduce the viral load in infected cats and im-prove clinical signs, it may not alter the natural course of the disease to a great extent. Pharmacology/Actions Zidovudine is considered an antiretroviral agent. While its exact mechanism of action is not fully understood, zidovudine is con-verted in vivo to an active metabolite (triphosphate) that interferes with viral RNA-directed DNA polymerase (reverse transcriptase). This causes a virustatic effect in retroviruses. Zidovudine has some activity against gram-negative bacteria and can be cytotoxic as well. Pharmacokinetics Zidovudine is well absorbed after oral administration. In cats, oral bioavailability is approximately 95%. When administered with food, peak levels may be decreased, but total area under the curve may not be affected; peak levels occur about one hour post-dosing in cats. The drug is widely distributed, including into the CSF. It is only marginally bound to plasma proteins. Zidovudine is rapidly metabolized and excreted in the urine. Half-life in cats is about 1. 5 hours. Contraindications/Precautions/Warnings Zidovudine is considered contraindicated in patients who have de-veloped life threatening hypersensitivity reactions to it in the past. Use zidovudine with caution in patients with bone marrow, re-nal or hepatic dysfunction. Dosage adjustment may be necessary in cats with renal or hepatic dysfunction. Adverse Effects In cats, reductions in RBC's, PCV and hemoglobin are the most common adverse effects reported. Anemia may be non-regenerative and is most commonly seen with the higher end of the dosage range (10-15 mg/kg). Diarrhea and weakness have also been reported. While there are many adverse effects reported in humans, granulo-cytopenia and GI effects appear to be the most likely to occur. 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. ) Zidovudine is excreted in milk. Clinical significance is not clear for nursing offspring. Overdosage/Acute Toxicity Human adults and children have survived oral overdoses of up to 50 g without permanent sequelae. Vomiting and transient hemato-logic effects are the most consistent adverse effects reported with overdoses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving zidovudine and may be of significance in veterinary patients: !TANTIFUNGALS, AZOLE (ketoconazole, etc. ): May increase zidovudine levels !TATOVAQUONE : May increase zidovudine levels !TDOXORUBICIN : May antagonize each other's effects; avoid use together !TINTERFERON ALFA : Increased risk for hematologic and hepato-toxicity !TPROBENECID : May increase zidovudine levels !TMYELO-/CYTOTOXIC DRUGS (e. g., chloramphenicol, doxorubicin, flucy-tosine, vincristine, vinblastine ): Administered with zidovudine may increase the risk of hematologic toxicity !TRIFAMPIN : May decrease blood levels (AUC) of zidovudine Laboratory Considerations !TNone were noted. Doses !TCATS: For adjunctive therapy of Fe LV and FIV: a) For FELV: 5 mg/kg PO or SC q12h. If giving SC dilute in sterile normal saline to prevent local irritation. Check CBC weekly the first month as anemia (non-regenerative) can be seen. If values are stable; may monitor monthly. Some cats develop mild decreases in hematocrit that resolves even if treatment is continued. (Hartmannn 2007) b) 5 mg/kg PO three times daily for five weeks, then a 4-week rest interval (Gomez, Gisbert et al. 2002) c) For FIV encephalopathy: 20 mg/kg PO q12h (Taylor 2003b) Monitoring !TCBC; PCV. If PCV drops below 20% stop drug for a few days and then resume at a lower dosage (Levy 2000) !TCD4/CD8 rates, if possible !TClinical efficacy Client Information !TMust be considered “experimental” therapy for cats !TMust be administered as prescribed for efficacy !TRegular blood tests required Chemistry/Synonyms A thymidine analog, zidovudine is synthetically produced and occurs as a white to beige-colored, odorless, crystalline solid. Approximately 20 mg are soluble in one m L of water. Zidovudine may also be known as: ZDV, azidodeoxythymi-dine, 3'-azido-2',3'-dideoxythymidine, azidothymidine, AZT, BW-A509U, BW-509U, compound-S, zidovudinum or Retrovir®; many other trade names are available. Storage/Stability Zidovudine oral tablets or capsules should be stored at room tem-perature. Protect from heat, light and moisture. The oral solution should be stored at room temperature. Zidovudine injection (for IV infusion) should be store at room temperature and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Zidovudine Tablets: 300 mg; Retrovir® (Glaxo Smith Kline); generic; (Rx) Zidovudine Capsules: 100 mg; Retrovir® (Glaxo Smith Kline); (Rx) Zidovudine Oral Syrup/Solution: 10 mg/m L in 240 m L; generic (Au-robindo); (Rx) Zidovudine Injection: 10 mg/m L in 20 m L single-use vials; Retrovir® (Glaxo Smith Kline); (Rx)

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942 ZINC ZINC ACETATE ZINC SULFATE ZINC GLUCONATE (zink) NUTRITIONAL; TRACE ELEMENT Prescriber Highlights TT Metal nutritional agent that may be used for zinc de-ficiency, to reduce copper toxicity in susceptible dog breeds (Bedlington Terriers, West Highland White Terri-ers) with hepatic copper toxicosis, & treat hepatic fibrosis in dogs. Has astringent & antiseptic activity topically. TT Contraindications: None; consider obtaining zinc & cop-per levels before treating. TT Adverse Effects: Large doses may cause GI disturbances or hematologic abnormalities (usually hemolysis), par-ticularly if a coexistent copper deficiency exists TT Zinc overdoses ( e. g., U. S. Pennies) can be serious Uses/Indications Zinc sulfate is used systemically as a nutritional supplement in a variety of species. Oral zinc acetate has been shown to reduce cop-per toxicity in susceptible dog breeds (Bedlington T erriers, West Highland White T erriers) with hepatic copper toxicosis. Zinc ther-apy may also be of benefit in the treatment of hepatic fibrosis in the dog. Zinc sulfate is used topically as an astringent and as a weak antiseptic both for dermatologic and ophthalmic conditions. Pharmacology/Actions Zinc is a necessary nutritional supplement; it is required by over 200 metalloenzymes for proper function. Enzyme systems that require zinc include alkaline phosphatase, alcohol dehydrogenase, carbonic anhydrase, and RNA polymerase. Zinc is also necessary to main-tain structural integrity of cell membranes and nucleic acids. Zinc dependent physiological processes include sexual maturation and reproduction, cell growth and division, vision, night vision, wound healing, immune response, and taste acuity. When administered orally, large doses of zinc can inhibit the ab-sorption of copper. Pharmacokinetics About 20-30% of dietary zinc is absorbed, principally from the duodenum and ileum. Bioavailability is dependent upon the food in which it is present. Phytates can chelate zinc and form insoluble complexes in an alkaline p H. Zinc is stored mostly in red and white blood cells, but is also found in the muscle, skin, bone, retina, pan-creas, liver, kidney, and prostate. Elimination is primarily via the feces, but some is also excreted by the kidneys and in sweat. Zinc found in feces may be reabsorbed in the colon. Contraindications/Precautions/Warnings Zinc supplementation should be carefully considered before ad-ministering to patients with copper deficiency. Adverse Effects Large doses may cause GI disturbances. Hematologic abnormali-ties (usually hemolysis) may occur with large doses or serum levels greater than 1000 mcg/d L, particularly if a coexistent copper defi-ciency exists. Zinc acetate or methionine may be less irritating to the stomach. Mixing the contents of the capsule with a small amount of tuna or hamburger may minimize vomiting. Reproductive/Nursing Safety Although zinc deficiency during pregnancy has been associated with adverse perinatal outcomes, other studies report no such oc-currences. In humans, since zinc deficiency is very rare, the routine use of zinc supplementation during pregnancy is not recommend-ed. 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 Signs associated with overdoses of zinc include hemolytic ane-mia, hypotension, jaundice, vomiting, and pulmonary edema. Suggestions for treatment of overdoses of oral zinc include remov-ing the source, dilution with milk or water, and chelation therapy using edetate calcium disodium (Calcium EDTA). Refer to that monograph for possible doses and usage information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving zinc and may be of sig-nificance in veterinary patients: T ! COPPER : Large doses of zinc can inhibit copper absorption in the intestine; if this interaction is not desired, separate copper and zinc supplements by at least two hours T ! FLUOROQUINOLONES (e. g., enrofloxacin, ciprofloxacin ): Zinc salts may reduce the oral absorption of some fluoroquinolones T ! PENICILLAMINE : May potentially inhibit zinc absorption; clinical significance is not clear T ! TETRACYCLINES : Zinc salts may chelate oral tetracycline and re-duce its absorption; separate doses by at least two hours T ! URSODIOL : May potentially inhibit zinc absorption; clinical sig-nificance is not clear Doses T ! DOGS: For adjunctive treatment and prophylaxis of hepatic copper toxicosis: a) Initially, give a loading dose of 100 mg elemental zinc (zinc acetate used in this study) twice daily (separate doses by at least 8 hours) for about 3 months; then reduce dose to 50 mg (elemental zinc) twice daily. If animal vomits, give doses with a small piece of meat. Do not give within one hour of a meal. Monitoring of zinc levels every 2-3 months initially is recommended. Target zinc levels are 200-500 micrograms/ dl. Do not allow levels to increase higher than 1000 micro-grams/dl. May require 3-6 months of therapy before signifi-cant efficacy is noted. (Brewer, Dick et al. 1992) b) 5-10 mg/kg elemental zinc q12h; use high end of dosage range initially for 3 months, then 50 mg PO q12h for main-tenance. Separate dosage from meals by 1-2 hours. Zinc ace-tate or methionine may be less irritating to the GI than other salts. Mixing the contents of the capsule with a small amount of tuna or hamburger may also minimize vomiting. In dogs with active copper-induced hepatitis, do not use zinc alone, but in combination with a chelator (e. g., D-penicillamine, trientine). Target zinc plasma levels >200 micrograms/dl but <400 micrograms/dl. Monitor levels every 2-3 months and adjust dosage as necessary. (Johnson 2000) c) 10 mg/kg elemental zinc (given as zinc acetate or zinc glucon-

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ZONISAMIDE 943 ate) PO twice daily. Give one hour before each meal. (Rothu-izen 2003) d) 1. 5-2. 5 mg/kg zinc gluconate PO three times daily; 0. 67 mg/kg zinc sulfate PO three times daily; or 100 mg (total dose) elemental zinc (as zinc acetate) PO twice daily. Goal is to achieve zinc plasma concentrations of 200-600 mcg/ dl. After a 3-6 month loading period, dose is decreased to approximately half the original dose. Serum zinc concentra-tions are measured every 4-6 months. If serum level drops below 150 mcg/dl, increase dose to original level. If vomiting a problem, may mix dosage with a tablespoonful of tuna fish (in oil). (Richter 2002) For hepatic fibrosis: a) 200 mg of elemental zinc PO once daily for a 10-25 kg dog. Keep zinc plasma levels between 200-300 mcg/dl. (Rutgers 2000) For zinc-related dermatoses: a) Rapidly growing dogs: 10 mg/kg, day PO of zinc sulfate (Wil-lemse 1992) b) For zinc-responsive dermatoses found in Siberian huskies, Alaskan malamutes, Great Danes, and Doberman pinschers: Zinc sulfate: 10 mg/kg PO with food either once daily or di-vided q12h. Alternatively, zinc methionine: 2 mg/kg PO once daily. Correct any dietary imbalances (high calcium and phytate). Lifetime therapy usually required. If vomiting oc-curs, lower dose or give with food. For syndrome seen in puppies: Dietary corrections alone usually resolve the syndrome, but zinc supplementation as above, can expedite process. Some puppies require supple-mentation until maturity. (Kwochka 1994) As an appetite stimulant: a) 1 mg/kg of elemental zinc PO once a day (Bartges 2003b) T ! CATS: For adjunctive therapy of severe hepatic lipidosis: a) 7-10 mg/kg PO once daily, in B-Complex mixture if pos-sible (Center 1994) As an appetite stimulant: a) 1 mg/kg of elemental zinc PO once a day (Bartges 2003b) Monitoring; Client Information T ! See information in individual doses above Client Information T ! Although it is best to give oral zinc acetate on an empty stomach, if vomiting occurs mix with hamburger or tuna fish to decrease this side effect Chemistry/Synonyms Zinc acetate occurs as white crystals or granules. It has a faint acet-ous odor and effloresces slightly. One gram is soluble in 2. 5 m L of water or 30 m L of alcohol. Zinc acetate contains 30% elemental zinc (100 mg zinc acetate = 30 mg elemental zinc). Zinc sulfate occurs as a colorless granular powder, small needles, or transparent prisms. It is odorless but has an astringent metal-lic taste. 1. 67 grams are soluble in one m L of water. Zinc sulfate is insoluble in alcohol and contains 23% zinc by weight (100 mg zinc sulfate = 23 mg elemental zinc). Zinc gluconate occurs as white or practically white powder or granules. It is soluble in water; very slightly soluble in alcohol. Zinc gluconate contains 14. 3% zinc (100 mg zinc gluconate = 14. 3 mg elemental zinc). Zinc acetate may also be known as: E650, or zinci acetas dihydricus. Zinc sulfate may also be known as: zinc sulphate; zinci sulfas, zincum sulfuricum; many trade names are available. Storage/Stability Store zinc acetate crystals in tight containers. Unless otherwise rec-ommended by the manufacturer, store zinc sulfate products in tight containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None as single-ingredient products for systemic use; several vitamin/ mineral supplements contain zinc, however. HUMAN-LABELED PRODUCTS: Zinc Acetate is available from chemical supply houses. An oral or-phan medication Galzin® is available. Zinc Injection: 1 mg/m L (as sulfate; as 4. 39 mg heptahydrate or 2. 46 mg anhydrous) in 10 m L and 30 m L vials; 5 mg/m L (as 21. 95 mg sul-fate) in 5 m L and 10 m L vials; 1 mg/m L (as 2. 09 mg chloride) in 10 m L vials; Zinca-Pak® (Smith and Nephew Solo Pak); generic; (Rx) Zinc Sulfate Tablets: 66 mg (15 mg zinc), 110 mg (25 mg zinc) & 200 mg (45 mg zinc); Zinc 15® and Orazinc® (Mericon); generic; (OTC) Zinc Sulfate Capsules: 220 mg (50 mg zinc); Orazinc® (Mericon); Ve-razinc® (Forest); Zinc-220® (Alto); Zincate® (Paddock); generic; (Rx or OTC depending on product) Zinc sulfate is also available in topical ophthalmic preparations. Zolazepam-see Tiletamine HCl/Zolazepam HCl ZONISAMIDE (zoh-niss-a-mide) Zonegran® ANTICONVULSANT Prescriber Highlights TT Antiseizure medication that may be useful as an “add-on” drug for refractory epilepsy TT Half-life of 15 hours makes twice daily dosing possible TT Adverse effect profile not fully elucidated for dogs; seda-tion, ataxia, & inappetence have been reported TT Known teratogen in dogs TT Contraindicated in patients hypersensitive to sulfon-amides TT Expense may be an issue Uses/Indications Zonisamide may be useful as an “add-on” drug for refractory epi-lepsy in dogs. Pharmacology/Actions The exact mechanism of action for zonisamide is not known. It may produce its antiseizure activity by blocking sodium channels and reducing transient inward currents, thereby stabilizing neu-ronal membranes and suppressing neuronal hypersynchronization. It does not appear to potentiate GABA. Zonisamide has weak car-bonic anhydrase inhibitory activity.

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944 ZONISAMIDE Pharmacokinetics In dogs, zonisamide is well absorbed after oral administration and has low protein binding. The elimination half-life in dogs is about 15 hours. Most of the drug is excreted via the kidneys into the urine, but about 20% is metabolized, primarily in the liver. Contraindications/Precautions/Warnings Zonisamide is contraindicated in patients hypersensitive to it or to any of the sulfonamide drugs. Adverse Effects Because there has been limited use of this drug in veterinary pa-tients the adverse effect profile is not fully known. Adverse ef-fects that have been reported in dogs include sedation, ataxia, and inappetence. In humans, the most common adverse effects associated with zonisamide include anorexia, nausea, dizziness, somnolence, agita-tion and headache. Rarely, serious dermatologic reactions (Stevens-Johnson syndrome, TEN), blood dyscrasias, oligohidrosis, and hy-perthermia have been reported in humans. Reproductive/Nursing Safety When zonisamide was administered to pregnant dogs at 10 or 30 mg/kg/day (approximate therapeutic dosages in dogs), ventricu-lar septal defects, cardiomegaly and various valvular and arterial anomalies were seen at the higher dose. A plasma level of 25 mcg/ m L was the threshold level for malformation. If this drug is to be used in pregnant dogs, the owner must accept the significant risks associated with its use. It is not known if zonisamide enters maternal milk; use with caution in nursing animals. Overdosage/Acute Toxicity The LD50 of zonisamide in dogs is reportedly 1 g/kg. In human overdoses, effects reported include coma, bradycardia, hypoten-sion, and respiratory depression. Treatment recommendations in-clude GI evacuation, if ingestion was recent, and supportive thera-py. Because of the drug's long half-life, support may be required for several days. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving zonisamide and may be of significance in veterinary patients: !TPHENOBARBITAL : While there is concern that drugs that induce liv-er enzymes (e. g., phenobarbital) can increase the metabolism and clearance of zonisamide, it is not known if this significantly alters the pharmacokinetics of zonisamide in dogs. Since most dogs subsequently receiving zonisamide have been on phenobarbital chronically and only about 20% of a dose of drug is biotrans-formed, it may not be significant. Laboratory Considerations !TNo specific laboratory interactions or considerations were noted !TWhile plasma concentrations of zonisamide are not routinely monitored in human patients, in dogs, the therapeutic range has been suggested to be from 10-40 mcg/m L Doses !TDOGS: a) For refractory epilepsy: 10 mg/kg q12h PO twice daily (Dew-ey, Guiliano et al. 2003) b) As a secondary anticonvulsant for refractory epilepsy: 8-12 mg/kg PO q8h (Inzana 2004) c) 8-12 mg/kg PO q8-12h (Knipe 2006a) d) Initial dose: 5-10 mg/kg PO q12h; gradual adaptation in dosing is recommended. Reduce phenobarbital doses by 25% at the time of starting zonisamide. (Podell 2006a) Monitoring !TEfficacy !TAdverse effects Client Information !TClients must understand that the clinical use of this agent is relatively “investigational” in veterinary patients, that it must be dosed often in dogs and, also, the potential costs !TCaution clients not to stop therapy abruptly or “rebound” sei-zures may occur !THave clients maintain a seizure diary to help determine efficacy Chemistry/Synonyms A sulfonamide unrelated to other antiseizure drugs, zonisamide oc-curs as a white powder with a p Ka of 10. 2. It is moderately soluble in water (0. 8 mg/m L). Zonisamide may also be known as: AD-810, CI-912, PD-110843, Excegran®, or Zonegran®. Storage/Stability Zonisamide capsules should be stored at 25°C (76°F); excursions permitted to 15-30°C (59-86°F). Store in a dry place and protect-ed from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Zonisamide Capsules: 25 mg, 50 mg & 100 mg; Zonegran® (Eisai); generic; (Rx)

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