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ACARBOSE (ay-kar-bose) Precose® ORAL ANTIDIABETIC Prescriber Highlights TT Antihyperglycemic agent that reduces the rate & amount of glucose absorbed from the gut after a meal; may be useful for mild reductions in blood glucose in dogs or cats TT Contraindications: Underweight animals, known hyper-sensitivity, diabetic ketoacidosis, inflammatory bowel dis-ease, colonic ulceration, partial intestinal obstruction or predis position to obstruction, chronic intestinal disease with mark ed disorder s of digestion or absorption & when excessive gas formation would be detrimental TT Dose-dependent diarrhea & flatulence are the adverse effects most likely to be noted TT Give with meals (preferably right before) TT Expense may be an issue Uses/Indications May be useful for mild reductions in blood glucose concentrations (250-350 mg/dl range) in dogs and cats with non-insulin-depen-dent diabetes mellitus and as adjunctive treatment of insulin de-pendent diabetes mellitus. Pharmacology/Actions Acarbose competitively inhibits pancreatic alpha-amylase and alpha-glucosidases found in the small intestine. This delays the diges tion of complex carbohydrates and disaccharides to glucose and other monosaccharides. Glucose is absorbed lower in the GI tract in lesser amounts than is normal thereby reducing insulin re-quirements during the postprandial hyperglycemic phase. Acarbose has no effect on la ctase. Pharmacokinetics In dogs about 4% of an oral dose is absorbed; in humans only about 2% of an oral dose is absorbed from the gut which is then excreted by the kidneys. Practically all remaining drug in the gut is metabo-lized in the GI tract by intestinal bacteria. Patients with severe re-nal dys function attain serum levels approximately 5 times those of normal subjec ts. Contraindications/Precautions/Warnings Acarbose is contraindicated in patients with known hypersensitiv-ity to the drug, diabetic ketoacidosis, inflammatory bowel disease, colonic ul ce ration, partial intestinal obstruction or predis position to obstruction, chronic intestinal disease with marked disorders of digestion or absorption, and when excessive gas formation would be detrimental. Acarbose is not indicated in patients of low body weight (some say normal body weight as well) as it may have delete-rious effects on nutrition status. Use caution in patients with renal dysfunction o r severe liver disease. Adverse Effects Adverse effects reported in cats include flatulence, soft stools and diarrhea; in dogs, diarrhea and weight loss. Adverse effects are more likely at higher doses. While acarbose alone does not cause hypo glycemia, it may con-tribute to it by reducing the rate and amount of glucose absorbed when the patie nt is receiving other hypoglycemic agents (insulin, oral hypoglycemics). Reproductive/Nursing Safety Safety in pregnancy has not been established; weigh any potential risks versus benefits in pregnant animals. In humans, the FDA cat-egorizes 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. ) Overdosage/Acute Toxicity Acute overdosages are likely to cause only diarrhea and flatulence. No treatment should be necessary. Should acute hypoglycemia occur secondary to other antihy poglycemics, parenteral glucose should be admin istered. If treating orally, use glucose (do not use sucrose). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acarbose and may be of significance in veterinary patients: T ! CHARCOAL : Intestinal adsorbents may reduce the efficacy of acarbose T ! DIGOXIN : Acarbose may reduce digoxin blood concentrations T ! HYPERGLYCEMIC AGENTS (corticosteroids, thiazides, estrogens, phe-nothiazines, thyroid hormones, and calcium chan nel blockers ): May negate the effects of acarbose T ! PANCREATIN, PANCRELIPASE, or AMYLASE : Exogenous enzyme for-mulations may reduce the efficacy of acarbose Laboratory Considerations T ! Increased serum aminotransferase levels have been noted in some humans taking high dosages for a long period Doses T ! DOGS: a)F or dogs poorly controlled with insulin and dietary therapy when another r eason for the poor control cannot be identi-fied: Initially 12. 5-25 mg total dose per dog PO with eachmeal. Give onl y at the time of feeding. May increase dose after two weeks to 50 mg per dog and then to 100 mg perdog (in large dogs, >25 kg) if response has been inadequate. Greater chance of diarrhea at the higher dosages. (Nelson2005) b)12. 5-20 mg (total dose) per meal PO (Daminet 2003) T ! CATS: a)12. 5-25 mg (total dose) PO with meals. When acarbose is used with a lo w carbohydrate diet it may improve glycemic control and reduce insulin dependence. (Scherk 2005c)

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b)12. 5 mg per cat PO twice daily with meals. May be able to reduce insulin dosage and thereby reduce hypoglycemia oc-currence. (Greco 2002b) c)12. 5-20 mg (total dose) per meal PO (Daminet 2003) Monitoring T ! Serum glucose T ! Adverse effects (diarrhea) Client Information T ! Give immedi ately prior to feeding for best results T ! If diarrhea becomes a problem, contact veterinarian T ! Acarbose does not cause low blood sugar, but it may contributeto it if the animal is receiving other hypoglycemic agents (insulin,oral hy p oglycemics) T ! May take up to two weeks for maximal effect Chemistry/Synonyms A complex oligosaccharide antihyperglycemic agent, acarbose oc-curs as white to off-white powder, is soluble in water and has a p Ka of 5. 1. Acarb ose may also be known as: Bay-g-5421, Precose®, Asucrose ®, Glicob ase®, Glucobay®, Glucor®, Glumida®, or Prandase®. Storage/Stability Do not store tablets above 25°C (77°F); protect from moisture. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED P RODUCTS: Acarbose Tablets: 25 mg, 50 mg & 100 mg; Precose® (Bayer); (Rx) ACEMANNAN (ase-man-in) NON-SPECIFIC IMMUNO STIMULANT/ANTIVIRAL Prescriber Highlights TT Non-specific injectable immunostimulant that has been tried in Fe LV-, FIV, or FIP-positive cats, & vaccine-induced fibrosarcomas (intralesional) TT Use is controversial; little, if any controlled study docu-mentation supporting efficacy in veterinary medicine TT Adverse effects include: Possible hypersensitivity reac-tions; bolus IV administration can cause salivation, weak-ness, collapse, tachycardia, tachypnea; intralesional in-jection can cause prolonged pain at site; intraperitoneal injection can cause monocyte infiltrates on peritoneal surfaces, liver, & spleen TT Topical products available; potentially can reduce wound healing time Uses/Indications Veterinary acemannan injection is labeled for use in dogs or cats as an aid in the treatment (i. e., surgery) and clinical management of fibrosarcoma. It has been used to treat Fe LV, FIV, and FIP infections in cats but clinical efficacy has not been adequately proven by con-trolled clinical studies. It reportedly has been used in horses, but no specific infor mation on this was located. Pharmacology/Actions Acemannan's immunostimulant activity is thought as a result of in-ducing increases in TNF-alpha and IL-1. At injection sites, increased lymphocy tic infiltration and accumulation have been noted. In tis-sue cultures, acemannan has suppressed HIV replication. Pharmacokinetics No information was located. Contraindications/Precautions/Warnings The manufacturer lists no contraindications to using acemannan, however, it should not be used in patients who have demonstrated past severe hypersensitivity reactions to it. Adverse Effects While the manufacturer does not list any specific adverse effects associated with use, hypersensitivity or localized injection re-actions are possible. Bolus IV administration can cause saliva-tion, weakness, collapse, hypotension, tachycardia and tachypnea. Intralesional injection can cause prolonged pain at the injection site. Intraperitoneal injection can cause monocyte infiltrates on peritoneal surfaces, liver, and spleen. Reproductive/Nursing Safety No specific information was located on reproductive or nursing safety. The product label states, “The effects of this compound have not been studied in pregnant animals” and, also, “... the chemical nature of acemannan and the absence of significant toxicity in sev-eral animal species suggest the compound is not a teratogen. ” Overdosage/Acute Toxicity Single IP injections of 50 mg/kg in dogs resulted in no significant signs of toxicity. Acemannan fed orally to dogs at rates of up to 1. 5 g/kg/day for 90 days showed no significant effects. Drug Interactions None were identified. Laboratory Considerations None were identified. Doses T ! DOGS/CATS: For labeled indications (aid in treatment and management of fibrosarcoma): a)Prior to use, reconstitute with 10 m L sterile diluent. Five to10 minutes may be necessary for complete dissolution. Shake well before using. Use within 4 hours after rehydration. Ad-minister by concurrent intraperitoneal (IP) and intralesionalinjections weekly for a minimum of 6 treatments. Recom-mended IP dose is 1 mg/kg. Recommended intralesionaldose is 2 mg injected deep into each tumor mass. When used as a prelude to surgery, give concurrent IP and intralesionalinjections weekly. Continue until delineation, necrosis ormaximum tumor enlargement due to edema and immunecellular infiltration occur. Rapid necrosis, which accompa-nies this response, may happen within 2 to 4 weeks. Surgicalexcision is recommended immediately upon delineation, ne-crosis or maximum tumor enlargement. (Label Information;Acemannan Imm unostimulant—VPL) Monitoring T ! Clinical efficacy T ! Adverse effects (most likely local reactions)

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

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

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

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

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monitoring may be warranted, particularly when clinical signs occur. Client Information T ! Follow directions carefully; do not exceed dosage or increase dos-ing frequency. Do not administer to cats or ferrets for any reason. Keep out of reach of children. Chemistry/Synonyms A synthetic non-opiate analgesic, acetaminophen (also known as paracetamol) occurs as a crystalline, white powder with a slightly bitter taste. It is soluble in boiling water and freely soluble in alco-hol. Acetaminophen is known in the U. K. as paracetamol. Acetaminophen may also be known as: paracetamol, MAPAP or APAP; man y trade names are available. Storage/Stability Acetaminophen products should be stored at temperatures less than 40°C. Do not freeze oral solution or suspension. Dosage Forms/Regulatory Status 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: There are many different trade names and products of acetamino-phen available. The most commonly known trade name is Tyleno l®. Acetaminophen is commonly available in, 325 mg, 500 mg, 650 mg tablets; 80 mg chewable tablets; 650 mg extended release tablets; 160mg, 500 mg, & 650 mg caplets; 500 mg gelcaps; 325 mg, & 500 mg capsules, 80 mg and 160 mg sprinkle capsules; 80 mg/0. 8 m L drops; 80 mg/2. 5 m L, 80 mg/5 m L, 120 mg/5 m L, & 160 mg/5 m L elixirs; 160 mg/5 m L, 500 mg/15 m L, and 100 mg/m L liquids and solutions; 80 mg, 120 mg, 125 mg 300 mg, 325 mg and 650 mg sup-positories. Combinations with other analgesics (aspirin, codeine phosphate, oxycodone or propoxyphene) are also available. ACETAZOLAMIDE ACETAZOLAMIDE SODIUM (ah-seet-a-zole-a-mide) Diamox®, Dazamide® CARBONIC ANHYDRASE INHIBITOR DIURETIC; ANTIGLAUCOMA AGENT Prescriber Highlights TT Used primarily for metabolic alkalosis or glaucoma in small animals; HYPP in horses TT Contraindicated in patients with significant hepatic, renal, pulmonary or adrenocortical insufficiency, hypona-tremia, hypokalemia, hyperchloremic acidosis or electro-lyte imbalance TT Give oral doses with food if GI upset occurs TT Electrolytes & acid/base status should be monitored with chronic or high dose therapy TT Monitor with tonometry if using for glaucoma Uses/Indications Acetazolamide has been used principally in veterinary medicine for its effects on aqueous humor production in the treatment of glaucoma, metabolic alkalosis, and for its diuretic action. It may be useful as an adjunctive treatment for syringomyelia in dogs. Acetazolamide's use in small animals is complicated by a relatively high occurrence of adverse effects. In horses, acetazolamide is used as an adjunctive treatment for hype rkalemic periodic paralysis (HYPP). In humans, the drug has been used as adjunctive therapy for epi-lepsy and for acute high-altitude sickness. Pharmacology/Actions The carbonic anhydrase inhibitors act by a noncompetitive, revers-ible inhibition of the enzyme carbonic anhydrase. This reduces the format ion of hydrogen and bicarbonate ions from carbon dioxide thereby reducing the availability of these ions for active transport into body secretions. Pharmacologic effects of the carbonic anhydrase inhibitors in-clude: decreased formation of aqueous humor, thus reducing in-traocular pressure, increased renal tubular secretion of sodium and potassium and, to a greater extent, bicarbonate, leading to increased urine alkalinity and volume. Acetazolamide has some anticon-vulsant activity, which is independent of its diuretic effects (mecha-nism is not fully understood, but may be due to carbonic anhydrase or a metabolic a cidosis effect). Pharmacokinetics The pharmacokinetics of this agent have apparently not been stud-ied in domestic animals. One report (Roberts 1985) states that after a dose o f 22 mg/kg, the onset of action is 30 minutes; maximal ef-fects occur in 2-4 hours; duration of action is about 4-6 hours in small animals. In h umans, the drug is well absorbed after oral administra-tion with peak levels occurring within 1-3 hours. It is distributed throughout the body with highest levels found in the kidneys, plas-ma and erythrocytes. Acetazolamide has been detected in the milk of lac tating dogs and it crosses the placenta (in unknown quanti-ties). Within 24 hours of administration, an average of 90% of the drug is e xcreted unchanged into the urine by tubular secretion and passive reabsorption processes. Contraindications/Precautions/Warnings Carbonic anhydrase inhibitors are contraindicated in patients with significant hepatic disease (may precipitate hepatic coma), renal or adrenocortical insufficiency, hyponatremia, hypokalemia, hyper-chloremic acidosis, or electrolyte imbalance. They should not be used in pat ients with severe pulmonary obstruction that are unable to increase alveolar ventilation or in those who are hypersensitive to them. Long-term use of carbonic anhydrase inhibitors is con-traindicated in patients with chronic, noncongestive, angle-closure glaucoma as angle closure may occur and the drug may mask the condition by lowering intraocular pressures. Acetazolamide should be used with caution in patients with se-vere respiratory acidosis or having preexisting hematologic abnor-malities. Cross sensitivity between acetazolamide and antibacterial sulfonamid es may occur. Adverse Effects Potential adverse effects that may be encountered include: GI distur-bances, CNS effects (sedation, depression, weakness, excitement, etc. ), he matologic effects (bone marrow depression), renal effects (crystalluria, dysuria, renal colic, polyuria), hypokalemia, hypergly-cemia, hyponatremia, hyperuricemia, hepatic insufficiency, derma-tologic effects (rash, etc. ), and hypersensitivity reactions.

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At the dosages used for HYPP in horses adverse effects are report-edly uncommon. Reproductive/Nursing Safety Acetazolamide has been implicated in fetal abnormalities in mice and rats when used at high (10X) dosages) and fetal toxicity has been noted when the drug has been used in pregnant humans. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In humans, the manufacturer states that either nursing or the drug must be discontinued if the mother is receiving acetazolamide. Veterinary significance is not clear. Overdosage/Acute Toxicity Information regarding overdosage of this drug was not locat-ed. Monitor serum electrolytes, blood gases, volume status, and CNS stat us during an acute overdose; treat symptomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving acetazolamide and may be of significance in veterinary patients: !!ALKALINE URINE : Drugs where acetazolamide-caused alkaline urine may affect their excretion rate: Decreased urinary excretion of quinidine, procainamide, tricyclic antidepressants; Increased urinary excretion of salicylates, phenobarbital !!ASPIRIN (or other salicylates ): Increased risk of acetazolamide ac-cumulation and toxicity; increased risk for metabolic acidosis !!DIGOXIN : As acetazolamide may cause hypokalemia, increased risk for toxicity !TINSULIN: Rarely, carbonic anhydrase inhibitors interfere with the hypoglycemic effects of insulin !!METHENAMINE COMPOUNDS : Acetazolamide may negate methe-namine effects in the urine !!DRUGS AFFECTING POTASSIUM (corticosteroids, amphotericin B, corti-cotropin, or other diuretics ): Concomitant use may exacerbate po-tassium depletion !!PRIMIDONE : Decreased primidone concentrations Laboratory Considerations !TBy alkalinizing the urine, carbonic anhydrase inhibitors may cause false positive results in determining urine protein when us-ing bromphenol blue reagent (Albustix®, A lbutest®, Labstix®), sul-fosalicylic acid (Bumintest®, E xton's Test Reagent), nitric acid ring test, or heat and acetic acid test methods !TCarbonic anhydrase inhibitors may decrease iodine uptake by the thyroid gland in hyperthyroid or euthyroid patients Doses Directions for reconstitution of injection: Reconstitute 500 mg vial with at least 5 m L of Sterile Water for Injection; use within 24 hours after reconstitution. !TDOGS: For adjunctive treatment of metabolic alkalosis: a) 10 mg/kg four times daily (may aggravate volume contraction and hypokalemia) (Hardy and Robinson 1986) Fo r adjunctive therapy of glaucoma: a) 10-25 mg/kg divided 2-3 times daily (Brooks 2002a) b) 50-75 mg/kg PO 2-3 times a day (Bedford 2003) c) 50 mg/kg IV one time; 7 mg/kg, PO three times daily (Vestre 1985) Fo r adjunctive therapy of hydrocephalus in pediatric patients: a) 0. 1 mg/kg PO q8h (Coates 2002) !TCATS: For adjunctive therapy of glaucoma: a) 50 mg/kg IV once; 7 mg/kg, PO three times daily (Vestre 1985) !THORSES: (Note : ARCI UCGFS Class 4 Drug) For adjunctive therapy of hyperkalemic periodic paralysis (HYPP): a) 2. 2-4. 4 mg/kg PO twice daily (Schott II 2004) b) 0. 5-2. 2 mg/kg PO twice daily (Mayhew 2005a) c) 3 mg/kg PO (dosing interval not specified) (Harris and May-hew 1998) !TRUMINANTS: a) 6-8 mg/kg IV, IM, or SC (Howard 1986) !TSWINE: a) 6-8 mg/kg IV, IM, or SC (Howard 1986) Monitoring !TIntraocular pressure tonometry (if used for glaucoma) !TBlood gases if used for alkalosis !TSerum electrolytes !TBaseline CBC with differential and periodic retests if using chron-ically !TOther adverse effects Client Information !TGive with food if using oral preparation and GI upset occurs !TNotify veterinarian if abnormal bleeding or bruising occurs or if animal develops tremors or a rash Chemistry/Synonyms A carbonic anhydrase inhibitor, acetazolamide occurs as a white to faintly yellowish-white, odorless, crystalline powder with p K as of 7. 4 and 9. 1. It is very slightly soluble in water, sparingly soluble in hot wat er (90-100°C) and alcohol. Acetazolamide sodium occurs as a white lyophilized solid and is freely soluble in water. The injection has a p H of 9. 2 after reconstitution with Sterile Water for Injection. Acetazolamide may also known as: acetazolam, acetazolamidum, or so dium acetazolamide; many trade names are available. Storage/Stability/Compatibility Acetazolamide products should be stored at room temperature. T o prepare parenteral solution: reconstitute with at least 5 m L of Sterile Water for Injection. After reconstitution, the injection is stable for one week when refrigerated, but as it contains no preserva-tives, it should be used within 24 hours. Acetazolamide sodium for injection is reportedly physically com-patible with all commonly used IV solutions and cimetidine HCl for injection. Dosage Forms/Regulatory Status 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: Acetazolamide Tablets: 125 mg, 250 mg; generic; (Rx) Acetazolamide Sustained-Release Capsules: 500 mg; Diamo x Se-quels® (Barr); (Rx)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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the kidneys into the urine; only about 1% of the drug is excreted unchanged into the urine. T otal body clearance in humans ranges from 1. 6-17. 6 m L/minute/kg. Clearance is decreased by about 50% in patients with alcoholic cirrhosis or in those that are obese. Clearance is reduced by approximately 30% in geriatric patients. Elimination half-life in humans is about 100 minutes. Contraindications/Precautions/Warnings Alfentanil is contraindicated in patients hypersensitive to opioids. Because of the drug's potency and potential for significant adverse effects, it should only be used in situations where patient vital signs can be continuously monitored. Initial dosage reduction may be required in geriatric or debilitated patients, particularly those with diminished cardiopulmonary function. Adverse Effects Adverse effects are generally dose related and consistent with other opiate agonists. Respiratory depression, and CNS depression are most likely to be encountered. In humans, bradycardia that is usu-ally responsive to anticholinergic agents can occur. Dose-related ske letal muscle rigidity is not uncommon and neuromuscular blockers are routinely used. Alfentanil has rarely been associated with asystole, hypercarbia and hypersensitivity reactions. Respiratory or CNS depression may be exacerbated if alfentanil is gi ven with other drugs that can cause those effects. Reproductive/Nursing Safety In humans, the FDA categorizes alfentanil as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). If alfentanil is administered systemically to the mother close to giv-ing birth, offspring may show behavioral alterations (hypotonia, de pression) associated with opioids. Although high dosages given for 10-30 days to laboratory animals have been associated with embryotoxicity, it is unclear if this is a result of direct effects of the drug or as a result of maternal toxicity secondary to reduced food and water intake. The effects of alfentanil on lactation or its safety for nursing off-spring is not well defined, but it is unlikely to cause significant ef-fects when used during anesthetic procedures in the mother. Overdosage/Acute Toxicity Intravenous, severe overdosages may cause circulatory collapse, pulmonary edema, seizures, cardiac arrest and death. Less severe overdoses may cause CNS and respiratory depression, coma, hy-potension, muscle flaccidity and miosis. Treatment is a combina-tion of supportive therapy, as necessary, and the administration of an o piate antagonist such as naloxone. Although alfentanil has a relatively rapid half-life, multiple doses of naloxone may be neces-sary. Because of the drug's potency, the use of a tuberculin syringe to measure dosages less than 1 m L with a dosage calculation and measurement double-check system, are recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving alfentanil and may be of significance in veterinary patients: !!DRUGS THAT INHIBIT HEPATIC ISOENZYME C YP3A4, such as erythromy-cin, cimetidine, ketoconazole, itraconazole, fluconazole or diltiazem : May increase the half-life and decrease the clearance of alfentanil leading to prolonged effect and an increased risk of respiratory depression !!DRUGS THAT DEPRESS CARDIAC FUNCTION OR REDUCE VAGAL TONE, such as beta-blockers or other anesthetic agents : May produce bra-dycardia or hypotension if used concurrently with alfentanil Laboratory Considerations !TPatients receiving opiates may have increased plasma levels of amy-lase or lipase secondary to increased biliary tract pressure. Values may be unreliable for 24 hours after administration of alfentanil. Doses (Note : in very obese patients, figure dosages based upon lean body weight. ) !TDOGS: As a premed: a) 5 mcg/kg alfentanil with 0. 3-0. 6 mg of atropine IV 30 sec-onds before injecting propofol can reduce the dose of propo-fol needed to induce anesthesia to 2 mg/kg, but apnea may stil l occur. (Hall, Clarke et al. 2001b) As an analgesic supplement to anesthesia: a) 2-5 mcg/kg IV q20 minutes. (Hall, Clarke et al. 2001b), (Hal l, Clarke et al. 2001a) b) For intra-operative analgesia in patients with intracranial disease: 0. 2 mcg/kg/min ute (Raisis 2005) Monitoring !TAnesthetic and/or analgesic efficacy !TCardiac and respiratory rate !TPulse oximetry or other methods to measure blood oxygenation when used for anesthesia Client Information !TAlfentanil is a potent opiate that should only be used by pro-fessionals in a setting where adequate patient monitoring is av ailable Chemistry/Synonyms A phenylpiperidine opioid anesthetic-analgesic related to fenta-nyl, alfentanil HCl occurs as a white to almost white powder. It is fre ely soluble in alcohol, water, chloroform or methanol. The com-mercially available injection has a p H of 4-6 and contains sodium chlo ride for isotonicity. Alfentanil is more lipid soluble than mor-phine, but less so than fentanyl. Alfentanil may also be known as: alfentanyl, Alf enta®, Fanaxal®, Fentalim®, Limifen®, or Rapifen®. Storage/Stability/Compatibility Alfentanil injection should be stored protected from light at room temperature. In concentrations of up to 80 mcg/m L, alfentanil in-jection has been shown to be compatible with Normal Saline, D5 in No rmal Saline, D5W, and Lactated Ringers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 1 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Alfentanil HCl for injection: 500 mcg/m L in 2 m L, 5 m L, 10 m L, and 20 m L amps; preservative free; Alfenta® (Akorn); Alfentanil HCl (Abbott); (Rx, C-II).

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

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Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving allopurinol and may be of significance in veterinary patients: !!AMINOPHYLLINE or THEOPHYLLINE : Large doses of allopurinol may decrease metabolism thereby increasing their serum levels !!AMOXICILLIN or AMPICILLIN : In humans, concomitant use with al-lopurinol has been implicated in increased occurrences of skin rashes; the veterinary significance of this interaction is unknown !!AZATHIOPRINE or MERCAPTOPURINE : Allopurinol may inhibit me-tabolism and increase toxicity; if concurrent use is necessary, dosag es of the antineoplastic/immunosuppressive agent should be reduced initially to 25-33% of their usual dose and then ad-justed, dependent upon patient's response !!CHLORPROPAMIDE : Allopurinol may increase risks for hypoglyce-mia and hepato-renal reactions !!CYCL OPHOSPHAM IDE: Increased bone marrow depression may oc-cur in patients receiving both allop urinol and cy clophosphamide !!CYCLOSPORINE : Allopurinol may increase cyclosporine levels !!DIURETICS (Furosemide, Thiazides, Diazoxide, and Alcohol ): Can in-crease uric acid levels !!ORAL ANTICOAGULANTS (e. g., Warfarin ): Allopurinol may reduce the metabolism of warfarin thereby increasing effect !!TRIMETHOPRIM/SULFA METHOXAZOLE : In a few human patients, thrombocytopenia has occurred when used with allopurinol !!URICOSURIC AGENTS (e. g., Probenecid, Sulfinpyrazone ): May increase the renal excretion of oxypurinol and thereby reduce xanthine oxidase inhibition; in treating hyperuricemia the additive effects on blood uric acid may, in fact, be beneficial to the patient !!URINARY ACIDIFIERS (e. g., Methionine, Ammonium Chloride ) May re-duce the solubility of uric acid in the urine and induce urolithiasis Doses !TDOGS: For urate uroliths: a) 7-10 mg/kg PO three times daily for both dissolution and pr evention. Goal is to reduce urine urate:creatinine ratio by 50%. (Senior 1989) b) For dissolution: 15 mg/kg PO q12h; only in conjunction with low purine foods. Fo r prevention: 10-20 mg/kg/day; because prolonged high doses of allopurinol may result in xanthine uroliths, it may be preferable to minimize recurrence with dietary therapy, with the option of treating infrequent episodes of urate uro-lith formation with dissolution protocols. (Osborne, Lulich et al. 2003a) c) Alkalinize urine to a p H of 6. 5-7 (see sodium bicarbonate mono graph), give low purine diet and eliminate any UTI. Al-lopurinol at 10 mg/kg three times daily for the first month, then 10 mg/kg once daily thereafter. Reduce dose in patients with renal failure. (Polzin and Osborne 1985), (Lage, Polzin, and Zenoble 1988) For Leishmaniasis: a) 15 mg/kg PO twice daily for months (Lappin 2000) b) If possible use with meglumine antimoniate, if not, use al-lopurinol alone at 10 mg/kg PO twice daily. If animal has re-nal insufficiency, use at 5 mg/kg PO twice daily. (Font 1999) c) Meglumine antimoniate (100 mg/kg/day SQ) until resolu-tion, with allopurinol at 20 mg/kg PO q12h for 9 months. An alternate protocol using allopurinol alone: allopurinol 10 mg/kg PO q8h or 10-20 mg/kg PO q12h for 1-4 months. (Brosey 2005) !TCATS: For urate uroliths: a) 9 mg/kg PO per day (Schultz 1986) !TBIRDS: For gout: a) In budgies and cockatiels: Crush one 100 mg tablet into 10 m L o f water. Add 20 drops of this solution to one ounce of drinking water. (Mc Donald 1989) b) For parakeets: Crush one 100 mg tablet into 10 m L of water. Add 20 drops of this solution to one ounce of drinking water or give 1 drop 4 times daily. (Clubb 1986) !TREPTILES: a) For elevated uric acid levels in renal disease in lizards: 20 mg/ kg PO onc e daily (de la Navarre 2003a) b) For gout: 20 mg/kg PO once daily. Suggested dosage based upo n human data as dose is not established for reptiles. (Johnson-Delaney 2005d) Monitoring !TUrine uric acid (for urolithiasis) !TAdverse effects !TPeriodic CBC, liver and renal function tests ( e. g., BUN, Creati-nine, liver enzymes); especially early in therapy Client Information !TUnless otherwise directed, administer after meals (usually 1 hour or so). Notify veterinarian if animal develops a rash, becomes le-thargic or ill. Chemistry/Synonyms A xanthine oxidase inhibitor, allopurinol occurs as a tasteless, fluffy white to off-white powder with a slight odor. It melts above 300° with decomposition and has an apparent p K a of 9. 4. Oxypurinol (aka oxipurinol, alloxanthine), its active metabolite, has a p K a of 7. 7. Allopuri nol is only very slightly soluble in both water and alcohol. Allopurinol may also be known as: allopurinolum, BW-56-158, HPP, or NSC-1390; many trade names are available. Storage/Stability/Compatibility Allopurinol tablets should be stored at room temperature in well-closed containers. The drug is stated to be stable in both light and air. The powder for injection should be stored at 25°C; may be ex-posed to 15-30°C. Once diluted to a concentration ≤ 6 mg/m L, store at room temperature and use within 10 hours; do not refriger-ate. Compatible IV solutions include D5W and normal saline. An extemporaneously prepared suspension containing 20 mg/ m L al lopurinol for oral use can be prepared from the commercially available tablets. Tablets are crushed and mixed with an amount of Cologel® suspending agent equal to N the final volume. A mixture of simple syrup and wild cherry syrup at a ratio of 2:1 is added to produce the final volume. This preparation has been reported to be stable for at least 14 days when stored in an amber bottle at either room temperature or when refrigerated. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Allopurinol Tablets: 100 mg & 300 mg; Zyloprim® (Glaxo Well-come); generic; (Rx) Allopurinol Powder for Injection: 500 mg preservative-free in 30 m L via ls; Aloprim ® (Nabi); Allopurinol Sodium (Bedford Labs); (Rx)

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

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T! !ANTACIDS : May slow the rate, but not the extent of oral absorption of alprazolam; administer 2 hours apart to avoid this potential interaction ! !CNS DEPRESSANT AGENTS (barbiturates, narcotics, anesthetics, etc. ): Additive effects may occur ! !DIGOXIN : Serum levels may be increased; monitor serum digoxin levels or clinical signs of toxicity ! !FLUOXETINE, FLUVOXAMINE : Increased alprazolam levels ! !HEPATICALLY METABOLIZED DRUGS (e. g., cimetidine, erythromycin, iso-niazid, ketoconazole, itraconazole ): Metabolism of alprazolam may be decreased and excessive sedation may occur ! !RIFAMPIN: May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines ! !TRICYCLIC ANTIDEPRESSANTS (e. g., amitriptyline, clomipramine, imip-ramine ): Alprazolam may increase levels of these drugs; clinical significance is not known and some state that clomipramine and alprazolam together may improve efficacy for phobias (e. g., thunderstorm phobia) Doses T ! DOGS: a) For treatment of canine anxiety disorders: 0. 01-0. 1 mg/kg PO as nee ded for panic, not to exceed 4 mg/dog/day. Start with 1-2 mg (total dose) for a medium-sized dog. (Overall 1997) b) For separation anxiety: 0. 25 mg-2 mg (total dose) once daily to three t imes daily PO. (Hunthausen 2006) c) For storm phobias: 0. 02-0. 4 mg/kg PO q4h as needed; helps to minimize impact of experiencing a severe storm (Crowell-Davis 2003c); 0. 02 mg/kg PO as needed one hour before anticipated storm and eve ry 4 hours as needed; used as an adjunct after behav-ior modification and prior clomipramine treatment (see clo-mipramine monograph for further information) (Crowell-Davis 2003d) d) Fo r phobias, night waking: 0. 01-0. 1 mg/kg or 0. 25-2 mg (total dose) pe r dog PO q6-12h PO (Siebert 2003c) T ! CATS: a) For treatment of feline anxiety disorders: 0. 125-0. 25 mg/kg PO q12h (Start at 0. 125 mg/kg PO) (Ove rall 1997) b) For refractory house soiling: 0. 1 mg/kg or 0. 125-0. 25 mg (total dose) pe r cat PO q8-12h (Siebert 2003c) c) For urine marking: 0. 05-0. 2 mg/kg PO q12-24h (Virga 2002) d) For fears/phobias/anxieties: 0. 125-0. 25 mg (total dose) PO once to thr ee times a day. (Landsberg 2005a) Monitoring T ! Efficacy T ! Adverse Effects T ! Consider monitoring hepatic enzymes particularly when treating cats chronically Client Information T ! ry to dose approximately one hour in advance of storms or oth-er anticipated stimuli that evokes negative responses T ! If difficulty with pilling the medication occurs, consider using the orally-disintegrating tablets; hands must be dry before handling T ! If excessive sedation or yellowing of the whites of eyes (especially in cats) occurs, contact veterinarian Chemistry/Synonyms A benzodiazepine, alprazolam occurs as a white to off-white, crys-talline powder. It is soluble in alcohol and insoluble in water. Alprazolam may also be known as D65 MT, U 31889, or alprazo-lamum; many trade names available internationally. Storage/Stability Alprazolam tablets should be stored at room temperature in tight, light-resistant containers. The orally disintegrating tablets should be stored at room temperature and protected from moisture. Dosage Forms/Regulatory Status 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: Alprazolam Tablets: 0. 25 mg, 0. 5 mg, 1 mg & 2 mg; Xanax®(Pfizer); generic; (Rx; C-IV) Alprazolam Extended-release Tablets: 0. 5 mg, 1 mg, 2 mg, & 3 mg; Xanax XR® (Pfize r); generic; (Rx; C-IV) Alprazolam Orally Disintegrating Tablets: 0. 25 mg, 0. 5 mg, 1 mg, & 2 mg; Nirav am® (Pfizer); (Rx; C-IV) Alprazolam Oral Solution: 1 mg/m L in 30 m L; Alpraz olam Inten-sol® (Roxane); (Rx; C-IV) ALTRENOGEST (al-tre-noe-jest) Regu-Mate®, Matrix® ORAL PROGESTIN Prescriber Highlights TT Progestational drug used in horses to suppress estrus or maintain pregnancy when progestin deficient; used in swine to synchronize estrus TT May be used in dogs for luteal deficiency or as a treat-ment to prevent premature delivery TT Many “handling” warnings for humans (see below) TT Very sensitive to light Uses/Indications Altrenogest (Regu-Mate®) is indicated (labeled) to suppress estrus in mares to allow a more predictable occurrence of estrus following withdrawal of the drug. It is used clinically to assist mares to es-tablish normal cycles during the transitional period from anestrus to the no rmal breeding season often in conjunction with an artifi-cial photoperiod. It is more effective in assisting in pregnancy at-tainment later in the transition period. Some authors (Squires et al. 1983) sug gest selecting mares with considerable follicular activ-ity (mares with one or more follicles 20 mm or greater in size) for treatme nt during the transitional phase. Mares that have been in estrus for 10 days or more and have active ovaries are also consid-ered excellent candidates for progestin treatment. Altrenogest is effective in normally cycling mares for minimizing the necessit y for estrus detection, for the synchronization of estrus, and permitting scheduled breeding. Estrus will ensue 2-5 days af-ter treatment is completed and most mares ovulate between 8-15 days aft er withdrawal. Altrenogest is also effective in suppressing

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

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TT ! Altrenogest can be absorbed after skin contact and absorption can be enhanced if the drug is covered by occlusive materials (e. g., under latex gloves, etc. ). If exposed to the skin, wash off im-mediately with soap and water. If the eyes are exposed, flush with water f or 15 minutes and get medical attention. If the product is swallowed, do not induce vomiting and contact a physician or poison control center. T ! his medication is prohibited from use in an extra-label manner to enhance food and/or fiber production in animals Chemistry/Synonyms An orally administered synthetic progestational agent, altrenogest has a chemical name of 17 alpha-Allyl-17beta-hydroxyestra-4,9,11-trien-3-one. Altrenogest may also be known as: allyl trenbolone, A-35957, A-41300, RH-2267, o r RU-2267, Regu-Mate®, or Matrix®. Storage/Stability Altrenogest oral solution should be stored at room temperature. Altrenogest is extremely sensitive to light; dispense in light-resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Altrenogest 0. 22% (2. 2 mg/m L) in oil solution in 150 m L and 1000 m L bottles; Regu-Mate®(Intervet); (Rx). Approved for use in horses not intended for food. This medication is banned in racing animals in some countries. Altrenogest 0. 22% (2. 2 mg/m L) in 1000 m L bottles; Matrix ® (In-tervet); (OTC, but extra-label use prohibited). Approved for use in sexually mature gilts that have had at least one estrous cycle. Gilts must not be slaughtered for human consumption for 21 days af-ter the last treatment. The FDA prohibits the extra-label use of this medication t o enhance food and/or fiber production in animals. HUMAN-LABELED PRODUCTS: None ALUMINUM HYDROXIDE (ah-loo-min-um hye-droks-ide) Amphogel® ORAL ANTACID/PHOSPHATE BINDER Prescriber Highlights TT Used to treat hyperphosphatemia in small animal pa-tients & sometimes as a gastric antacid for ulcers TT Chronic use may lead to electrolyte abnormalities; pos-sible aluminum toxicity TT Many potential drug interactions TT Availability has been an issue Uses/Indications Orally administered aluminum hydroxide is used to reduce hyper-phosphatemia in patients with renal failure. Pharmacology/Actions Aluminum salts reduce the amount of phosphorus absorbed from the intestine by physically binding to dietary phosphorus. Contraindications/Precautions/Warnings Aluminum-containing antacids may inhibit gastric emptying; use cautiously in patients with gastric outlet obstruction. Adverse Effects In small animals, the most likely side effect of aluminum hydrox-ide is constipation. If the patient is receiving a low phosphate diet and the patie nt chronically receives aluminum antacids, hypophos-phatemia can develop. Potentially, aluminum toxicity could occur with pr olonged use but is thought unlikely to occur in small animal patients. Reproductive/Nursing Safety In a system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), these drugs are categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse ef-fects in laboratory animals or women. ) Overdosage/Acute Toxicity Acute toxicity is unlikely with an oral overdose. If necessary, GI and electrolyte imbalances that occur with chronic or acute overdose should be treated symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving oral aluminum salts and may be of significance in veterinary patients: Aluminum salts can decrease the amount absorbed or the pharma-cologic effect of: ! !ALLOPURINOL ! !CHLOROQUINE ! !CORTICOSTEROIDS ! !DIGOXIN ! !ETHAMBUTOL ! !FLUOROQUINOLONES ! !H-2 ANTAGONISTS (RANITIDINE, FA MOTIDINE, etc. ) ! !IRON SALTS ! !ISONIAZID ! !PENICILLAMINE ! !PHENOTHIAZINES ! !TETRACYCLINES ! !THYROID HORMONES Separate oral doses of aluminum hydroxide and these drugs by two hours to help reduce this interaction. Doses T ! DOGS: For hyperphosphatemia: a) Aluminum hydroxide: Initially at 30-90 mg/kg per day. Dos-age must be individualized. Capsules or suspension are pre-ferred as they are more easily mixed with food and dispersed throughout ingesta. Evaluate serum phosphate levels at 10-14 day intervals to determine optimum dosage. (Polzin and Osborne 1985) b) Aluminum hydroxide: 30-90 mg/kg PO once a day to three times a day with meals (M organ 1988) c) 15-45 mg/kg PO q12h (Bartges 2002c) For adj unctive therapy for gastric ulcers: a) Aluminum hydroxide suspension or aluminum hydroxide/ magnesium h ydroxide suspension: 2-10 m L PO q2-4h (Hall and Twedt 1988) b) Aluminum hydroxide tablets: 0. 5-1 tablet PO q6h (Matz 1995)

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

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

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

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

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

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

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Laboratory Considerations T ! Serum potassium may be elevated by aminocaproic acid, especially in patients with preexisting renal failure Doses T ! DOGS: For adjunctive treatment of degenerative myelopathy (seen pri-marily in German shepherds): a) In combination with exercise, vitamin support (vitamin B-complex, vitamin E), and analgesia (if required; using acet-aminophen): Aminocaproic acid: 500 mg (regardless of size of animal, ap proximate dose is 15 mg/kg) PO q8h. Mix 192 m L of the 250 mg/m L injection with 96 m L of hematinic compound (e. g., Lixotinic®) producing a 288 m L final vol-ume. Give 3 m L per dose (500 mg). Store solution in refriger-ator. Clinical improvement seen within 8 weeks. (Clemmons 1991) b) Aminocaproic acid 500 mg/dog PO q8h indefinitely. Used in conj unction with acetylcysteine at 25 mg/kg PO q8h for 2 weeks, then q8h every other day. The 20% solution should be diluted to 5% with chicken broth or suitable diluent. Other treatments may include prednisone (0. 25-0. 5 mg/kg PO daily for 10 days then every other day), Vitamin C (1000 mg PO q12h) and Vitamin E (1000 Int. Units PO q12). Note : No treatment has been shown to be effective in published trials. (Shell 2003a) As an antifibrinolytic: a) No published doses for dogs, but has been used anecdotally at 50-100 mg/kg IV or PO q6h. (Hopper 2006b) Client Information T ! Drug costs to treat a German shepherd-sized dog can be substantial T ! As no well controlled studies have documented that this drug is effective for treating degenerative myelopathy, its use should be considered investigational Chemistry/Synonyms An inhibitor of fibrinolysis, aminocaproic acid is a synthetic monamino carboxylic acid occurring as a fine, white crystalline powder. It is slightly soluble in alcohol and freely soluble in water and has p Ka's of 4. 43 and 10. 75. The injectable product has its p H adjusted to approximately 6. 8. Aminocaproic acid may also be known as: acidum aminocap-roicum, CL-10304 CY-116, EACA, epsilon aminocaproic acid, JD-177, NSC-26154, Amicar®, Cap racid®, Capramol®, Caproamin®, Caprolisin®, Epsicaprom®, Hemocaprol®, Hemocid®, Hexalense®, or Ipsilon®. Storage/Stability/Compatibility Products should be stored at room temperature. Avoid freezing liq-uid preparations. Discoloration will occur if aldehydes or aldehydic sugars are present. When given as an intravenous infusion, normal saline, D 5W and Ringer's Injection have been recommended for use as the infusion diluent. 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: Aminocaproic Acid Tablets: 500 mg & 1000 mg; Amicar® (Xano-dyne); Aminocaproic Acid (Versa Pharm); (Rx) Aminocaproic Oral Solution: 250 mg/m L in 237 m L & 473 m L; Aminocapr oic Acid (Versa Pharm); (Rx) Aminocaproic Syrup: 250 mg/m L in 473 m L; Amicar® (X anodyne); (Rx) Aminocaproic Acid Injection for Intravenous Infusion: 250 mg/m L in 20 m L vials; ge neric; (Rx) AMINOPENTAMIDE HYDROGEN SULFATE (a-mee-noe-pent-a-mide) Centrine® ANTICHOLINERGIC/ANTISPASMODIC Prescriber Highlights TT Anticholinergic/antispasmodic for GI indications in small animals TT Typical adverse effect profile (“dry, hot, red”); potentially could cause tachycardia TT Contraindicated in glaucoma; relatively contraindicated in tachycardias, heart disease, GI obstruction, etc. Uses/Indications The manufacturer states that the drug is indicated “in the treatment of acute abdominal visceral spasm, pylorospasm or hypertrophic gastritis and associated nausea, vomiting and/or diarrhea” for use in dogs and cats. Pharmacology/Actions Aminopentamide is an anticholinergic agent that when compared to atropine has been described as having a greater effect on reduc-ing colonic contractions and less mydriatic and salivary effects. It repo rtedly may also reduce gastric acid secretion. Pharmacokinetics No information was located. Contraindications/Precautions/Warnings The manufacturer lists glaucoma as an absolute contraindication to therapy and to use the drug cautiously, if at all, in patients with pylo-ric obstruction. Additionally, aminopentamide should not be used if the patient has a history of hypersensitivity to anticholinergic drugs, tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemor-rhage, GI obstructive disease, paralytic ileus, severe ulcerative colitis, obstruc tive uropathy or myasthenia gravis (unless used to reverse adverse muscarinic effects secondary to therapy). Antimuscarinic agents should be used with extreme caution in patients w ith known or suspected GI infections, or with autonomic neuropathy. Atropine or other antimuscarinic agents can decrease GI motility and prolong retention of the causative agent(s) or toxin(s) resulting in prolonged clinical signs. Antimuscarinic agents should be used with caution in patients with hepat ic disease, renal disease, hyperthyroidism, hypertension, CHF, tachyarrhythmias, prostatic hypertrophy, esophageal reflux, and in geriatric or pediatric patients.

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Adverse Effects Adverse effects resulting from aminopentamide therapy may in-clude dry mouth, dry eyes, blurred vision, and urinary hesitancy. Urinary retention is a symptom of too high a dose and the drug should be withdrawn until resolved. Overdosage/Acute Toxicity No specific information was located regarding acute overdosage clinical signs or treatment for this agent. The following discussion is from the Atropine monograph that could be used as a guideline for treating overdoses: If a recent oral ingestion, emptying of gut contents and admin-istration of activated charcoal and saline cathartics may be war-ranted. Treat clinical signs supportively and symptomatically. Do not use phe nothiazines as they may contribute to the anticholin-ergic effects. Fluid therapy and standard treatments for shock may be institu ted. The use of physostigmine is controversial and should probably be rese rved for cases where the patient exhibits either extreme agi-tation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are se-vere or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult), if no response, may repeat every 20 minutes until reversal of toxic antimuscarinic ef-fects or cholinergic effects takes place. The human pediatric dose is 0. 02 mg/kg slo w IV (repeat q10 minutes as above) and may be a reasonable choice for treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine. Drug Interactions No specific interactions were noted for this product. The follow-ing drug interactions have either been reported or are theoretical in humans or animals receiving atropine, a similar drug and may be of significance in veterinary patients: ! !ANTIHISTAMINES, PROCAINAMIDE, QUINIDINE, MEPERIDINE, BENZODI-AZEPINES, PHENOTHIAZINES : May enhance the activity of atropine and its derivatives ! !PRIMIDONE, DISOPYRAMIDE, NITRATES : May potentiate the adverse effects of atropine and its derivatives ! !CORTICOSTEROIDS (long-term use ): May increase intraocular pressure ! !NITROFURANTOIN, THIAZIDE DIURETICS, SYMPATHOMIMETICS : Atro-pine and its derivatives may enhance actions ! !METOCLOPRAMIDE : Atropine and its derivatives may antagonize metoclopramide actions Doses T ! DOGS: a) May be administered every 8-12 hours via IM, SC or oral routes. If the desired effect is not attained, the dosage may be gradually increased up to 5 times those listed below: Animals weighing: 10 lbs or less: 0. 1 mg; 11-20 lbs: 0. 2 mg; 21-50 lbs: 0. 3 mg; 51-100 lbs: 0. 4 mg; over 100 lbs: 0. 5 mg (Package Insert; Centrine® —Fort Dodge) b) T o decrease tenesmus in malabsorption/maldigestion syn-dromes: 0. 1-0. 4 mg SC, or IM twice daily-three times daily (Chiapel la 1988) c) As an antiemetic: 0. 1-0. 4 mg SC, or IM two to three times daily (Johnso n 1984) T ! CATS: a) As in “a” above in dogs b) As an antiemetic: 0. 1-0. 4 mg SC, or IM two to three times daily (Johnso n 1984) c) As second-line adjunctive therapy for refractory IBD: 0. 1-0. 4 mg/kg SC two to thre e times daily (Washabau 2000) Monitoring T ! Clinical efficacy T ! Adverse effects (see above) Client Information T ! Contact veterinarian if animal has difficulty urinating or if ani-mal is bothered by dry eyes or mouth Chemistry/Synonyms An antispasmodic, anticholinergic agent, aminopentamide hydro-gen sulfate has a chemical name of 4-(dimethylamino)-2,2-diphe-nylvaleramide. Aminopentamide hydrogen sulfate may also be known as dime-vamid or Centrine®. Storage/Stability Store aminopentamide tablets and injection at controlled room temperature (15-30°C; 59-86°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Aminopentamide Hydrogen Sulfate Tablets: 0. 2 mg; Centrine®(Fort Dodge); (Rx). Approved for use in dogs and cats only. Aminopentamide Hydrogen Sulfate Injection: 0. 5 mg/m L in 10 m L vials; Cent rine® (Fort Dodge); (Rx). Approved for use in dogs and cats only. HUMAN-LABELED PRODUCTS: None AMINOPHYLLINE THEOPHYLLINE (am-in-off-i-lin); (thee-off-i-lin) PHOSPHODIESTERASE INHIBITOR BRONCHODILATOR Prescriber Highlights TT Bronchodilator drug with diuretic activity; used for bron-chospasm & cardiogenic pulmonary edema TT Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels TT Therapeutic drug monitoring recommended TT Many drug interactions Uses/Indications The theophyllines are used primarily for their bronchodilatory ef-fects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity. Pharmacology/Actions The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of c AMP may also

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inhibit the release of histamine and slow reacting substance of ana-phylaxis (SRS-A). The myocardial and neuromuscular transmission eff ects that the theophyllines possess may be a result of translocating intracellular ionized calcium. The theophyllines directly relax smooth muscles in the bronchi and pulmo nary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chrono-tropic and inotropic action, stimulate the CNS and can cause respi-ratory stimulation (centrally-mediated). Pharmacokinetics The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sus-tained release products are used. One study in dogs that compared var ious sustained-release products (Koritz, Neff-Davis, and Munsiff 1986), found bioavailabilities ranging from approximately 30-76% depending on the product used. Theophylline is distributed throughout the extracellular fluids and b ody tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distri-bution of theophylline for dogs has been reported to be 0. 82 L/kg. The volume of distribution in cats is reported to be 0. 46 L/kg, and in horses, 0. 85-1. 02 L/kg. Because of the low volumes of distribu-tion and theophylline's low lipid solubility, obese patients should be dose d on a lean body weight basis. Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weak bronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clear-ance of theophylline. The reported elimination half-lives (mean val-ues) in various species are: dogs ≈ 5. 7 hours; cats ≈ 7. 8 hours, pigs ≈ 11 hours; and horses ≈ 11. 9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veteri-nary patients, particularly those with concurrent illnesses. Contraindications/Precautions/Warnings The theophyllines are contraindicated in patients who are hyper-sensitive to any of the xanthines, including theobromine or caffeine. Pat ients who are hypersensitive to ethylenediamine should not take aminophylline. The theophyllines should be administered with caution in pa-tients with severe cardiac disease, seizure disorders, gastric ulcers, hy perthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhyth-mias, patients with cardiac arrhythmias should receive theophylline onl y with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline. Adverse Effects The theophyllines can produce CNS stimulation and gastrointesti-nal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments. Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fe tus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Clinical signs of toxicity (see above) are usually associated with lev-els greater than 20 mcg/m L in humans and become more severe as the se rum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/m L. Treatment of theophylline toxicity is supportive. After an oral ingest ion, the gut should be emptied, charcoal and a cathartic ad-ministered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The pa-tient should be constantly monitored for cardiac arrhythmias and tac hycardia. Fluid and electrolytes should be monitored and cor-rected as necessary. Hyperthermia may be treated with phenothiaz-ines and tachycardia treated with propranolol if either condition is co nsidered life threatening. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aminophylline or theo-phylline and may be of significance in veterinary patients: The following drugs can decrease theophylline levels: !TBARBITURATES (phenobarbital ) !TCARBAMAZEPINE (may increase or decrease levels) !TCHARCOAL !THYDANTOINS (phenytoin ) !TISONIAZID (may increase or decrease levels) !TKETOCONAZOLE !TLOOP DIURETICS (furosemide ); (may increase or decrease levels) !TRIFAMPIN !TSYMPATHOMIMETICS (beta-agonists ) The following drugs can increase theophylline levels: !TALLOPURINOL !TBETA-BLOCKERS (non-selective such as propranolol ) !TCALCIUM CHANNEL BLOCKERS (e. g., diltiazem, verapamil ) !TCIMETIDINE !TCORTICOSTEROIDS !TFLUOROQUINOLONES (enrofloxacin, ciprofloxacin ): If adding either, consider reducing the dose of theophylline by 30%. Monitor for toxicity/efficacy. Marbofloxacin reduces clearance of theophylline in dogs, but not with clinical significance. In animals with renal impairment, marbofloxacin may interfere with theophylline me-tabolism in a clinically relevant manner. !TMACROLIDES (e. g., erythromycin; clindamycin, lincomycin ) !TTHIABENDAZOLE !TTHYROID HORMONES (in hypothyroid patients) !TTHEOPHYLLINE may decrease the effects of following drugs: !TBENZODIAZEPINES

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

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

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Tfied a Class III antiarrhythmic agent that also blocks sodium and calci um channels, and beta-adrenergic receptors. Major properties include prolongation of myocardial cell action-potential duration and refractory period. Pharmacokinetics Amiodarone may be administered parenterally or orally. Amiodarone is widely distributed throughout the body and can ac-cumulate in adipose tissue. Amiodarone is metabolized by the liver into the active metabolite desethylamiodarone. After oral adminis-tration of a single dose in normal dogs, amiodarone's plasma half-life averaged 7. 5 hours, but repeated dosing increased its half-life from 11 hours to 3. 2 days. In horses, amiodarone has a low oral bioavailability (range from 6- 34%) and peak levels of amiodarone and desethylamiodarone occur about 7-8 hours after an oral dose. After IV administration amiodarone is rapidly distributed with a high apparent volume of distribution of 31 L/kg. In horses, amiodarone is relatively high-ly bound to plasma proteins (96%). Clearance was 0. 35 L/kg/hr and me dian elimination half-lives for amiodarone and desethyla-miodarone were approximately 51 and 75 hours, respectively (De Cle rcq, Baert et al. 2006). In humans, oral absorption is slow and variable, with bioavail-abilities ranging from 22-86%. Elimination half-lives for amio-darone and desethylamiodarone range from 2. 5-10 days after a single dose, but with chronic dosing, average 53 days and 60 days, respectively. Contraindications/Precautions/Warnings Amiodarone is considered contraindicated in patients (humans) hypersensitive to it, having severe sinus-node dysfunction with se-vere sinus bradycardia, 2nd or 3rd degree heart block, or bradycar-dial syncope. Clinical experience in veterinary patients is limited. Consider use o nly when other less toxic and more commonly used drugs are ineffective. Adverse Effects Gastrointestinal effects (e. g., anorexia, vomiting) are apparently the most likely adverse effects seen in the limited number of canine patients treated. Hepatopathy (bilirubinemia, increased hepatic enzymes) has been reported in dogs on amiodarone. Because he-patic effects can occur before clinical signs are noted, routine serial ev aluation of liver enzymes and bilirubin is recommended. Other adverse effects reported in dogs include bradycardia, neutropenia, thrombocytopenia, or positive Coombs' test. During IV infusion, pain at injection site, and facial pruritus and hyperemia have been noted. Corneal deposits may be seen in dogs treated with amio-darone, but this affect apparently occurs less frequently in dogs than in humans. I n human patients, adverse effects are very common while on amiodar one therapy. Those that most commonly cause discontinu-ation of the drug include: pulmonary infiltrates or pulmonary fi-brosis (sometimes fatal), liver enzyme elevations, congestive heart failur e, paroxysmal ventricular tachycardia, and thyroid dysfunc-tion (hypo-or hyperthyroidism). An odd effect seen in some indi-viduals is a bluish cast to their skin. Reversible corneal deposits are see n in a majority of humans treated with amiodarone. Clinical experience in dogs is limited; the adverse effect profile of this drug in people warrants its use in veterinary patients only when other less toxic agents are ineffective and treatment is deemed necessary. Reproductive/Nursing Safety In laboratory animals, amiodarone has been embryotoxic at high doses and congenital thyroid abnormalities have been detected in offspring. Use during pregnancy only when the potential benefits outweigh the risks of the drug. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Overdosage/Acute Toxicity Clinical overdosage experience is limited; most likely adverse effects seen are hypotension, bradycardia, cardiogenic shock, A V block, and hepatotoxicity. Treatment is supportive. Bradycardia may be managed with a pacemaker or beta-1 agonists (e. g., isoproterenol); hypotension managed with positive inotropic agents or vasopres-sors. Neither amiodarone nor its active metabolite are dialyzable. Drug Interactions Several potentially significant interactions may occur with amio-darone. The following is a partial list of interactions that have either be en reported or are theoretical in humans or animals receiving amiodarone and may be of significance in veterinary patients: Amiodarone may significantly increase the serum levels and/or pharmacologic or toxic effects of: !!ANTICOAGULANTS (warfarin ) !!DIGOXIN !!CYCLOSPORINE !!LIDOCAINE !!METHOTREXA TE (with prolonged amiodarone administration ) !!PHENYTOIN !!PROCAINAMIDE !!QUINIDINE Amiodarone may have additive effects on QTc interval ; possible seri-ous arrhythmias may result: !!AZOLE ANTIFUNGALS (ketoconazole, itraconazole, etc. ) !!CISAPRIDE !!DISOPYRAMIDE !!DOLASETRON !!FLUOROQUINOLONE ANTIBIOTICS (some, such as moxifloxacin, not en-rofloxacin, marbofloxacin, etc. ) !!MACROLIDE ANTIBIOTICS (e. g., erythromycin ) Other amiodarone drug interactions: !!ANESTHETICS, GENERAL : Increased risks for hypotension or arrhythmias !!BETA-ADRENERGIC BLOCKERS : Possible potentiation of bradycardia, A V block or sinus arrest !!CALCIUM-CHANNEL BLOCKERS (e. g., diltiazem, verapamil ): Possible potentiation of bradycardia, A V block or sinus arrest !!CIMETIDINE : Increased amiodarone levels !!CYCLOSPORINE : Increased cyclosporine levels; may increase creatinine !!FENTANYL : Possible hypotension, bradycardia !!RIFAMPIN : Decreased amiodarone levels Laboratory Considerations !TWhile most human patients remain euthyroid while receiving amiodarone, it may cause an increase in serum T 4 and serum re-verse T 3 levels, and a reduction in serum T 3 levels !The human therapeutic serum concentrations of 1-2. 5 mcg/m L are believed to apply to dogs as well !TAmiodarone may cause a positive Coombs' test result

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TDoses Note : Some human references state that because of the potential for drug interactions with previous drug therapies, the life-threatening nature of the arrhythmias being treated, and the unpredictability of response from amiodarone, the drug should be initially given (loaded) over several days in an inpatient setting where adequate monitoring can occur. T ! DOGS: For conversion of atrial fibrillation: a) At the time of writing (2007) one case report (Oyama and Prosek 2006) and one retrospective evaluation (Saunders, Miller et al. 2006) have been published using amiodarone to convert atrial fibrillation in dogs. Dosage recommendations are yet to be fully defined; monitor the current literature for further recommendations. For recurrent ventricular tachycardia not controlled with other less toxic drug s: a) 10-25 mg/kg PO twice daily for 7 days, followed by 5-7. 5 mg/kg PO twic e daily for 14 days, followed by 7. 5 mg/kg PO once daily (Calvert 1995) b) For ventricular arrhythmias secondary to occult cardiomyo-pathy in Doberman pinschers: 10 mg/kg PO twice daily for one we ek and then 8 mg/kg PO once daily. For severe V-Tach, mexiletine is added at 5-8 mg/kg three times daily for one week. Once efficacy confirmed, patient weaned off mexiletine. (Calvert and Mieurs 2000) c) Amiodarone as above in “b”, but after 6 months may be re-duced to 5 mg/kg once daily. (Meurs 2005) d) 10-20 mg/kg PO q12h (Fox 2003a) T ! HORSES: For conversion of atrial fibrillation or ventricular tachycardia: a) 5 mg/kg/hr for one hour, followed by 0. 83 mg/kg/hr for 23 hours and the n 1. 9 mg/kg/hour for the following 30 hours. In the study (A fib), infusion was discontinued when con-version occurred or when any side effects were noted. 4 of 6 horses c onverted from A fib; one horse from V tach. In order to increase success rate and decrease adverse effects, regimen should be further adapted based upon PK/PD studies in hors-es. (De Clercq, van Loon et al. 2006a), (De Clercq, van Loon et al. 2006b) Monitoring T ! Efficacy (ECG) T ! oxicity (GI effects; CBC, serial liver enzymes; thyroid function tests; blood pressure; pulmonary radiographs if clinical signs such as dyspnea/cough occur) Client Information T ! Because of the “experimental”nature (relatively few canine/equine patients have received this agent) and the toxicity dangers associ-ated with its use, clients should give informed consent before the drug is pr escr ibed. Chemistry/Synonyms An iodinated benzofuran, amiodarone is unique structurally and pharmacologically from other antiarrhythmic agents. It occurs as a white to cream colored lipophilic powder having a p Ka of approxi-mately 6. 6. Amiodarone 200 mg tablets each contain approximately 75 mg of iodine. A miodarone HCl may also be known as: amiodaroni hydrochlo-ridum, L-3428, 51087N, or SKF-33134-A; many trade names are available. Storage/Stability/Compatibility Tablets should be stored in tight containers, at room temperature and protected from light. A 3-year expiration date is assigned from the date of manufacture. Injection should be stored at room temperature and protected from lig ht or excessive heat. While administering, light protection is not necessary. Use D5W as the IV diluent. Amiodarone is report-edly compatible with dobutamine, lidocaine, potassium chloride, procainamide, propafenone, and verapamil. Variable compatibility is reported with furosemide and quinidine gluconate. Dosage Forms/Regulatory Status 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: Amiodarone Oral Tablets: 100 mg, 200 mg & 400 mg; Cordarone® (Wyeth-Ayerst); Pacerone® (Upsher Smith); generic; (Rx) Amiodarone Concentrate for Injection (for IV Infusion): 50 mg/m L in 3 m L amps & vials; Cordar one® (Wyeth-Ayerst); generic; (Rx) Amitraz — See the Topical Dermatologic Agents section in the appendix AMITRIPTYLINE HCL (a-mih-trip-ti-leen) Elavil® TRICYCLIC BEHA VIOR MODIFIER; ANTI-PRURITIC; NEUROPATHIC PAIN MODIFIER Prescriber Highlights TT Tricyclic “antidepressant” used primarily for behavior dis-orders & neuropathic pain/pruritus in small animals TT May reduce seizure thresholds in epileptic animals TT Sedation & anticholinergic effects most likely adverse effects TT Overdoses can be very serious in both animals & humans Uses/Indications Amitriptyline has been used for behavioral conditions such as sepa-ration anxiety or generalized anxiety in dogs, and excessive groom-ing, spraying and anxiety in cats. Amitriptyline may be useful for adjunct ive treatment of pruritus, or chronic pain of neuropathic origin in dogs and cats. In cats, it potentially could be useful for ad-junctive treatment of lower urinary tract disease. Amitriptyline has been t ried to reduce feather plucking in birds. Pharmacology/Actions Amitriptyline (and its active metabolite, nortriptyline) has a com-plicated pharmacologic profile. From a slightly oversimplified view-point, it has 3 main characteristics: blockage of the amine pump, thereb y increasing neurotransmitter levels (principally serotonin, but also norepinephrine), sedation, and central and peripheral anti-cholinergic activity. Other pharmacologic effects include stabilizing mast cel ls via H-1 receptor antagonism, and antagonism of gluta-mate receptors and sodium channels. In animals, tricyclic antide-pressants are similar to the actions of phenothiazines in altering avoidanc e behaviors.

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

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

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There is concern that using amlodipine alone for treating hy-pertension in cats with renal disease may expose glomeruli to highe r pressures secondary to efferent arteriolar constriction. This is caused by localized increases in renin-angiotensin-aldosterone axis activity thereby allowing progressive damage to glomeruli. It is postulated that using an ACE inhibitor with amlodipine may help prevent this occurrence (Stepian 2006a). Adverse Effects Because of amlodipine's relatively slow onset of action, hypoten-sion and inappetence is usually absent in cats. Infrequently, cats may develop azotemia, lethargy, hypokalemia, reflex tachycardia and weight loss. In humans taking amlodipine, headache (7. 3% in-cidence) is the most frequent problem reported. Reproductive/Nursing Safety While no evidence of impaired fertility was noted in rats given 8X overdoses, amlodipine has been shown to be fetotoxic (intrauterine death rates increased 5 fold) in laboratory animals (rats, rabbits) at very high dosages. No evidence of teratogenicity or mutagenicity was observed in lab animal studies. In rats, amlodipine prolonged labor. It is unknown whether amlodipine enters maternal milk. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity There were 69 exposures to amlodipine reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 59 were dogs with 7 showing clini-cal signs; the remaining 10 cases were cats with 2 showing clinical signs. Common findings in dogs, recorded in decreasing frequency included anorexia, lethargy, tachycardia, acidosis and bradycardia. Common findings in cats, recorded in decreasing frequency includ-ed lethargy and polydipsia. Limited experience with other calcium channel blockers in hu-mans has shown that profound hypotension and bradycardia may res ult. When possible, massive overdoses should be managed with gut emptying and supportive treatment. Beta-agonists and intrave-nous calcium may be beneficial. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving amlodipine and may be of significance in veterinary patients: No clinically significant drug-drug interactions have been noted spe cifically with amlodipine at this time. However, concomitant use of diuretics, beta-blockers, other vasodilators or other agents that may reduce blood pressure (e. g., fentanyl ) may cause hypotension if used with amlodipine. Grapefruit juice/powder may alter bioavailability. Laboratory Considerations No specific concerns were noted Doses !TCATS: For treatment of systemic hypertension: a) 0. 625 mg (1/4 of a 2. 5 mg tablet) PO once daily; some larger cats (>4 kg) or those with severe hypertension may require doses as high as 1. 25 mg PO twice daily. Titrate dosage care-fully, based upon BP determinations. (Brown and Henik 2000); ( Trepanier 1999) b) 0. 625-1. 25 mg (total dose) PO once daily. Drug of choice; oft en successful as a single agent. Can be combined with an ACEI, beta-blocker or diuretic if needed. Maximum effect seen within 7 days of therapy. (Sparkes 2003a) !TDOGS: For adjunctive therapy for refractory heart failure: a) For treatment of advanced mitral valve degeneration as an afte rload reducer after ACE inhibitor maintenance therapy has been established: 0. 2-0. 4 mg/kg PO twice daily. Initiate therapy at 0. 1 mg/kg PO twice daily and up-titrate weekly while monitoring blood pressure. (Kraus 2003) b) As an arterial vasodilator particularly in dogs moderately re-fractory, or recurrent CHF secondary to mitral regurgitation and maintaine d blood pressures: 0. 1 mg/kg q12-24h initial-ly; titrate up as needed to 0. 25 mg/kg PO q12-24h; monitor blo od pressure. (De Francesco 2006) For treatment of systemic hypertension in dogs with chronic re-nal disease: a) 0. 05-0. 25 mg/kg PO once daily. In many dogs, amlodipine app ears to be less effective, even at high doses (1 mg/kg/day). (Brown, Brown et al. 2006) b) 0. 1-0. 2 mg/kg PO q12-24h (Stepian 2006a) Monitoring !TBlood pressure !TOphthalmic exam !TAdverse effects Client Information !TMay give with food !TMissing dosages can cause rapid redevelopment of symptoms and damage secondary to hypertension Chemistry/Synonyms Amlodipine besylate, a dihydropyridine calcium channel-blocking agent, occurs as a white crystalline powder that is slightly soluble in water and sparingly soluble in alcohol. Amlodipine Besylate may also as: amlodipini besilas, UK-48340-26, o r UK-48340-11 (amlodipine maleate); many trade names are available. Storage/Stability Store amlodipine tablets at room temperature, in tight, light resis-tant containers. Dosage Forms/Regulatory Status 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: Amlodipine Tablets: 2. 5 mg, 5 mg, 10 mg; Norvasc® (Pfizer); Am-vaz® (Reddy); (Rx) Fixed-dose combination products with benazepril (Lotrel ®) o r atorvastatin (Caduet®) are available.

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

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

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Uses/Indications Ammonium molybdate and ammonium tetrathiomolybdate (TTM) AMOXICILLIN are used for the investigational or compassionate treatment of cop-(a-mox-i-sill-in) Amoxil®, Amoxi-Tabs® per poisoning in food animals, primarily sheep. AMINOPENICILLIN Adverse Effects After apparent successful treatment for copper poisoning with am-Prescriber Highlights monium tetrathiomolybdate (TTM), a flock of sheep became infer-tile, progressively unthrifty, and died 2-3 years later. The authors TT Bactericidal aminopenicillin with same spectrum as concluded the TTM was retained in the CNS, pituitary and adrenal ampicillin (ineffective against bacteria that produce glands and caused a toxic endocrinopathy (Haywood, Dincer et al. beta-lactamase) 2004). TT Most likely adverse effects are GI-related, but hypersensi-tivity & other adverse effects rarely occur Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-TT Available in oral & parenteral dosage forms in USA 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. ) Uses/Indications The aminopenicillins have been used for a wide range of infections Doses in various species. FDA-approved indications/species, as well as Note : In food animals, FARAD recommends a minimum 10 day pre-non-approved uses, are listed in the Dosages section below. slaughter withdrawal time and a minimum 5 day milk withholding interv al. (Haskell, Payne et al. 2005) Pharmacology/Actions Like other penicillins, amoxicillin is a time-dependent, bactericidal Ammonium tetrathiomolybdate does not go into solution readily (usually) agent that acts by inhibiting cell wall synthesis. Although and ammonium molybdate administered orally is often preferred. there may be some slight differences in activity against certain or-T ! SHEEP: ganisms, amoxicillin generally shares the same spectrum of activity For treatment of copper poisoning: and uses as ampicillin. Because it is better absorbed orally (in non-a) Food animals: Ammonium molybdate: 200 mg per head ruminants), hig he r serum levels may be attained than with ampicil-PO once daily for 3 weeks. Ammonium tetrathiomolybdate: lin. 1. 7-3. 4 mg per head IV or SC every other day for 3 treat-Peni cillins are usually bactericidal against susceptible bacteria and ments (Post and Keller 2000) act by inhibiting mucopeptide synthesis in the cell wall resulting in b) 100 mg with 1-gram sodium sulfate by mouth daily (Debuf a def ective barrier and an osmotically unstable spheroplast. The ex-1991) act me chanism for this effect has not been definitively determined, c) 200 mg ammonium or sodium molybdate plus 500 mg of so-but b eta-lactam antibiotics have been shown to bind to several en-dium thiosulfate given daily PO for up to 3 weeks (Thompson zyme s (carboxypeptidases, transpeptidases, endopeptidases) within and Buck 1993) the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that various beta-lactam antibiotics d) Ammonium tetrathiomolybdate: 1. 7 mg/kg IV or 3. 4 mg/kg have for these enzymes (also known as penicillin-binding proteins; SC every other day for 3 treatments. Alternatively, ammonium PBPs ) help explain the differences in spectrums of activity the drugs molybdate 50-500 mg PO once daily and sodium thiosulfate have that are not explained by the influence of beta-lactamases. Like 300-1000 mg PO once daily for 3 weeks. (Plumlee 1996) othe r beta-lactam antibiotics, penicillins are generally considered Dosage Forms/Regulatory Status/Synonyms more effective against actively growing bacteria. The aminopenicillins, also called the “broad-spectrum” or am-VETERINARY-LABELED PRODUCTS: None. picillin penicillins, have increased activity against many strains of Note : Ammonium Molybdate or ammonium tetrathiomolybdate gram-negative aerobes not covered by either the natural penicillins can be obtained from various chemical supply houses, but it is rec-or penicillinase-resistant penicillins, including some strains of E. ommended to contact the FDA before treating for guidance when coli, Klebsiella, and Haemophilus. Like the natural penicillins, they contemplating using molybdate. are susceptible to inactivation by beta-lactamase-producing bacteria HUMAN-LABELED PRODUCTS: (e. g., Staph aureus). Although not as active as the natural penicil-Ammonium Molybdate Injection: 25 mcg/m L (as 46 mcg/m L am-lins, they do have activity against many anaerobic bacteria, including monium molybdate tetrahydrate) in 10 m L vial); Molypen ®(Ameri-Clostridial organisms. Organisms that are generally not suscepti-can Pharmaceutical Partners); generic; (Rx) ble inc l ude Pseudomonas aeruginosa, Serratia, Indole-positive Proteus (Proteus mirabilis is susc e ptible), Enterobacter, Citrobacter, Ammonium molybdate may also be known as: Molybde ne Inject-and Acinetobacter. The aminopenicillins also are inactive against able®, or Moly pen®. Ammonium tetrathiomolybdate may also be Rickettsia, mycobacteria, fungi, Mycoplasma, and viruses. known as TTM. In order to reduce the inactivation of penicillins by beta-lacta-mases, potassium clavulanate and sulbactam have been developed to ina c tivate these enzymes and thus extend the spectrum of those penicillins. When used with a penicillin, these combinations are of-ten effective against many beta-lactamase-producing strains of oth-erwise resistant E. coli, Pasturella spp., Staphylococcus spp., Klebsiella, and Proteus. Type I beta-lactamases that are often associated with E. coli, Enterobacter, and Pseudomonas are not generally inhibited by clavulanic acid.

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

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

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

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

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

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

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

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

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Chemistry/Synonyms A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of ampho-tericin B must contain not less than 750 micrograms of anhydrous drug. A mphotericin A may be found as a contaminant in concen-trations not exceeding 5%. The commercially available powder for injectio n contains sodium desoxycholate as a solubilizing agent. Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec®), amphotericin B lipid complex (ABLC, Abelcet®), and amphotericin B liposomal (ABL, L-AMB, Ambisome®). Amphotericin B may also be known as: amphotericin; amphot-ericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphoter icin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available. Storage/Stability/Compatibility Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives—see directions for preparation in the Dosage Form section below). After reconstitution, if protected from light, the solution is sta-ble for 24 hours at room temperature and for 1 week if kept refrig-erated. After diluting with D 5W (must ha ve p H >4. 3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is ex-posed to light for 8-24 hours. Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D 5W, D 5W in sodium chloride 0. 2%, heparin sodium, heparin sodium with hydrocortisone so-dium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicar bonate. Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer's, D 5-normal saline, D 5-lactate d Ringer's, amino acids 4. 25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodi-um, chlorpromazine HCl, cimetidine HCl, diphenhydramine HCl, dopamine HC l, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCl, metaraminol bitartrate, methyldopate HCl, nitrofurantoin sodium, oxytetracycline HCl, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracy-cline HCl, and verapamil HCl. Compatibility is dependent upon facto rs 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: Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin® (Gensia Sicor); Fungizone® Intravenous (Apoth-econ); generic (Pharma-T ek); (Rx) Directions for reconstitution/administration: Using strict aseptic techniq ue and a 20 gauge or larger needle, rapidly inject 10 m L of sterile water for injection (without a bacteriostatic agent) directly into the l yophilized cake; immediately shake well until solution is clear. A 5 mg/m L colloidal solution results. Further dilute (1:50) for administration to a concentration of 0. 1 mg/m L with 5% dextrose in water (p H >4. 2). An in-line filter may be used during adminis-tration, but must have a pore diameter >1 micron. Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 m L (as lipid c omplex) in 10 m L & 20 m L vials with 5 micron filter needles: Abelcet® (Enzon); (Rx) Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholester yl) in 20 m L vials; 100 mg (as cholesteryl) in 50 m L vi-als; Amphotec® (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose v ials with 5-micron filter; Am Bisome® (Fujisawa; (Rx) Amphotericin B is also available in topical formulations: Fungi-zone ® (Apothecon); (Rx) AMPICILLIN AMPICILLIN SODIUM AMPICILLIN TRIHYDRATE (am-pi-sill-in; sul-bak-tam) Polyflex® AMINOPENICILLIN Prescriber Highlights TT Bactericidal aminopenicillin with same spectrum as amoxicillin (ineffective against bacteria that produce beta-lactamase) TT Most likely adverse effects are GI-related, but hypersen-sitivity & other adverse effects rarely occur; may cause more GI effects than amoxicillin when used orally TT More susceptible than is amoxicillin to food reducing oral absorption TT Available in both parenteral & oral forms Uses/Indications In dogs and cats, ampicillin is not as well absorbed after oral ad-ministration as amoxicillin and its oral use has largely been sup-planted by amoxicillin. It is used commonly in parenteral dosage forms w hen an aminopenicillin is indicated in all species. The aminopenicillins, also called the “broad-spectrum” or am-picillin penicillins, have increased activity against many strains of gram-neg ative aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus. Pharmacology/Actions Like other penicillins, ampicillin is a time-dependent, bactericidal (usually) agent that acts via inhibiting cell wall synthesis. Ampicillin and the other aminopenicillins have increased activity against many strains of gram-negative aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella and Haemophilus. Like the natural penicillins, they are susceptible to inactivation by beta-lactamase-producing bacteria (e. g., Staph aureus). Although not as active as the natural penicillins, they do have activity against many anaero-bic bacteria, including Clostridial organisms. Organisms that are

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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No special precautions are required for handling asparaginase, but any inadvertent skin contact should be washed off, as the drug can be a contact irritant. Adverse Effects Asparaginase adverse reactions are classified in two main cat-egories, hypersensitivity reactions and effects on protein synthesis. Hy persensitivity reactions can occur with clinical signs of vomit-ing, diarrhea, urticaria, pruritus, dyspnea, restlessness, hypotension and c ollapse. The likelihood of hypersensitivity reactions occurring increases with subsequent doses and intravenous administration. Some clinicians recommend giving a test dose before the full dose to test for local hypersensitivity. Most oncologists now recommend administering antihistamines (e. g., diphenhydramine (at 2 mg/kg in dogs and 1 mg/kg in cats SC 30 minutes prior to administration) prior to dosing. If a hypersensitivity reaction occurs, diphenhy-dramine (0. 2-0. 5 mg/kg slow IV), dexamethasone sodium phos-phate (1-2 mg/kg IV), intravenous fluids and, if severe, epinephrine (0. 1-0. 3 m L of a 1:1000 solution IV) have been suggested (O'Keefe and Har ris 1990). The other broad category of toxicity is associated with aspara-ginase's effects on protein synthesis. Hemorrhagic pancreatitis or other gastrointestinal disturbances, hepatotoxicity and coagulation defects may be noted. Large doses may be associated with hyper-glycemia secondary to altered insulin synthesis. Bone marrow de-pression is an uncommon consequence of asparaginase therapy, but leuk openia has been reported. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fe tus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Little information was located regarding overdosages with this agent. It would be expected that toxicity secondary to the protein synthesis altering effects of the drug would be encountered. In dogs, it has been reported that the maximally tolerated dose of asparaginase is 10,000 IU/kg and the lethal dose is 50,000 IU/kg. It is recommended to treat supportively if an overdose occurs. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving asparaginase and may be of significance in veterinary patients: !TMETHOTREXATE : Asparaginase may reduce methotrexate effective-ness against tumor cells until serum asparagine levels return to nor mal !TPREDNISONE : Use with asparaginase may increase risk for hyper-glycemia; in humans, asparaginase is usually administered after pr ednisone !TVINCRISTINE : In humans, increased toxicity (neuropathy and erythropoiesis disruption) may occur when asparaginase (IV) is given concurrently with or be fore vincristine. Myelosuppression reportedly occurs in a minority of dogs treated with vincristine/ asparaginase; some veterinary oncologists separate the dosing by a few days to a week, but others do not feel this is beneficial. Laboratory Considerations !TSERUM AMMONIA AND UREA NITROGEN: levels may be increased by the action of the drug !TTHYROXINE-BINDING GLOBULIN: Asparaginase may cause rapid (with-in 2 days) and profound decreases in circulating TBG, which may alte r interpretation of thyroid function studies; values may return to normal after approximately 4 weeks Doses For more information, refer to the protocols found in the appendix or other dosages/protocols found in numerous references, includ-ing: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th E d. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). Note : Many oncologists recommend administering antihistamines such as diphenhydramine at 2 mg/kg for dogs and 1 mg/kg for cats SC 30 minutes prior to administration. !TDOGS: For lymphoid malignancies (Usually used in combination proto-cols with other drugs; rarely used alone): a) For induction therapy (as part of a protocol): 10,000 Units/ m2 SC or IM (Kitchell and Dhaliwal 2000) Fo r evaluation of hypercalcemia of undetermined etiology to rule out occult lymphoma: a) Pre-treat with an antihistamine, then asparaginase at 20,000 IU/m2 IV. Measure serum calcium prior to therapy and ev-ery 12 hours after administration, for as long as 72 hours. A de cline in serum calcium, usually into the normal range, is strongly suggestive of occult lymphoma. (Nelson 2002a) For relapsed or refractory canine lymphoma (LSA) with lomus-tine and prednisone: a) Lomustine at 70 mg/m2 (for dogs weighing 15 kg or more (60 mg/m2 (f or dogs weighing less than 15 kg) PO every three weeks for a total of 5 doses or until disease progression. In dogs with neutrophil counts less than 500 cells/microliter 1 week after lomustine treatment, doses are decreased by 10 mg/m2 for subsequent doses. As lomustine comes in 10 mg, 40 mg, & 100 mg capsules, round lomustine doses down if necessary. Asparaginase at 400 Units/kg SC concurrently with the first two lomustine treatments and then discontinued. Prednisone started at 2 mg/kg PO once daily and then tapered over the protocol duration to 1 mg/kg PO every other day. (Saba, Thamm et al. 2007) !TCATS: For lymphoid malignancies (usually used in combination proto-cols with other drugs; rarely used alone): a) 10,000 Units/m2 SC, intraperitoneally, or IM every 1-3 weeks (Cou to 1989b) b) 400 Units/kg SC or IM (as part of a protocol) (Kitchell and Dhaliwal 2000) Fo r evaluation of hypercalcemia of undetermined etiology to rule out occult lymphoma: a) Pre-treat with an antihistamine, then asparaginase at 20,000 IU/m2 IV. Measure serum calcium prior to therapy and ev-ery 12 hours after administration, for as long as 72 hours. A de cline in serum calcium, usually into the normal range, is strongly suggestive of occult lymphoma. (Nelson 2002a) Monitoring !TAnimals should have hepatic, renal, pancreatic (blood glucose, amylase) and hematopoietic function determined prior to initiat-ing therapy and regularly monitored during therapy. Client Information !TClients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality

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

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

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

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

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

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T T!TANESTHETICS (myocardial depressant ): Additive myocardial depres-sion may occur with the concurrent use of atenolol and myocar-dial depressant anesthetic agents !TCALCIUM-CHANNEL BLOCKERS (e. g., diltiazem, verapamil, amlodipine ): Concurrent use of beta-blockers with calcium channel blockers (or other negative inotropics) should be done with caution, par-ticularly in patients with preexisting cardiomyopathy or CHF !TCLONIDINE : Atenolol may exacerbate rebound hypertension after stopping clonidine therapy !TFUROSEMIDE, HYDRALAZINE OR OTHER HYPOTENSIVE PRODUCING DRUGS : May increase the hypotensive effects of atenolol !TPHENOTHIAZINES : With atenolol may exhibit enhanced hypotensive effects !TRESERPINE : Potential for additive effects (hypotension, bradycardia) !TSYMPATHOMIMETICS (metaproterenol, terbutaline, beta-effects of epi-nephrine, phenylpropanolamine, etc. ): May have their actions blocked by atenolol and they may, in turn, reduce the efficacy of atenolol Doses !TDOGS: For indications where beta-blockade may be indicated (cardiac arrhythmias, obstructive heart disease, hypertension, myocardial infarction, etc. ): a) 0. 2-1 mg/kg PO q12-24h (Ware 2000) b) 0. 25-1 mg/kg PO q12-24h (Hogan 2004) c) 6. 25-25 mg (total dose) PO q12h (Muir and Bonagura 1994); (Fue ntes 1999) d) For moderate to severe sub-valvular aortic stenosis (SAS): 0. 5-1 mg/kg PO twice a day (Meurs 2006c) e) T o attempt to decrease syncopal episodes associated with pul-monic stenosis: 0. 25-1 mg/kg PO twice a day (Meurs 2006c) Fo r treatment of hypertension: a) 0. 25-1 mg/kg PO q12h (Stepian 2006b) b) For hypertension: 0. 5 mg/kg initially PO q12-24h; may com-bine with vasodilators and/or diuretics (Brown and Henik 2000) c) 0. 25-1 mg/kg PO q12-24h (Snyder and Cooke 2005) !TCATS: For treatment of hypertension: a) 2 mg/kg once daily; hyperthyroid cats being started on methi-mazole are treated usually for 2 weeks with atenolol. It is im-portant to closely monitor geriatric cats as renal disease may be a concurrent problem with hyperthyroidism or hyperten-sion. (Littman 1992) b) 6. 25-12. 5 mg per cat per day. Starting dose should be low and t itrate to effect. Do not start treatment immediately prior to anesthesia or surgery without a suitable period of dosage titration. (Mooney and Thoday 2000) c) 0. 5 mg/kg initially PO q12-24h; may combine with vasodila-tors and/or diuretics (Brown and Henik 2000) d) 2 mg/kg PO q12-24h (Snyder and Cooke 2005) e) 6. 25-12. 5 mg (total dose) PO q12-24h. Treatment of choice fo r hyperthyroid, hypertensive cats. Beta-blockers are rarely sufficient alone to treat hypertension due to other causes. (Waddell 2005) f) 3 mg/kg PO q12h (or 6. 25-12. 5 mg total dose) PO q12h (Ste-pian 2006b) For indications where beta blockade may be indicated (cardiac arr hythmias, obstructive heart disease, hypertension, myocardial infarction, etc. ): a) 6. 25-12. 5 mg (total dose) PO q12-24h (Ware and Keene 2000); (F ox 2000) !TFERRETS: For hypertrophic cardiomyopathy: a) 6. 25 mg (total dose) PO once daily (Williams 2000) b) 3. 13-6. 25 mg (total dose) PO once daily (Johnson-Delaney 2005c) Monitoring !TCardiac function, pulse rate, ECG if necessary, BP if indicated !Toxicity (see Adverse Effects/Overdosage) Client Information !To be effective, the animal must receive all doses as prescribed. Notify veterinarian if animal becomes lethargic or becomes exer-cise intolerant; develops shortness of breath or cough; or develops a c hange in behavior or attitude. Do not stop therapy without first conferring with veterinarian. Chemistry/Synonyms A beta 1-adrenergic blocking agent, atenolol occurs as a white, crys-talline powder. At 37°C, 26. 5 mg are soluble in 1 m L of water. The p H of the commercially available injection is adjusted to 5. 5-6. 5. Atenolol may also be known as atenololum, or ICI-66082; many tr ade names are available. Storage/Stability/Compatibility Tablets should be stored at room temperature and protected from heat, light and moisture. The injection solution should be stored at room temperature and protected from light. Atenolol injection is reported to be physically compatible with morphine sulfate injection and meperidine HCl for at least 4 hours. Dextrose injections, sodium chloride injections and combina-tions of the two are recommended for use as diluents when given pare nterally. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more informa-tion. HUMAN-LABELED PRODUCTS: Atenolol Tablets: 25, 50, & 100 mg; Tenormin® (Astra Zeneca); ge-neric; (Rx) Atenolol Injection: 5 mg/m L in 10 m L amps; Te normin®(Astra Zen-eca); (Rx) Also available in an oral fixed dose combination product with chlo-rthalidone.

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ATIPAMEZOLE HCL (at-i-pam-a-zole) Antisedan® ALPHA-2 ADRENERGIC ANTAGONIST Prescriber Highlights TT Alpha 2 adrenergic antagonist; antagonizes agonists such as medetomidine or xylazine TT No safety data on use in pregnant or lactating animals TT May reverse effects rapidly, including analgesia; animals should be observed & protected from self-harm or caus-ing harm to others TT Adverse Effects may include vomiting, diarrhea, hyper-salivation, tremors, or excitation Uses/Indications Atipamezole is labeled for use as a reversal agent for medetomidine and dexmedetomidine. It potentially could be useful for reversal of other alpha 2-adrenergic agonists as well (e. g., amitraz, xylazine, clonidine, tizanidine, brimonidine). Pharmacology/Actions Atipamezole competitively inhibits alpha 2-adrenergic receptors, thereby acting as a reversal agent for alpha 2-adrenergic agonists (e. g., medetomidine). Net pharmacologic effects are to reduce seda-tion, decrease blood pressure, increase heart and respiratory rates, and reduc e the analgesic effects of alpha 2-adrenergic agonists. Pharmacokinetics After IM administration in the dog, peak plasma levels occur in about 10 minutes. Atipamezole is apparently metabolized in the liver to compounds that are eliminated in the urine. The drug has an average plasma elimination half-life of about 2-3 hours. Contraindications/Precautions/Warnings While the manufacturer lists no absolute contraindications to the use of atipamezole, the drug is not recommended in pregnant or lactating animals due to the lack of data establishing safety. Caution should be used in administration of anesthetic agents to elderly or debilitated animals. When used as a reversal agent (antidote) for alpha 2-agonist t ox-icity, atipamezole's effects may subside before non-toxic levels of the offending ag ent are reached; repeat dosing may be necessary. Adverse Effects Potential adverse effects include occasional vomiting, diarrhea, hyper salivation, tremors, and brief excitation or apprehensiveness. Because reversal can occur rapidly, care should be exercised as animals emerg ing from sedation and analgesia may exhibit ap-prehensive or aggressive behaviors. After reversal, animals should be pr otected from falling. Additional analgesia (e. g., butorphanol) should be considered, particularly after painful procedures. Reproductive/Nursing Safety The manufacturer states that the drug is not recommended in preg-nant or lactating animals, or in animals intended for breeding due to lac k of data establishing safety in these animals. No other data was noted. Overdosage/Acute Toxicity Dogs receiving up to 10X the listed dosage apparently tolerated the drug without major effects. When overdosed, dose related effects seen included panting, excitement, trembling, vomiting, soft or liq-uid feces, vasodilatation of sclera and some muscle injury at the IM inject ion site. Specific overdose therapy should generally not be necessary. Drug Interactions The manufacturer states that information on the use of atipam-ezole with other drugs is lacking, therefore, caution should be taken when using with other drugs (other than medetomidine). The fol-lowing drug interactions have either been reported or are theoreti-cal in humans or animals receiving atipamezole and may be of sig-nificance in veterinary patients: T ! ALPHA1-ADRENERGIC BLOCKERS (e. g., prazosin ): Atipamezole is a relatively specific alpha-2 blocker it can also partially block al-pha1 receptors and reduce the effects of prazosin T ! ALPHA2-ADRENERGICS AGONISTS (e. g., detomidine, clonidine, brimo-nidine, xylazine, amitraz, etc. ): Atipamezole can reduce the effects (toxic or therapeutic) of these agents Doses T ! DOGS: For reversal of medetomidine: a) Give IM an equal volume of Antise dan® and Domitor® is ad-ministered (m L per m L). The actual concentration of Anti-se dan®will be 5X that of Domitor®, as Antisedan®is 5 mg/m L versus Domitor®'s 1 mg/m L. (Package Insert; Antisedan®— Pfizer) b) As above, but may give IV as well as IM. If it has been at least 45 minut es since medetomidine was given, may give atipa-mezole at half the volume of medetomidine if administered IV. If after 10-15 minutes an IM dose of atipamezole has not seemed to reverse the effects of medetomidine, an additional dose of atipamezole at H the volume of the medetomidine dose may be given. (Mc Grath and Ko 1997) For treatment of amitraz toxicity: a) 50 mcg/kg IM (Hugnet, Buronrosse et al. 1996) T ! CATS: For reversal of medetomidine as part of a medetomidine/ bu-torphanol or buprenorphine/ketamine/carprofen or meloxicam anesthesia/analgesia injectab le combination: a) Use an equal volume IM of atipamezole as medetomidine was used in the comb ination. (Ko 2005) T ! RABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For medetomidine reversal: 1 mcg/kg SC, IV or IP. Will re verse analgesia as well. (Ivey and Morrisey 2000) b) Mice, Rats, Gerbils, Hamsters, Guinea pigs: T o reverse xyla-zine or medetomidine: 0. 1-1 mg/kg IM, IP, IV or SC (Adam-cak and Otten 2000) T ! RUMINANTS: a) For reversal of alpha 2-adrene rgic agonists in bovine, new world camelids, ovine and caprine species: 0. 02-0. 1 mg/kg IV to effect (Haskell 2005b) T ! BIRDS: a) As a reversal agent for alpha 2-adrene rgic agonists (e. g., xyla-zine, detomidine, etc. ): 0. 5 mg/kg IM (Clyde and Paul-Mur-phy 2000)

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

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

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TIt is not known whether this drug is excreted in milk. Safety for use in the n ur sing mother has not been established. Adverse Effects Clinically significant adverse effects are apparently quite rare in patients (<1% in humans) receiving recommended doses of atra-curium and usually are secondary to histamine release. They can incl ude: allergic reactions, inadequate or prolonged block, hypoten-sion vasodilatation, bradycardia, tachycardia, dyspnea, broncho-, laryng o-spasm, rash, urticaria, and a reaction at the injection site. Patients developing hypotension usually have preexisting severe car-diovascular disease. Overdosage/Acute Toxicity Overdosage possibilities can be minimized by monitoring muscle twitch responses to peripheral nerve stimulation. Increased risks of hypotension and histamine release occur with overdoses, as well as prolonged duration of muscle blockade. Besides treating conservatively (mechanical ventilation, O 2, flu -ids, etc. ), reversal of blockade may be accomplished by administer-ing an anticholinesterase agent (edrophonium, physostigmine, or neost igmine) with an anticholinergic (atropine or glycopyrrolate). Reversal is usually attempted (in humans) approximately 20-35 minutes after the initial dose, or 10-30 minutes after the last mainte-nance dose. Reversal is usually complete within 8-10 minutes. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atracurium and may be of significance in veterinary patients: The following agents may enhance the neuromuscular blocking ac tivity of atracurium: !TAMINOGLYCOSIDE ANTIBIOTICS (gentamicin, etc. ) !TANESTHETICS, GENERAL (enflurane, isoflurane, halothane ) !TBACITRACIN, POLYMYXIN B (systemic ) !TPROCAINAMIDE !TQUINIDINE !TLITHIUM !TMAGNESIUM SALTS !TANTICONVULSANTS (phenytoin, carbamazepine ): Have been reported to both decrease the effects and duration of neuromuscular block-ade !TOTHER MUSCLE RELAXANT DRUGS: May cause a synergistic or antago-nistic effect !TSUCCINYLCHOLINE: May speed the onset of action and enhance the neuromuscular blocking actions of atracurium. Do not give atra-curium until succinylcholine effects have diminished. Doses !TDOGS: a) Induction dose: 0. 22 mg/kg IV, give 1/10th to 1/6th of this dose initially as a “priming” dose, followed 4-6 minutes later with the remainder and a sedative/hypnotic agent. Intraoperative dose: 0. 11 mg/kg IV (Mandsager 1988) b) After acepromazine and/or meperidine premedication, give 0. 5 mg/kg IV initially. Induce anesthesia with thiopental or methohe xital; after intratracheal intubation maintain anes-thesia with nitrous oxide:oxygen (2:1) and halothane (0. 5%) using c ontrolled ventilation. Additional doses of atracurium may be administered at 0. 2 mg/kg IV. (Jones 1985b) c) For neuromuscular blockade augmentation during corneal surg ery: 0. 15 mg/kg IV (Nasisse 2004) d) As a muscle relaxant to facilitate intubation in patients with severe blunt trauma: IV started and acepromazine 0. 01 mg/kg plus butorphanol 0. 1 mg/kg plus ketamine 1 mg/kg is infused. If patient requires intubation, give atracurium at 0. 25 mg/kg IV push. (Crowe 2004) e) For induction of respiratory muscle paralysis during me-chanical ventilation: Loading dose: 0. 2-0. 5 mg/kg IV, then a co nstant rate infusion 5 minutes later of 3-9 mcg/kg/min. Use D5W or 0. 9% sodium chloride for diluent; do not mix with other drugs. Respiratory and cardiovascular monitoring should be provided. (Dhupa 2005) !TCATS: a) Induction dose: 0. 22 mg/kg IV, give 1/10th to 1/6th of this dose initially as a “priming” dose, followed 4-6 minutes later with the remainder and a sedative/hypnotic agent. Intraoperative dose: 0. 11 mg/kg IV (Mandsager 1988) b) For induction of respiratory muscle paralysis during me-chanical ventilation: Loading dose: 0. 2-0. 5 mg/kg IV, then a co nstant rate infusion 5 minutes later of 0. 37 mcg/kg/min. Use D5W or 0. 9% sodium chloride for diluent; do not mix with other drugs. Respiratory and cardiovascular monitoring should be provided. (Dhupa 2005) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For paralysis for periophthalmic surgery: 0. 1 mg/kg (Ivey and Morrisey 2000) !THORSES: (Note : ARCI UCGFS Class 2 Drug) a) Intraoperative dose: 0. 055 mg/kg IV (Mandsager 1988) Monitoring !TLevel of neuromuscular blockade !TCardiac rate Client Information !This drug should only be used by professionals familiar with its use. Chemistry/Synonyms A synthetic, non-depolarizing neuromuscular blocking agent, atra-curium, is a bisquaternary, non-choline diester structurally similar to metocurine and tubocurarine. It occurs as white to pale yellow powder; 50 mg are soluble in 1 m L of water, 200 mg are soluble in 1 m L of alcohol, and 35 mg are soluble in 1 m L of normal saline. Atracurium besylate may also be known as: 33A74, atracurium besilat e, BW-33A, Abbottracurium®, Atracur®, Faulcurium®, Ifacur®, Laurak®, Mycurium®, Relatrac®, Sitrac®, Trablok®, Tracrium®, or Tracur®. Storage/Stability/Compatibility The commercially available injection occurs as clear, colorless solu-tion and is a sterile solution of the drug in sterile water for injection. The p H of this solution is 3. 25-3. 65. Atracurium injection should be stored in the refrigerator and protected against freezing. At room temperature, approximately 5% potency loss occurs each month; when refrigerated, a 6% potency loss occurs over a years' time. Atracurium is compatible with the standard IV solutions, but while stable in lactated Ringer's for 8 hours, degradation occurs more rapidly. It should not be mixed in the same IV bag or syringe, or given through the same needle with alkaline drugs (e. g., barbitu-rates) or solutions (sodium bicarbonate) as precipitation may occur. It is incompatible with propofol, diazepam, thiopental, aminophyl-line, cefazolin, heparin, ranitidine, and sodium nitroprusside.

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T TDosage 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: Atracurium Besylate Injection: 10 mg/m L in 5 m L single-use and 10 m L multi-use vials; Tracrium® (Glaxo Wellcome); Atracurium Besylate (Bedford Labs); (Rx) ATROPINE SULFATE (a-troe-peen) ANTICHOLINERGIC Prescriber Highlights TT Prototype antimuscarinic agent used for a variety of indi-cations (bradycardia, premed, antidote, etc. ) TT Contraindicated in conditions where anticholinergic ef-fects would be detrimental (e. g., narrow angle glaucoma, tachycardias, ileus, urinar y obstruction, etc. ) TT Adverse effects are dose related & anticholinergic in nature: 1) dry secretions, 2) initial bradycardia, then tachycardia, 3) slow gut & urinary tract, 4) mydriasis/ cycloplegia TT Drug interactions Uses/Indications The principal veterinary indications for systemic atropine include: T ! Preanesthetic to prevent or reduce secretions of the respiratory tract T ! reat sinus bradycardia, sinoatrial arrest, and incomplete A V block T ! Differentiate vagally-mediated bradycardia for other causes T ! As an antidote for overdoses of cholinergic agents ( e. g., phys-ostigmine, etc. ) T ! As an antidote for organophosphate, carbamate, muscarinic mushroom, blue-green algae intoxication T ! Hypersialism T ! reatment of bronchoconstrictive disease Pharmacology/Actions Atropine, like other antimuscarinic agents, competitively inhib-its acetylcholine or other cholinergic stimulants at postganglionic parasympathet ic neuroeffector sites. High doses may block nico-tinic receptors at the autonomic ganglia and at the neuromuscu-lar junction. Pharmacologic effects are dose related. At low doses salivatio n, bronchial secretions, and sweating (not horses) are in-hibited. At moderate systemic doses, atropine dilates and inhibits acco mmodation of the pupil, and increases heart rate. High doses will decrease GI and urinary tract motility. Very high doses will in-hibit gastric secretion. Pharmacokinetics Atropine sulfate is well absorbed after oral administration, IM in-jection, inhalation, or endotracheal administration. After IV ad-ministration peak effects in heart rates occur within 3-4 minutes. Atropine is well distributed throughout the body and crosses into the CNS, across the placenta, and can distribute into the milk in small quantities. Atropine is metabolized in the liver and excreted into the urine. Appr oximately 30-50% of a dose is excreted unchanged into the urine. The plasma half-life in humans has been reported to be be-tween 2-3 hours. Contraindications/Precautions/Warnings Atropine is contraindicated in patients with narrow-angle glau-coma, synechiae (adhesions) between the iris and lens, hypersen-sitivity to anticholinergic drugs, tachycardias secondary to thyro-toxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac stat us during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ulcerative colitis, obstructive uropathy, and myasthenia gravis (unless used to reverse adverse muscarinic ef-fects secondary to therapy). Atropine may aggravate some signs seen w ith amitraz toxicity, leading to hy pertension and further in-hibition of peristalsis. Antimuscarinic agents should be used with extreme caution in patients w ith known or suspected GI infections. Atropine or other antimuscarinic agents can decrease GI motility and prolong reten-tion of the causative agent(s) or toxin(s) resulting in prolonged clinical signs. Antimuscarinic agents must also be used with ex-treme caution in patients with autonomic neuropathy. Antimuscarinic agents should be used with caution in patients with hepat ic or renal disease, geriatric or pediatric patients, hyper-thyroidism, hypertension, CHF, tachyarrhythmias, prostatic hyper-trophy, or esophageal reflux. Systemic atropine should be used cau-tiously in horses as it may decrease gut motility and induce colic in suscep tible animals. It may also reduce the arrhythmogenic doses of epinephrine. Use of atropine in cattle may result in inappetence and rumen stasis that may persist for several days. When used in food animals at doses up to 0. 2 mg/kg, FARAD reco mmends a 28 day meat and 6 day milk withdrawal time. (Haskell, Payne et al. 2005) Adverse Effects Adverse effects are basically extensions of the drug's pharmacologic effects and are generally dose related. At usual doses, effects tend to be mild in relatively healthy patients. The more severe effects listed tend to occur with high or toxic doses. GI effects can include dry mouth (xerostomia), dysphagia, constipation, vomiting, and thirst. GU effects may include urinary retention or hesitancy. CNS effects may include stimulation, drowsiness, ataxia, seizures, respiratory depression, etc. Ophthalmic effects include blurred vision, pupil dilation, cycloplegia, and photophobia. Cardiovascular effects in-clude sinus tachycardia (at higher doses), bradycardia (initially or at very low doses), hypertension, hypotension, arrhythmias (ectopic complexes), and circulatory failure. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these dr ugs are safe if they are not administered when the animal is near term. ) Atropine use in pregnancy may cause fetal tachycardia.

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Overdosage/Acute Toxicity For signs and symptoms of atropine toxicity see adverse effects above. If a recent oral ingestion, emptying of gut contents and administra-tion of activated charcoal and saline cathartics may be warranted. Tr eat clinical signs supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholinergic effects. Fluid therapy and standard treatments for shock may be instituted. The use of physostigmine is controversial and should probably be reserved for cases where the patient exhibits either extreme agi-tation and is at risk for injuring themselves or others, or for cases whe re supraventricular tachycardias and sinus tachycardias are se-vere or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult). If no response, may re-peat every 20 minutes until reversal of toxic antimuscarinic effects or cholinergic effects takes place. The human pediatric dose is 0. 02 mg/kg slow IV (repeat q10 minutes as above) and may be a rea-sonable choice for initial treatment of small animals. Physostigmine ad verse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving atropine and may be of significance in veterinary patients: The following drugs may enhance the activity or toxicity of atro-pine and its derivatives: !TAMANTADINE !TANTICHOLINERGIC AGENTS (other ) !TANTICHOLINERGIC MUSCLE RELAXANTS !TANTIHISTAMINES (e. g., diphenhydramine ) !TDISOPYRAMIDE !TMEPERIDINE !TPHENOTHIAZINES !TPROCAINAMIDE !TPRIMIDONE !TTRICYCLIC ANTIDEPRESSANTS (e. g., amitriptyline, clomipramine ) !TAMITRAZ : Atropine may aggravate some signs seen with amitraz toxicity; leading to hypertension and further inhibition of peri-stalsis !TANTACIDS : May decrease PO atropine absorption; give oral atro-pine at least 1 hour prior to oral antacids !TCORTICOSTEROIDS (long-term use ): may increase intraocular pressure !TDIGOXIN (slow-dissolving ): Atropine may increase serum digoxin levels; use regular digoxin tablets or oral liquid !TKETOCONAZOLE : Increased gastric p H may decrease GI absorption; administer oral atropine 2 hours after ketoconazole !TMETOCLOPRAMIDE : Atropine and its derivatives may antagonize the actions of metoclopramide Doses !TDOGS: As a preanesthetic adjuvant: a) 0. 022-0. 044 mg/kg IM or SC (Muir) b) 0. 074 mg/kg IV, IM or SC (Package Insert; At ropine Injectable, S. A. —Fort Dodge) c) 0. 02-0. 04 mg/kg SC, IM or IV (Morgan 1988) For adjunctive treatment of bradycardias, Incomplete A V block, et c. : a) 0. 022-0. 044 mg/kg IM, SC, or IV as needed; or 0. 04 mg/kg PO thre e to four times daily (Morgan 1988) b) 0. 02-0. 04 mg/kg IV or IM (Russell and Rush 1995) T o differentiate vagally-mediated bradyarrhythmias from non-vagal bradyarrhythmias (Atropine Response T est): RISHNIW P REFERENCE: 1) Record ECG at baseline; 2) Administer 0. 04 mg/kg atropine IV; 3) Wait 15 minutes; 4) Record ECG for at least 2 minutes (use slow paper speed). If the response is incomplete, repeat steps 2-4. Persistent sinus tachycardia at >140 bpm is expected in most dogs with vagally-mediated bradycardia. KITTLESON P REFERENCE: 1) Record ECG at baseline; 2) Admin-ister 0. 04 mg/kg atropine SQ; 3) Wait 30 minutes; 4) Record ECG for at least 2 minutes (use slow paper speed). Persistent sinus tachycardia at >140 bpm is expected in most dogs with vagally-mediated bradycardia. (Rishniw and Kittleson 2007) For treatment of cholinergic toxicity: a) 0. 2-2 mg/kg; give Gth of the dose IV and the remainder SC or IM (Morgan 1988) b) 0. 2-0. 5 mg/kg; G o f the dose IV and the remainder IM or SC (Firth 2000) Fo r treatment of bronchoconstriction: a) 0. 02-0. 04 mg/kg for a duration of effect of 1-1. 5 hours (Papic h 1986) !TCATS: As a preanesthetic adjuvant: a) 0. 022-0. 044 mg/kg IM or SC (Muir) b) 0. 074 mg/kg IV, IM or SC (Package Insert; At ropine Injectable, S. A. —Fort Dodge) c) 0. 02-0. 04 mg/kg SC, IM or IV (Morgan 1988) Fo r treatment of bradycardias: a) 0. 022-0. 044 mg/kg IM, SC, or IV as needed; or 0. 04 mg/kg PO thre e to four times daily (Morgan 1988) b) 0. 02-0. 04 mg/kg SC, IM or IV q4-6h (Miller 1985) Fo r treatment of cholinergic toxicity: a) 0. 2-2 mg/kg; give Gth of the dose IV and the remainder SC or IM (Morgan 1988) b) 0. 2-0. 5 mg/kg; G o f the dose IV and the remainder IM or SC (Post and Keller 2000) !TFERRETS: a) As a premed: 0. 05 mg/kg SC or IM (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For prevention of bradycardia, and to decrease air-way secretions: 0. 04-2 mg/kg; re-dosed q10-15 minutes as nee ded to produce mydriasis. b) T o treat organophosphate toxicity: 10 mg/kg SC q20 minutes (Iv ey and Morrisey 2000) !TCATTLE: Note : When used in food animals at doses up to 0. 2 mg/kg, FAR-AD recommends a 28 day meat and 6 day milk withdrawal time. (Hask ell, Payne et al. 2005) As a preanesthetic: a) Because of a lack of extended efficacy and potential adverse rea ctions, atropine is not used routinely as a preoperative agent in ruminants. If it is desired for use, a dose of 0. 06-0. 12 mg/kg IM has been suggested. (Thurmon and Benson 1986) For adjunctive treatment of bovine hypersensitivity disease: a) 1 gram per cow once daily followed by 0. 5 gram/cow in 2-3 day s (method of administration not specified) (Manning and Scheidt 1986)

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TFor treatment of cholinergic toxicity (organophosphates): a) 0. 5 mg/kg (average dose); give Gth o f the dose IV and the remainder SC or IM; may repeat q3-4h for 1-2 days (Bailey 1986) !THORSES: (Note : ARCI UCGFS Class 3 Drug) For treatment of bradyarrhythmias due to increased parasym-pathetic tone: a) 0. 01-0. 02 mg/kg IV (Mogg 1999) b) 0. 045 mg/kg parenterally (Hilwig 1987) As a b ronchodilator: a) 5 mg IV for a 400-500 kg animal (Beech 1987) b) 5-7 mg/kg IV for a 450 kg horse can serve as a rescue medi-cation in cases with severe airway obstruction, but it has an abb reviated duration of action (0. 5-2 hours) and adverse effects (ileus, CNS toxicity, tachycardia, increased mucus se-cretion, and impaired mucociliary clearance) limit its use to a single r escue dose. (Rush 2006b) For organophosphate poisoning: a) Approximately 1 mg/kg given to effect, IV (use mydriasis and absenc e of salivation as therapy endpoints), may repeat every 1. 5-2 hours as required subcutaneously (Oehme 1987) b) 0. 22 mg/kg, Gth o f the dose administered IV and the remain-der SC or IM (Package Insert; At ropine Injectable, L. A. — Fort Dodge) !TSWINE: The equine dose (above) may be used to initially treat organo-phosphate toxicity in swine. As an a djunctive preanesthetic agent: a) 0. 04 mg/kg IM (Thurmon and Benson 1986) !TSHEEP, GOATS: As a preanesthetic: a) Because of a lack of extended efficacy and potential adverse rea ctions, atropine is not used routinely as a preoperative agent in ruminants. If it is desired for use, a dose of 0. 15-0. 3 mg/kg IM has been suggested. (Thurmon and Benson 1986) For treating organophosphate toxicity: a) Use the dose for cattle (above). !TBIRDS: For organophosphate poisoning: a) 0. 1-0. 2 mg/kg IM or SC as needed (Clubb 1986) b) 0. 2 mg/kg IM every 3-4 hours as needed; Gth the initial dose is administered. Use with pralidoxime (not in raptors) at 10-20 mg/kg IM q8-12h as needed. Do not use prali-doxime in carbamate poisonings. T o assist in diagnosing organophosphate poisoning (with histo ry, clinical signs, etc. ) in birds presenting with bradycar-dia: May administer atropine at 0. 02 mg/kg IV. If bradycar-dia does not reverse, may consider organophosphate toxicity. (La Bo nd 2006) As a preanesthetic: a) 0. 04-0. 1 mg/kg IM or SC once (Clubb 1986) !TREPTILES: For organophosphate toxicity in most species: a) 0. 1-0. 2 mg/kg SC or IM as needed. (Gauvin 1993) Fo r ptyalism in tortoises: a) 0. 05 mg/kg (50 ￿cg/kg) SC or IM once daily (Gauvin 1993) Monitoring Dependent on dose and indication: !THeart rate and rhythm !Thirst/appetite; urination/defecation capability !TMouth/secretions dryness Client Information !TParenteral atropine administration is best performed by profes-sional staff and where adequate cardiac monitoring is available. !TIf animal is receiving atropine systemically, allow animal free ac-cess to water and encourage drinking if dry mouth is a problem. Chemistry/Synonyms The prototype tertiary amine antimuscarinic agent, atropine sul-fate is derived from the naturally occurring atropine. It is a racemic mixtur e of d-hyoscyamine and l-hyoscyamine. The l-form of the drug is active, while the d-form has practically no antimuscarinic activity. Atropine sulfate occurs as colorless and odorless crystals, or white, crystalline powder. One gram of atropine sulfate is soluble in approximately 0. 5 m L of water, 5 m L of alcohol, or 2. 5 m L of glycerin. Aqueous solutions are practically neutral or only slightly acidic. Commercially available injections may have the p H adjusted to 3. 0-6. 5. Atropine may also be known as dl-hyoscyamine. Atropine sulfate may also be known as: atrop. sulph., atropine sulphate, or atropini sulfas; many trade names are available. Storage/Stability/Compatibility Atropine sulfate tablets or soluble tablets should be stored in well-closed containers at room temperature (15-30°C). Atropine sulfate for injection should be stored at room temperature; avoid freezing. Atropine sulfate for injection is reportedly compatible with the following agents: benzquinamide HCl, butorphanol tartrate, chlorpromazine HCl, cimetidine HCl (not with pentobarbital), dimenhydrinate, diphenhydramine HCl, dobutamine HCl, dro-peridol, fentanyl citrate, glycopyrrolate, hydromorphone HCl, hy-droxyzine HCl (also with meperidine), meperidine HCl, morphine sulfat e, nalbuphine HCl, pentazocine lactate, pentobarbital sodium (OK for 5 minutes, not 24 hours), perphenazine, prochlorperazine edisylate, promazine HCl, promethazine HCl (also with meperi-dine), and scopolamine HBr. Atropine sulfate is reported physically incompatible with norepi-nephrine bitartrate, metaraminol bitartrate, methohexital sodium, and so dium bicarbonate. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Atropine Sulfate for Injection: 0. 54 mg/m L (1/120 grain); Atroject ® (Vetus), Atropine SA® (Butler), generic, (various); (Rx) Atropine Sulfate for Injection: 15 mg/m L (organophosphate treat-ment) 100 m L vial; Atro pine L. A. ® (Butler), (RXV); generic (vari-ous) (Rx) Atropine is labeled for use in dogs, cats, horses, cattle, sheep, and swine in the USA. No withdrawal times are mandated when used in food animals in the USA, but FARAD recommends a 28 day meat and 6 day milk withdrawal time. (Haskell, Payne et al. 2005). In the UK, slaughter withdrawal for cattle, sheep, and pigs is 14 days when used as an antimuscarinic and 28 days when used as an antidote; milk withdrawal is 3 days when used as an antimuscarinic and 6 days when used as an antidote. For guidance with determining use associated withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix)

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The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Atropine Sulfate for Injection: 0. 05 mg/m L in 5 m L syringes; Atropine Sulfate (Hospira); (Rx) 0. 1 mg/m L in 5 and 10 m L syringes; Atropine Sulfate (Hospira); (Rx) 0. 3 mg/m L in 1 m L and 30 m L vials; generic; (Rx) 0. 4 mg/m L in 1 m L amps and 1, 20, and 30 m L vials; generic; (Rx) 0. 5mg/m L in 1 and 30 m L vials & 5 m L syring es; generic; (Rx) 0. 8 mg/m L in 0. 5 and 1 m L amps and 0. 5 m L syringes; generic; (Rx) 1 mg/m L in 1 m L amps and vials and 10 m L syringes; generic; (Rx) 0. 5 mg, 1 mg & 2 mg pre-filled, auto-injectors; Atro P en®(Meridian Medical T echnologies); (Rx) Atropine Sulfate Tablets: 0. 4 mg; Sal-Tropine® (Hope); (Rx) See also the monograph for atropine sulfate for ophthalmic use in the appe ndix. Atropine sulfate ophthalmic drops have been used buccally to decrease excessive oral secretions in human patients. AURANOFIN (au-rane-oh-fin) Ridaura® ORAL GOLD IMMUNOSUPPRESSIVE Prescriber Highlights TT Orally administered gold; used for pemphigus & idiopath-ic polyarthritis in dogs or cats TT Can be quite toxic & expensive, intensive ongoing moni-toring required; dosages must be compounded from 3 mg capsules TT Probably less toxic, but also less efficacy than injectable gold TT Considered contraindicated in SLE (exacerbates) TT Known teratogen & maternotoxic TT Renal, hepatic & GI toxicity possible; dose dependent immune-mediated thrombocytopenia, hemolytic anemia or leukopenias have been seen Uses/Indications Auranofin has been used to treat idiopathic polyarthritis and pem-phigus foliaceous in dogs and cats. Several clinicians report that while auranofin may b e less toxic, it also less efficacious than inject-able gold (aurothioglucose). Pharmacology/Actions Auranofin is an orally available gold salt. Gold has antiinflammato-ry, antirheumatic, immunomodulating, and antimicrobial (in vitro) effec ts. The exact mechanisms for these actions are not well under-stood. Gold is taken up by macrophages where it inhibits phagocy-tosis and may inhibit lysosomal enzyme activity. Gold also inhib-its the release of histamine, and the production of prostaglandins. While gold does have antimicrobial effects in vitro, it is not clinically useful for this purpose. Auranofin suppresses helper T-cells, without affect ing suppressor T-cell populations. Pharmacokinetics Unlike other available gold salts, auranofin is absorbed when given by mouth (20-25% of the gold) primarily in the small and large intestines. In contrast to the other gold salts, auranofin is only mod-erately bound to plasma proteins (the others are highly bound). Auranofin cr osses the placenta and is distributed into maternal milk. Tissues with the highest levels of gold are kidneys, spleen, lungs, adrenals and liver. Accumulation of gold does not appear to occur, unlike the parenteral gold salts. About 15% of an administered dose (60% of the absorbed dose) is excreted by the kidneys, the remain-der in the feces. Contraindications/Precautions/Warnings Auranofin should only be administered to animals where other less expensive and toxic therapies are ineffective and the veterinarian and owner are aware of the potential pitfalls of auranofin therapy and are willing to accept the associated risks and expenses. Gold salts are contraindicated in SLE as they may exacerbate the signs associ-ated with this disease. Adverse Effects A dose dependent immune-mediated thrombocytopenia, hemolytic anemia or leukopenias have been noted in dogs. Discontinuation of the drug and administration of steroids has been recommended. Auranofin has a higher incidence of dose dependent GI disturbances (particularly diarrhea) in dogs than with the injectable products. Discontinuation of the drug or a lowered dose will generally resolve the problem. Renal toxicity manifested by proteinuria is possible as is hepatotoxicity (increased liver enzymes). These effects are less likely than either the GI or hematologic effects. Dermatosis and cor-neal ulcers have also been associated with auranofin therapy. Reproductive/Nursing Safety Auranofin has been demonstrated to be teratogenic and mater-notoxic in laboratory animals; it should not be used during preg-nancy unless the owner accepts the potential risks of use. In humans, the FDA cat egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Following auranofin administration, gold is excreted in the milk of ro dents. Trace amounts appear in the serum and red blood cells of nursing offspring. As this may cause adverse effects in nursing off-spring, switching to milk replacer is recommended if auranofin is to be co ntinued in the dam. Because gold is slowly excreted, persistence in milk will occur even after the drug is discontinued. Overdosage/Acute Toxicity Very limited data is available. The minimum lethal oral dose in rats is 30 mg/kg. It is recommended that gut-emptying protocols be employed after an acute overdose when applicable. Chelating agents (e. g., penicillamine, dimercaprol) for severe toxicities have been used, but are controversial. One human patient who took an overdose over 10 days developed various neurologic sequelae, but eventually (after 3 months) recovered completely after discontinua-tion of the drug and chelation therapy.

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Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving auranofin and may be of significance in veterinary patients: T ! CYTOTOXIC AGENTS (including high dose corticosteroids ): Aura-nofin's safety when used with these agents has not been estab-lished; use with caution T ! PENICILLAMINE or ANTIMALARIAL DRUGS : Use with gold salts is not recommended due to the increased potential for hematologic or renal toxicity Laboratory Considerations T ! In humans, response to tuberculin skin tests may be enhanced; veterinary significance is unclear Doses T ! DOGS: a) For immune-mediated arthropathies and dermatopathies: 0. 05-0. 2 mg/kg (up to 9 mg/day total dose) PO q12h (Vaden and Cohn 1994), (Kohn 2003) b) F or treatment of pemphigus complex (with corticosteroids): 0. 12-0. 2 mg/kg twice daily (White 2000) T ! CATS: a) As a rescue drug for feline pemphigus and for idiopathic der-matoses and plasma cell pododermatitis/stomatitis: 0. 2-0. 3 mg/kg twice daily; must be reformulated for accurate dosing. (Morris 2004) Monitoring The following should be performed prior to therapy, then once monthly for 2-3 months, then every other month: T ! Hepatic and renal function tests (including urinalysis); T ! CBC, with platelet counts; Note : eosinophilia may denote im-pending reactions Client Information T ! Clients must understand that several months may be required before a positive response may be seen. T ! Commitment to the twice daily dosing schedule, the costs asso-ciated with therapy, and the potential adverse effects should be discussed be f ore initiating therapy. Chemistry/Synonyms An orally administered gold compound, auranofin occurs as a white, odorless, crystalline powder. It is very slightly soluble in wa-ter and soluble in alcohol. Auranofin contains 29% gold. Auranofin may also be known as: SKF-39162, SKF-D-39162, Crisinor®, Crisofin®, Goldar®, Ridaura® or Ridauran®. Storage/Stability Store capsules in tight, light resistant containers at room tempera-ture. After manufacture, expiration dates of 4 years are assigned to the capsules. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Auranofin Capsules: 3 mg; Ridaura® (SK-Beecham); (Rx) Aurothioglucose — See Gold Salts, Injectable AZAPERONE (a-zap-peer-ohne) Stresnil® BUTYROPHENONE TRANQUILIZER Prescriber Highlights TT A butyrophenone tranquilizer for swine; also used in wildlife TT Do not give IV, allow pigs to be undisturbed for 20 min-utes after injecting TT No analgesic activity TT May cause transient piling, salivation & shivering Uses/Indications Azaperone is officially indicated for the “control of aggressiveness when mixing or regrouping weanling or feeder pigs weighing up to 36. 4 kg” (Package Insert, Stresnil ®—P/M; Mallinckrodt). It is also used clinically as a general tranquilizer for swine, to allow piglets to be accepted by aggressive sows, and as a preoperative agent prior to general anesthesia or cesarean section with local anesthesia. Azaperone has been used as a neuroleptic in horses, but some horses d evelop adverse reactions (sweating, muscle tremors, panic reaction, CNS excitement) and IV administration has resulted in significant arterial hypotension. Because of these effects, most clini-cians avoid the use of this drug in equines. Pharmacology/Actions The butyrophenones as a class cause tranquilization and sedation (sedation may be less than with the phenothiazines), anti-emetic ac-tivity, reduced motor activity, and inhibition of CNS catecholamines (dopamine, no repinephrine). Azaperone appears to have minimal effects on respiration and may inhibit some of the respiratory de-pressant actions of general anesthetics. A slight reduction of arte-rial blood pressure has been measured in pigs after IM injections of azape rone, apparently due to slight alpha-adrenergic blockade. Azaperone has been demonstrated to prevent the development of halothane-induced malignant hyperthermia in susceptible pigs. Preliminary studies have suggested that the effects of butyrophe-nones may be antagonized by 4-aminopyridine. Pharmacokinetics Minimal information was located regarding actual pharmacokinetic parameters, but the drug is considered to have a fairly rapid onset of action following IM injections in pigs (5-10 minutes) with a peak effect at approximately 30 minutes post injection. It has a duration of action of 2-3 hours in young pigs and 3-4 hours in older swine. The drug is metabolized in the liver with 13% of it excreted in the feces. At 16 hours post-dose, practically all of the drug is eliminated from the body; however in the UK a 10-day slaughter withdrawal has been assigned. Contraindications/Precautions/Warnings When used as directed, the manufacturer reports no contraindica-tions (other than for slaughter withdrawal) for the drug. It should not be g iven IV as a significant excitatory phase may be seen in pigs. Avoid use in very cold conditions as cardiovascular collapse may occur secondary to peripheral vasodilation. Do not exceed dosing recommendation in boars as the drug may cause the penis to b e extruded.

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Because Vietnamese Pot Bellied pigs may have delayed absorp-tion due to sequestration of the drug in body fat, re-dose with ex-treme caution; deaths have resulted after repeat dosing. Adverse Effects Transient salivation, piling, panting and shivering have been re-ported in pigs. Pigs should be left undisturbed after injection (for appro ximately 20 minutes) until the drug's full effects have been ex-pressed; disturbances during this period may trigger excitement. Azaperone has minimal analgesic effects and is not a substitute for ap propriate anesthesia or analgesia. Doses above 1 mg/kg may cause the penis to be extruded in boars. Overdosage/Acute Toxicity Overdoses (>1 mg/kg) in boars may cause penis extrusion leading to damage. Drug Interactions No specific drug interactions have been reported for azaperone. The following interactions have been reported for the closely related compounds, haloperidol or droperidol: T ! CNS DEPRESSANT AGENTS (barbiturates, narcotics, anesthetics, etc. ) may cause additive CNS depression if used with butyrophenones Doses T ! SWINE: For approved indication of mixing feeder or weanling pigs: a) 2. 2 mg/kg deeply IM (see client information below) (Package Insert; S tresnil® —P/M Mallinckrodt; Note : No longer on US market) For labeled indications (Stresnil®—Janssen U. K. ): a) Note : all doses are to be given IM directly behind the ear using a long hypodermic needle and given as closely behind the ear as possible and perpendicular to the skin. Aggression (prevention and cure of fighting; including re-grouping of piglets, porkers, fattening pigs): 2 mg/kg (1 m L/20 kg) Treatment of aggression in sows: 2 mg/kg (1 m L/20 kg) Stress (restlessness, anxiety, etc. ): 1-2 mg/kg (0. 5-1 m L/20 kg) Transpo rt of boars: 1 mg/kg (0. 5 m L/20 kg) Transport of weaners: 0. 4-2 mg/kg (0. 4-1 m L/20 kg) Obstetrics: 1 mg/kg (0. 5 m L/20 kg) As a premed: 1-2 mg/kg (0. 5-1 m L/20 kg) Monitoring T ! Level of sedation Client Information T ! Must be injected IM deeply, either behind the ear and perpen-dicular to the skin or in the back of the ham. All animals in groups to be mixed must be treated. Chemistry/Synonyms A butyrophenone neuroleptic, azaperone occurs as a white to yel-lowish-white macrocrystalline powder with a melting point between 90-95°C. I t is practically insoluble in water; 1 gram is soluble in 29 m L of alcohol. Azaperone may also be known as azaperonum, R-1929, Stresnil ®, or Suicalm®. Storage/Stability/Compatibility Azaperone should be stored at controlled room temperature (15-25°C) and away from light. Do not store above 25°C. Once the vial is opened it should be used within 28 days. No information was located regarding mixing azaperone with other compounds. Dosage Forms/Regulatory Status VETERINARY-LABELED P RODUCTS: Note : Not currently marketed in the USA: Azaperone 40 mg/m L for Injection in 20 m L vials (6 vials/ box); Stresnil® (Schering-Plough); (Rx). In the UK: Azaperone 40 mg/m L for Injection in 100 m L vials; Stres -nil® (Janssen—UK); (POM-V) Pigs may be slaughtered for human consump tion only after 10 days from the last treatment. The ARCI (Racing Commissioners International) has designated this drug as a class 2 substanc e. See the appendix for more information. HUMAN-LABELED PRODUCTS: None AZATHIOPRINE AZATHIOPRINE SODIUM (ay-za-thye-oh-preen) Imuran® IMMUNOSUPPRESSANT Prescriber Highlights TT Purine antagonist immunosuppressive used for a variety of autoimmune diseases TT Known mutagen & teratogen; use with caution in pa-tients with hepatic disease TT Bone marrow depression principal adverse effect; GI ef-fects (including GI distress, pancreatitis & hepatotoxicity) also seen TT Usually not used in cats as they are very sensitive to bone marrow effects Uses/Indications In veterinary medicine, azathioprine is used primarily as an im-munosuppressive agent in the treatment of immune-mediated diseases in do gs. See Doses below for more information. For auto-agglutinizing immune mediated hemolytic anemia, azathioprine is gener ally recommended to start at the time of diagnosis. When used in combination with cyclosporine, azathioprine has been used to prevent rejection of MHC-matched renal allografts in dogs. Although the drug can be very toxic to bone marrow in cats, it is sometimes use d to treat feline autoimmune skin diseases. Pharmacology/Actions While the exact mechanism how azathioprine exerts its immuno-suppressive action has not been determined, it is probably depen-dent on several factors. Azathioprine antagonizes purine metabo-lism thereby inhibiting RNA, DNA synthesis and mitosis. It may also cause chro mosome breaks secondary to incorporation into nucleic acids and cellular metabolism may become disrupted by the drug's ability to inhibit coenzyme formation. Azathioprine has greater ac-tivity on delayed hypersensitivity and cellular immunity than on humoral antibody responses. Clinical response to azathioprine may require up to 6 weeks.

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Pharmacokinetics Azathioprine is absorbed from the GI tract and is rapidly metabo-lized to mercaptopurine; it is then further metabolized to several other compounds. These metabolites are excreted by the kidneys. Only minimal amounts of either azathioprine or mercaptopurine are excreted unchanged. Cats have low activity of thiopurine methyltransferase (TPMT), one of the routes used to metabolize azathioprine. Approximately 11% of humans have low thiopurine methyltransferase activity, and these individuals have a greater incidence of bone marrow sup-pression, but also greater azathioprine efficacy. Dogs have variable TMPT a ctivity levels similar to that seen in humans, which may explain why some canine patients respond better and/or develop more myelotoxicity than others. However, one study (Rodriguez, Mackin et al. 2004) in dogs did not show significant correlation between TMPT activity in red blood cells and drug toxicity. Contraindications/Precautions/Warnings Azathioprine is contraindicated in patients hypersensitive to it. The drug should be used cautiously in patients with hepatic dysfunction. Use of azathioprine in cats is controversial; they seem to be more susceptible to azathioprine's bone marrow suppressive effects. Adverse Effects The principal adverse effect associated with azathioprine is bone marrow suppression. Cats are more prone to develop these effects and the drug is generally not recommended for use in this species. Leukopenia is the most prevalent consequence, but anemias and thrombocytopenia may also be seen. GI upset, poor hair growth, acute pancreatitis and hepatotoxicity have been associated with azathioprine therapy in dogs. Because azathioprine depresses the immune system, animals may be susceptible to infections or neoplastic illnesses with long-term use. In recovering dogs with immune-mediated hemolytic anemia, tape r the withdrawal of the drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound hyperimmune response. Reproductive/Nursing Safety Azathioprine is mutagenic and teratogenic in lab animals. In hu-mans, the FDA categorizes this drug as category D fo r 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 safe ty 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. ) Azathioprine is distributed into milk; it is recommended to use milk re placer while the dam is receiving azathioprine. Overdosage/Acute Toxicity No specific information was located regarding acute overdose of azathioprine. It is suggested to use standard protocols to empty the GI tract if ingestion was recent and to treat supportively. Contact an animal poison control center for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving azathioprine and may be of significance in veterinary patients: !TACE INHIBITORS (benazepril, enalapril, etc. ): Increased potential for hematologic toxicity !TALLOPURINOL : The hepatic metabolism of azathioprine may be decreased by concomitant administration of allopurinol; in humans, it is recommended to reduce the azathioprine dose to G-N usual if both drugs are to be used together !TAMINOSALICYLATES (sulfasalazine, mesalamine, olsalazine ): Increased risk for azathioprine toxicity !TNON-DEPOLARIZING MUSCLE RELAXANTS (e. g., pancuronium, tubocura-rine): The neuromuscular blocking activity of these drugs may be inhibited or reversed by azathioprine !TCORTICOSTEROIDS : Although azathioprine is often used with corti-costeroids, there is greater potential risk for toxicity development !TDRUGS A FFECTING MYELOPOIESIS (e. g., trimethoprim/sulfa, cyclophos-phamide, etc. ): Increased potential for hematologic toxicity !TWARFARIN : Potential for reduced anticoagulant effect Doses !TDOGS: As an immunosuppressive: a) For inflammatory bowel disease: Initially 2 mg/kg PO once daily for 2 weeks, then tapered to 2 mg/kg PO every other day for 2-4 weeks, then 1 mg/kg PO every other day. May take 2-6 weeks before beneficial effects are seen. (Moore 2004) b) For immune-mediated anemia, colitis, immune-mediated skin disease, and acquired myasthenia gravis: 2 mg/kg PO once daily (q24h); long-term therapy 0. 5-1 mg/kg PO every other day, with prednisolone administered on the alternate days (Papich 2001) c) For adjunctive therapy in myasthenia gravis in non-respon-sive patients: Initially, 1 mg/kg PO once daily. CBC is evalu-ated every 1-2 weeks. If neutrophil and platelet counts are nor mal after 2 weeks, dose is increased to 2 mg/kg PO once daily. CBC is repeated every week for the first month and then monthly thereafter. Recommend to discontinue aza-thioprine if WBC falls below 4,000 cells/mc L or neutrophil count is less than 1,000 cells/mc L. Serum ACHR antibody concentrations reevaluated q4-6 weeks. Azathioprine dose is tapered to every other day when clinical remission occurs and serum ACHR antibody concentrations are normalized. (Coates 2000) d) For lymphoplasmacytic enteritis if clinical response to pred-nisolone is poor or the adverse effects (of prednisolone) pre-dominate: azathioprine 2 mg/kg PO once daily for 5 days, then o n alternate days to prednisolone (Simpson 2003a) e) For severe cases (autoagglutination, hemolytic crisis with rapid decline of hematocrit, intravascular hemolysis, Cocker Spaniels) of immune-mediated hemolytic anemia: 2. 2 mg/kg PO once daily (q24h) in addition to prednisone (initially at 2. 2 mg/kg PO q12h until hematocrit reaches 25-30%; then dose is gradually tapered by approximately 25% q2-3 weeks until a dose of 0. 5 mg/kg PO q48h is reached). (Macintire 2006d) f) For adjunctive therapy in immune-mediated hemolytic ane-mia: 2 mg/kg PO once daily or on alternate days; continue until remission; then attempt to reduce prednisone to al-ternate day therapy. Azathioprine may be given on the days pre dnisone is not. If remission persists for 4 weeks, azathio-prine may be discontinued. For dogs sensitive to the side ef-fects of glucocorticoids, azathioprine may be used on alter-nate days. (Miller 2000) g) For severe and refractory inflammatory bowel disease: 2. 2 mg/ kg PO once daily; a lag time of 3-5 weeks is expected before clinical improvement is noted (Jergens and Willard 2000)

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Th) For adjunctive treatment of ocular fibrous histiocytomas: 2 mg/kg PO daily for 2 weeks, reevaluate, and reduce to 1 mg/ kg every other day for 2 weeks, then 1 mg/kg once weekly for 1 month (Riis 1986) i) In combination with cyclosporine, to prevent rejection of MHC-matc hed renal allografts in dogs: 1-5 mg/kg PO every other day (Gregory 2000) j) For perianal fistulas (anal furunculosis): In the study, ini-tially 2 mg/kg PO once daily (q24h) until a reduction in the size, number or inflammation of the fistulas was seen or total WBC <5000 cells/mc L or neutrophil count was <3500 cells/ mc L or platelet count <160,000 cells/mc L. Then reduce to 2 mg/kg PO every other day (q48h) and continued for 12 weeks as long as myelosuppression doesn't develop. After 12 weeks, reduce dose to 1 mg/kg PO every other day (q48h) with a planned therapy duration of 12 months. Prednisone was giv-en at 2 mg/kg PO once daily for the first two weeks of therapy; then at 1 mg/kg PO once daily for another 2 weeks and then discontinued. All dogs were placed on a limited antigen diet. No correlation with efficacy and lymphocyte blastogenesis ef-fect. Complete or partial remission in 64% of treated dogs, whic h is less than systemic cyclosporine or topical tacrolimus treatment, but azathioprine treatment is less expensive. (Har-kin, Phillips et al. 2007) k) For treatment of glomerulonephritis: 2 mg/kg PO once dai-ly. Immunosuppressive treatment is controversial. (Labato 2006) !TCATS: Note : Most do not recommend azathioprine for use in cats be-cause of the potential for development of fatal toxicity and the difficulty in a ccurately dosing. As an immunosuppressive: a) For immune-mediated dermatologic diseases: Cats are prone to develop bone marrow toxicity from azathioprine and the drug is generally recommended not to be used in this species. However, if the drug is to be used, the dose is 1. 1 mg/kg PO every other day. (Rosenkrantz 1989) b) For severe and refractory inflammatory bowel disease: Must be used with caution; myelotoxicity with severe neutropenia is possible. Azathioprine at 0. 3 mg/kg PO once every other day; may take 3-5 weeks before any beneficial effects. Admin-istration can be enhanced by crushing one 50 mg tablet and susp ending it in 15 m L of syrup resulting in a concentration of 3. 3 mg/m L. Must be shaken well before each use. If cat be-comes ill, rectal temperature and WBC should be determined immediat ely. (Willard 2002) !TFERRETS: As an immunosuppressive: a) For treating inflammatory bowel disease: Treatments include pr ednisone (1 mg/kg PO q12-24h), azathioprine (0. 9 mg/kg PO q24-72h), and dietary management. (Johnson 2006c) !THORSES: As an immunosuppressive: a) For various autoimmune skin diseases (e. g., pe mphigus fo-liaceous): 1-3 mg/kg PO q24h for 1 month, then every other day (q48h). May cause thrombocytopenia. Azathioprine used as a steroid-sparing drug; used with corticosteroids in an at-tempt to eventually decrease the amount of steroid needed. (W hite 2006) Monitoring !THemograms (including platelets) should be monitored closely; initially every 1-2 weeks and every1-2 months (some rec-ommend q2 weeks) once on maintenance therapy. It is rec-ommended by some clinicians that if the WBC count drops to be tween 5,000-7,000 cells/mm3 the dose be reduced by 25%. If WBC count drops below 5,000 cells/mm3 treatment should be discontinued until leukopenia resolves. !TLiver function tests; serum amylase, if indicated !TEfficacy Client Information !There is the possibility of severe toxicity developing from this drug including drug-related neoplasms or mortality; routine test-ing to detect toxic effects are necessary !TContact veterinarian should the animal exhibit symptoms of ab-normal bleeding, bruising, lack of appetite, vomiting or infection !TAlthough, no special precautions are necessary with handling in-tact tablets, wash hands after administering the drug; if using a co mpounded formulation, wear protective gloves or wash hands immediately after administration Chemistry/Synonyms Related structurally to adenine, guanine and hypoxanthine, azathio-prine is a purine antagonist antimetabolite that is used primarily fo r its immunosuppressive properties. Azathioprine occurs as an odorless, pale yellow powder that is insoluble in water and slightly soluble in alcohol. Azathioprine sodium powder for injection oc-curs as a bright yellow, amorphous mass. After reconstituting with ste rile water for injection to a concentration of 10 mg/m L, it has an approximate p H of 9. 6. Azathioprine/Azathioprine sodium may also be known as: aza-thioprinum, BW-57322, or NSC-39084; many trade names are avail-able. Storage/Stability/Compatibility Azathioprine tablets should be stored at room temperature in well-closed containers and protected from light. The sodium powder for injection should be stored at room tem-perature and protected from light. It is reportedly stable at neutral or a cidic p H, but will hydrolyze to mercaptopurine in alkaline solu-tions. This conversion is enhanced upon warming or in the presence of sulfhydryl-containing compounds (e. g., cysteine). After reconsti-tuting, the injection should be used within 24-hours as no preserva-tive is present. Azathioprine sodium is reportedly compatible with the following intravenous solutions: dextrose 5% in water, and sodium chloride 0. 45% or 0. 9%. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized ref-erences or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Azathioprine Tablets: 25 mg, 50 mg, 75 mg & 100 mg; Azasan®(aai P-harma); Imuran® (Prometheus); (Rx) A zathioprine Sodium Injection: 100 mg (as sodium)/vial in 20 m L vials; generic; (Rx)

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AZITHROMYCIN (ay-zith-roe-my-sin) Zithromax® MACROLIDE ANTIBIOTIC Prescriber Highlights TT Oral & parenteral human macrolide antibiotic; poten-tially useful for a wide range of infections in veterinary patients TT Very long tissue half-lives in dogs & cats TT Contraindications: Hypersensitivity to macrolides TT Caution: Hepatic disease TT Adverse Effects: Potentially GI distress, but less so than with erythromycin TT Relatively expensive, but prices are dropping secondary to the availability of generic products Uses/Indications Azithromycin with its relative broad spectrum and favorable phar-macokinetic profile may be useful for a variety of infections in vete rinary species. Little data is published at this time, however. Azithromycin has been shown to be ineffective in the treatment of Mycoplasma haemofelis in cats. Azithromycin may be potentially useful for treating Rhodococcus infect ions in foals. Pharmacology/Actions Like other macrolide antibiotics, azithromycin inhibits protein synthesis by pene trating the cell wall and binding to the 50S ribo-somal subunits in susceptible bacteria. It is considered a bacterio-static antibiotic. Azithromycin has a relatively broad spectrum. It has in vitr o activity (does not necessarily indicate clinical efficacy) against gram-positive organisms such as Streptococcus pneumoniae, Staph aureus; gram-negative organisms such as Haemophilus influenzae; Bordetella spp. ; and Mycoplasma pneumoniae, Borrelia burgdorferi and Toxoplasma spp. Pharmacokinetics The pharmacokinetics of azithromycin have been described in cats and dogs. In dogs, the drug has excellent bioavailability after oral administration (97%). Tissue concentrations apparently do not mirror those in the serum after multiple doses and tissue half-lives in the dogs may be up to 90 hours. Greater than 50% of an oral dose is excreted unchanged in the bile. In cats, oral bioavailability is 58%. Tissue half-lives are less than in dogs, and range from 13 hours in adipose tissue to 72 hours in cardiac muscle. As with dogs, cats ex-crete the majority of a given dose in the bile. In foals, azithromycin is variably absorbed after oral administra-tion with a mean systemic bioavailability ranging from 40-60%. It has a very high volume of distribution (11. 6-18. 6 L/kg). Elimination half-life is approximately 20-26 hours. The drug con-centrates in bronchoalveolar cells and pulmonary epithelial fluid. Elimination half-life in PMN' s is about 2 days. In adult horses, oral bioavailability is low (1-7%). When compared to erythromycin, azithromycin has better ab-sorption characteristics, longer tissue half-lives, and higher concen-trations in tissues and white blood cells. Goats have an elimination half-life of 32. 5 hours (IV), 45 hours (IM), an appar ent volume of distribution (steady-state) of 34. 5 L/ kg and a clearance of 0. 85 L/kg/hr. Rabbits have an elimination half-life of 24. 1 hours (IV), and 25. 1 hours (IM). IM injection has a high bioavailability, but causes some deg ree of muscle damage at the injection site. Sheep have an elimination half-life average of 48 hours (IV), 61 hours (IM), an apparent volume of distribution (steady-state) of 34. 5 L/kg and a clearance of 0. 52 L/kg/hr. Contraindications/Precautions/Warnings Azithromycin is contraindicated in animals hypersensitive to any of the macrolides. It should be used with caution in patients with impaired hepatic function. Adverse Effects Azithromycin can cause vomiting in dogs if high doses are given. When compared to erythromycin, azithromycin has less GI adverse effects. Other adverse effects, particularly those associated with the liver, may become apparent in dogs and cats as more experience is attained. Local IV site reactions have occurred in patients receiving IV azithromycin. Reproductive/Nursing Safety Safety during pregnancy has not been fully established; use only when clearly necessary. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Overdosage/Acute Toxicity Acute oral overdoses are unlikely to cause significant morbidity other than vomiting, diarrhea and GI cramping. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving azithromycin and may be of significance in veterinary patients: T ! ANTACIDS (oral; magnesium-and aluminum-containing ): May reduce the rate of absorption of azithromycin; suggest separating dos-ages by 2 hours T ! CISAPRIDE : No data on azithromycin, but other macrolides con-traindicated with cisapride; use with caution T ! CYCLOSPORINE : Azithromycin may potentially increase cy-closporine blood levels; monitor carefully T ! DIGOXIN : No data on azithromycin, but other macrolides can in-crease digoxin levels; monitor carefully T ! PIMOZIDE : Azithromycin use is contraindicated in patients taking pimozide (unlikely to be used in vet med—used for T ourette's disorder in humans). Acute deaths have occurred. Doses T ! DOGS: For susceptible infections: a) 5-10 mg/kg PO once daily for 3-5 days (Trepanier 1999), (Sykes 2003) b) 5 mg/kg PO once daily for 2 days, then every 3-5 days for a total of 5 d oses (Aucoin 2002b) c) For “Derm” infections: 5-10 mg/kg PO once daily for 5-7 days. F or animals that are difficult to pill, a dose given every 5 days (after the initial 5-7 day course of therapy) may be ef-fective if continued treatment is necessary. (Merchant 2000)

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d) For canine pyoderma: 10 mg/kg PO once daily for 5-10 days (Ramadinha, R ibeiro et al. 2002) e) For Babesia gibsoni (Asian g enotype) infections: Atovaquone 13. 3 mg/kg PO q8h with a fatty meal and Azithromycin 10 mg/kg PO onc e daily. Give both drugs for 10 days. Reserve immunosuppressive therapy for cases that are not rapidly re-sponding (3-5 days) to anti-protozoal therapy. (Birkenheuer, Levy et al. 2004), (Birkenheuer 2006) T ! CATS: For susceptible infections: a) 5-10 mg/kg PO once daily for 3-5 days (Trepanier 1999), (Sykes 2003) b) 5 mg/kg PO once daily for 2 days, then every 3-5 days for a total numbe r of doses of 5 (Aucoin 2002b) c) For “Derm” infections: 7-15 mg/kg PO q12h daily for 5-7 days. F or animals that are difficult to pill, a dose given every 5 days (after the initial 5-7 day course of therapy) may be ef-fective if continued treatment is necessary. (Merchant 2000) d) For susceptible upper respiratory infections: 5-10 mg/kg PO once dail y for 5 days, then q72h (every 3rd day) long-term. If there is an initial positive response to the antibiotic, therapy should be continued for 6-8 weeks without changing the an-tibiotic. (Scherk 2006) T ! HORSES: For treatment of R. equi infections in foals: a) 10 mg/kg PO once daily. Because of persistence of high levels in bro nchoalveolar cells and pulmonary epithelial lining flu-id, after 5 days of once daily treatment, every other day (q48h) dosing may be ap propriate. (Jacks, Giguere et al. 2001) T ! RODENTS/SMALL MAMMALS: a) Rabbits: For Staphylococcus osteomyelitis: 50 mg/kg PO once daily with 40 mg/kg of rifampin q12h PO (Ivey and Morrisey 2000) b) Rabbits: For jaw abscesses: 15-30 mg/kg PO once daily (q24h). Syst emic antibiotic treatment is continued for 2-4 weeks post-operatively. Advise owners to discontinue treat-ment if anorexia or diarrhea occurs. (Johnson 2006f) c) Guinea pigs: For Pneumonia: 15-30 mg/kg PO once daily (q24h). Adv ise owners to discontinue treatment if soft stools develop. (Johnson 2006d) Monitoring T ! Clinical efficacy T ! Adverse effects Client Information T ! Give medication as prescribed. Do not refrigerate oral suspension and shake well before each use. If using the suspension, preferably give to an animal with an empty stomach. Discard any unused oral suspension after 14 days. T ! Contact veterinarian if animal develops severe diarrhea or vomit-ing, or if condition deteriorates after beginning therapy. Chemistry/Synonyms A semisynthetic azalide macrolide antibiotic, azithromycin dihy-drate occurs as a white crystalline powder. In one m L of water at neutr al p H and at 37° C, 39 mg are soluble. Although commercial preparations are available as the dihydrate, potency is noted as the anhydrous form. Azithromycin may also be known as: azithromycinum, acitro-micina, CP-62993, or XZ-450; many trade names are available. Storage/Stability/Compatibility The commercially available tablets should be stored at tempera-tures less than 30°C. Products for reconstitution for oral suspension should be st ored between 5-30°C before reconstitution with water. After reconstitution the multiple dose product may be stored be-tween 5-30°C for up to ten days and then discarded. The single dose packe ts should be given immediately after reconstitution. The injectable product should be stored below 30°C. After recon-stitution with sterile water for injection, solutions containing 100 mg/m L are stab le for 24 hours if stored below 30°C. Azithromycin injection is physically and chemically compatible with several intra-venous solutions, including: half-normal and normal saline, D5W, LRS, D5 with 0. 3% or 0. 45% sodium chloride, and D5 in LRS. When azithromycin injection is diluted into 250-500 m L of one of the above solutions, it remains physically and chemically stable for 24 hours at room temperature and up to 7 days if kept refrigerated at 5°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None Preparations compounded for dogs and cats may be available from compounding pharmacies. HUMAN-LABELED PRODUCTS: Azithromycin Tablets: 250 mg, 500 mg & 600 mg (as dihydrate); Zithromax® (Pfizer); generic; (Rx) Azithromycin Powder for Oral Suspension: 100 mg/5 m L (as dihy-drate) when reconstituted in 300 mg bottles; 200 mg/5 m L in 600 mg, 900 mg, & 1200 mg bottles; and 1 g/packet (as dihydrate) in 2 single-dose packets; Zithromax® (Pfizer); generic; 167 mg per 5 m L (as dihydrate) when reconstituted in 2 g bottles; Zmax®(Pfizer); (Rx) Azithromycin Powder for Injection (lyophilized): 500 mg in 10 m L vials; Zithromax ® (Pfizer); generic; (Rx) AZTREONAM (az-tree-oh-nam) Azactam® INJECTABLE MONOBACTAM ANTIBACTERIAL Prescriber Highlights TT Monobactam injectable antibiotic with good activity against a variety of gram-negative aerobic bacteria TT May be considered for use for treating serious infections, when aminoglycosides or fluoroquinolones are ineffective or relatively contraindicated TT Very limited information available regarding dosing & adverse effect profile Uses/Indications Aztreonam is a monobactam antibiotic that may be considered for use in small animals for treating serious infections caused by a wide variety of aerobic and facultative gram-negative bacteria, includ-ing strains of Citro bacter, Enterobacter, E. coli, Klebsiella, Proteus, Pseudomonas and Serratia. The drug exhibits good penetration into most tissues and low toxic potential and may be of benefit in treating infections when an aminoglycoside or a fluoroquinolone are either ineffective or are relatively contraindicated. Any consideration for using aztreonam must be tempered with the knowledge that little

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clinical experience or research findings have been published with regard to target species. Aztreonam has also been used to treat pet fish (koi) infected with Aeromonas salmonocida. Pharmacology/Actions Aztreonam is a bactericidal antibiotic that binds to penicillin-bind-ing protein-3 thereby inhibiting bacterial cell wall synthesis result-ing in cell lyses and death of susceptible bacteria. Aztreonam is rela-tively stable to the effects of bacterial beta-lactamases and unlike many other beta-lactam antibiotics, it does not induce the activity of beta-lactamases. Aztreonam has activity against many species and most strains of the following gram-negative bacteria: Aeromonas, Citrobacter, Enterobacter, E. coli, Klebsiella, Pasturella, Proteus, Pseudomonas and Serratia. It is not clinically efficacious against gram-positive or an-aerobic bacteria. Aztreonam can be synergistic against Ps eudomonas aeruginosa and other gram-negative bacilli when used with aminoglycosides. Pharmacokinetics There is limited information published on the pharmacokinetic pa-rameters of aztreonam in dogs and none was located for cats. In dogs, after a 20mg/kg dose was administered IM, peak plasma lev els of approximately 40 mcg/m L occurred in about 20 minutes. Serum protein binding is about 20-30%, compared to 65% in humans. High tissue levels are found in the kidney (approx. 2. 5X that of plasma). Liver concentrations approximate those found in plasma and lower levels are found in the lung and spleen. The drug is primarily (80%) excreted unchanged in the dog. Elimination half-lives are approximately 0. 7 hours after IV administration and 0. 9 hours after IM administration. These values are approximately twic e as short as those reported in humans (ages 1 yr to adult) with normal renal function. Contraindications/Precaution/Warnings Aztreonam should not be used in patients with documented severe hypersensitivity to the compound. Patients with serious renal dys-function may need dosage adjustment. Use cautiously in patients with se rious liver dysfunction. Adverse Effects Adverse effect profiles for aztreonam specific to target species were not located. Aztreonam's adverse effects in humans are similar to those of other beta-lactam antibiotics: hypersensitivity, gastrointes-tinal effects including GI bacterial overgrowth/Pseudomembranous colit is, pain and/or swelling after IM injection, and phlebitis after IV administration. Transient increases in liver enzymes, serum cre-atinine, and coagulation indices have been noted. Reproductive/Nursing Safety Aztreonam crosses that placenta and can be detected in fetal circu-lation. However, no evidence of teratogenicity or fetal toxicity have be en reported after doses of up to 5 times normal were given to pregnant rats and rabbits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Aztreonam has been detected in human breast milk at levels app roximately 1% of those found in serum. As the drug is not absorbed orally, it is likely safe to use in nursing animals though antibiotic-associated diarrhea is possible. Overdosage/Acute Toxicity There is little reason for concern in patients with adequate renal function. The IV LD 50 for mice is 3. 3 g/kg. Hemodialysis or perito-neal dialysis may be used to clear aztreonam from the circulation. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aztreonam and may be of significance in veterinary patients: !TPROBENECID : Can reduce the renal tubular secretion of aztreonam, thereby maintaining higher systemic levels for a longer period of time; this potential “beneficial” interaction requires further investigation before dosing recommendations can be made for veterinary patients For in vitro int eractions, see the Storage-Stability-Compatibility section. Laboratory Considerations !TAztreonam may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose oxidase (Tes-Tape®, Clinist ix®) are not affected by aztreonam. Doses !TDOGS: NOTE: Dosages for this medication are not well established for use in veterinary patients. For dogs, an anecdotal dosing suggestion is to use the human pediatric dose of 30 mg/kg IM or IV q6-8h. When compared to humans, aztreonam has a shorter half-life, but is about half as bound to plasma proteins; the human pedi-atric dose may be a reasonable choice until more data becomes ava ilable. !TFISH: a) For treating Aer omonas salmonicida in koi: 100 mg/kg IM or ICe (intracoelemic) every 48 hours for 7 treatments. (Lewbart 2005) Monitoring !TBecause monobactams usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is re-quired unless toxic signs develop !TSerum levels and therapeutic drug monitoring are not routinely performed with this agent Client Information !TVeterinary professionals only should administer this medication !TBecause of the dosing intervals required, this drug is best admin-istered to inpatients only Chemistry/Synonyms Aztreonam is a synthetic monobactam antimicrobial. It occurs as a white, odorless crystalline powder. Aztreonam may also be know as: Aztreonamum, Azthreonam, Atst reonaami, SQ-26776, Monobac®, Azactam®, Aztreotic®, Azenam®, Primbactam®, Trezam®, or Urobactam®. Storage/Stability/Compatibility Commercially available powder for reconstitution should be stored at room temperature (15°-30°C). For IM use, add at least 3 m L of diluent (sterile water for injec-tion, bacteriostatic sterile water for injection, NS, or bacteriostatic sodi um chloride injection. ) Solutions are stable for 48 hours at room temperature, 7 days if refrigerated. For direct IV use, add 6-10 m L of sterile water for injection to eac h 15 or 30 m L vial. If the medication is to be given as an infu-sion, add at least 3 m L of sterile water for injection for each gram of

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aztreonam powder; then add the resulting solution to a suitable IV diluent (NS, LRS, D 5W, etc. ) so that the final concentration does not exceed 20 mg/m L. Inspect all solutions for visible particulate mat-ter. Solutions may be colorless or a light, straw yellow color; upon standing, a lig ht pink color may develop which does not affect the drug's potency. Intravenous solutions not exceeding concentrations of 20 mg/m L are stable for 48 hours at room temperature, 7 days if refrigerated. The package insert has specific directions for freezing solutions after dilution. Intravenous admixtures containing aztreonam are compatible with clindamycin, amikacin, gentamicin, tobramycin, ampicillin-sulbactam, imipenem-cilastatin, morphine, propofol, piperacillin-tazobactam, ticarcillin-clavulanate, ranitidine, sodium bicarbonate, potassium c hloride, butorphanol, furosemide, hydromorphone, ce-fotaxime, cefuroxime, ceftriaxone and cefazolin. It is not compatible with metronidazole, nafcillin, amphotericin B, or vancomycin. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Aztreonam Powder for injection (lyophilized cake): 500 mg in 15 m L vials, 1 g in single-dose 15 m L vials and single dose 100 m L btls for infusion, & 2 g in 30 m L vials and single dose 100 m L btls for infusion; Azactam® (Squibb); (Rx) Aztreonam is not commercially available in Canada. BACLOFEN (bak-loe-fen) Lioresal® GABA DERIV ATIVE MUSCLE RELAXANT Prescriber Highlights TT Muscle relaxant that may be used for treating urinary retention in dogs TT Do not use in cats TT Adverse Effects: sedation, weakness, pruritus, & gastroin-testinal distress TT Do not stop therapy abruptly TT Overdoses potentially serious Uses/Indications Baclofen may be useful to decrease urethral resistance in dogs to treat urinary retention. It is not recommended for cats. Pharmacology/Actions Considered a skeletal muscle relaxant, baclofen's mechanism of ac-tion is not well understood but it acts at the spinal cord level and de-creases the frequency and amplitude of muscle spasm. It apparently decreases muscle spasticity by reducing gamma efferent neuronal activity. In the urethra, it reduces striated sphincter tone. Pharmacokinetics After oral administration, baclofen is rapidly and well absorbed but, at least in humans, there is wide interpatient variation. The drug is widely distributed with only a small percentage crossing the blood-brain barrier. Baclofen is eliminated primarily by the kidneys and less than 15% of a dose is metabolized by the liver. Elimination half-lives in humans range from 2. 5-4 hours. Contraindications/Precautions/Warnings Baclofen is contraindicated in patients hypersensitive to it and is not recommended for use in cats. It should be used with caution in pa-tients who have seizure disorders and working dogs that must be alert. D o not give the intrathecal medication by any other route. Adverse Effects Adverse effects reported in dogs include sedation, weakness, pruri-tus, salivation, and gastrointestinal distress (nausea, abdominal cramping). Disco ntinue this medication gradually as hallucinations and seizures ha ve been reported in human patients who have abruptly stopped the medication. Reproductive/Nursing Safety Very high doses caused fetal abnormalities in rodents. It is unknown if normal dosages affect fetuses; use during pregnancy with care. 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 unknown if baclofen enters maternal milk in quantities suf-ficient to cause effects in offspring. Overdosage/Acute Toxicity Deaths in dogs have been reported with baclofen doses as low as 8 mg/kg. Oral overdoses as low as 1. 3 mg/kg may cause vomiting, depression, and vocalization. Other signs that may be noted include hypotonia or muscle twitching. Massive overdoses may cause re-spiratory depression, coma, or seizures. Onset of clinical signs after over doses in dogs can occur from 15 minutes to 7 hours after inges-tion and can persist for hours to days. There were 1023 exposures to baclofen reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 991 were dogs with 196 showing clini-cal signs, 29 cats with 7 showing clinical signs, and the remaining 3 rep orted cases were wild canine that showed no clinical signs. Common findings in dogs recorded in decreasing frequency in-cluded vocalization, hypersalivation, vomiting, ataxia and lethargy. Common findings in cats recorded in decreasing frequency included ataxia, hypothermia, vomiting and lethargy. In alert patients, consider emptying the gut using standard tech-niques. Avoid the use of magnesium containing saline cathartics as they may compound CNS depression. Forced fluid diuresis may en-hance baclofen excretion. Obtunded patients with respiratory de-pression may need to be mechanically ventilated. Monitor ECG and treat ar rhythmias if needed. For patients who are vocalizing or dis-oriented, cyproheptadine (1. 1 mg/kg orally or rectally) may be effec-tive in alleviating the signs. Atropine has been suggested to improve ventilat ion, heart rate, BP, and body temperature. Diazepam may be useful for treating seizures. Contact an animal poison control center for further information and guidance. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving baclofen and may be of significance in veterinary patients: ! !CNS DEPRESSANTS (other ): May cause additive CNS depression Laboratory Considerations T ! Increased AST, alkaline phosphate and blood glucose have been re-ported in humans

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Doses !TDOGS: T o treat urinary retention by decreasing urethral resistance: a) 1-2 mg/kg PO q8h (Lane 2000), (Coates 1999), (Labato 2005), (Lulic h 2004) b) 5-10 mg (total dose) PO q8h (Senior 1999) Monitoring !TEfficacy !TAdverse effects Client Information !TDo not stop therapy abruptly without veterinarian approval Chemistry/Synonyms A skeletal muscle relaxant that acts at the spinal cord level, baclofen occurs as white to off-white crystals. It is slightly soluble in water and has p Ka values of 5. 4 and 9. 5. Baclofen may also be known as: aminomethyl chlorohydrocin-namic acid, Ba-34647, baclofenum, Baclo ®, Baclohexal®, Baclon®, Baclopar®, Baclosal®, Baclospas®, Balgifen®, Clinispas®, Clofen®, Kemstro®, Lebic ®, Lioresal®, Liotec®, Miorel®, Neurospas®, Nu-Baclo®, Pacifen®, or Vioridon®. Storage/Stability/Compatibility Do not store tablets above 30°C (86°F). Intrathecal product should be stored at room temperature; do not freeze or heat sterilize. An oral liquid compounding recipe has been described (Olin 2000): T o prepare a 5 mg/m L liquid (35 day expiration date). Grind fifteen 20 mg tablets in a glass mortar to fine powder. Wet the pow-der with 10 m L of glycerin and form a fine paste. Slowly add 15 m L of simple syrup to the paste and transfer to a glass amber bottle. Rinse the mortar and pestle with another 15 m L of simple syrup and transfer to the bottle. Repeat until final volume is 60 m L. Shake well before each use and store in the refrigerator. 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: Baclofen Tablets: 10 mg, & 20 mg; Lioresal® (Novartis); gener-ic; (Rx); 10 mg & 20 mg orally disintegrating tablets: Kemst ro® (Schwarz);(Rx) Baclofen for Intrathecal: 0. 05 mg/m L, 10 mg per 20 m L (500 mcg/ m L) & 10 mg per 5 m L (2000 mcg/m L); Lioresal® Intrathecal (Medtronic); (Rx) BAL in Oil — see Dimercaprol BARBITURATE PHARMACOLOGY (bar-bich-yoo-rate; bar-bi-toor-ate) Also see the monographs for Methohexital, Phenobarbital, Pentobarbital, and Thiopental. While barbiturates are generally considered CNS depressants, they can invoke all levels of CNS mood alteration from paradoxical ex-citement to deep coma and death. While the exact mechanisms for the CNS e ffects caused by barbiturates are unknown, they have been shown to inhibit the release of acetylcholine, norepinephrine, and glutamate. The barbiturates also have effects on GABA and pento-barbital has been shown to be GABA-mimetic. At high anesthetic doses, bar biturates have been demonstrated to inhibit the uptake of calcium at nerve endings. The degree of depression produced is dependent on the dosage, rout e of administration, pharmacokinetics of the drug, and species treated. Additionally, effects may be altered by patient age, physi-cal condition, or concurrent use of other drugs. The barbiturates dep ress the sensory cortex, lessen motor activity, and produce seda-tion at low dosages. In humans, it has been shown that barbiturates red uce the rapid-eye movement (REM) stage of sleep. Barbiturates have no true intrinsic analgesic activity. In most species, barbiturates cause a dose-dependent respira-tory depression, but, in some species, they can cause slight respira-tory stimulation. At sedative/hypnotic doses, respiratory depression is similar t o that during normal physiologic sleep. As doses increase, the medullary respiratory center is progressively depressed with re-sultant decreases in rate, depth, and volume. Respiratory arrest may occur at doses four times lower than those will cause cardiac arrest. These drugs must be used very cautiously in cats; they are particu-larly sensitive to the respiratory depressant effects of barbiturates. Besides the cardiac arresting effects of the barbiturates at eutha-natizing dosages, the barbiturates have other cardiovascular effects. In the dog, pentobarbital has been demonstrated to cause tachycar-dia, decreased myocardial contractility and stroke volume, and de-creased mean arterial pressure and total peripheral resistance. The barbiturates cause reduced tone and motility of the intes-tinal musculature, probably secondary to its central depressant ac-tion. The thiobarbiturates (thiamylal, thiopental) may, after initial dep ression, cause an increase in both tone and motility of the in-testinal musculature; however, these effects do not appear to have much clinical significance. Administration of barbiturates reduc-es the sensitivity of the motor end-plate to acetylcholine thereby slightly relaxing skeletal muscle. Because the musculature is not completely relaxed, other skeletal muscle relaxants may be neces-sary for surgical procedures. There is no direct effect on the kidney by the barbiturates, but seve re renal impairment may occur secondary to hypotensive effects in overdose situations. Liver function is not directly affected when used acutely, but hepatic microsomal enzyme induction is well documented with extended barbiturate (especially phenobarbital) administration. Although barbiturates reduce oxygen consumption of all tissues, no change in metabolic rate is measurable when given at sedative dosages. Basal metabolic rates may be reduced with re-sultant decreases in body temperature when barbiturates are given at anesthetic d oses.

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BENAZEPRIL HCL (ben-a-za-pril) Fortekor®, Lotensin® ANGIOTENSIN CO NVERTING ENZYME (ACE) INHIBITOR Prescriber Highlights TT ACE inhibitor that may be useful for treating heart fail-ure, hypertension, chronic renal failure & protein-losing glomerulonephropathies in dogs & cats TT Caution in patients with hyponatremia, coronary or cere-brovascular insufficiency, SLE, hematologic disorders TT GI disturbances most likely adverse effects, but hypoten-sion, renal dysfunction, hyperkalemia possible TT Mildly fetotoxic at high dosages Uses/Indications Benazepril may be useful as a vasodilator in the treatment of heart failure and as an antihypertensive agent, particularly in dogs. Reasonable evidence exists that ACE-inhibitors increase survival (when compared to placebo) in dogs with dilated cardiomyopathy and mitral valve disease. Benazepril may be of benefit in treating the clinical signs asso ciated with valvular heart disease and left to right shunts. ACE inhibitors may also be of benefit in the adjunctive treat-ment of chronic renal failure and for protein losing nephropathies. In cats, benazepril (or enalapril) can be used for treating hyper-tension, adjunctive treatment of hypertrophic cardiomyopathy, and reducing p rotein loss associated with chronic renal failure. Pharmacology/Actions Benazepril is a prodrug and has little pharmacologic activity of its own. After being hydrolyzed in the liver to benazeprilat, the drug inhibits the conversion of angiotensin-I to angiotensin-II by inhibit-ing angiotensin-converting enzyme (ACE). Angiotensin-II acts both as a vaso constrictor and stimulates production of aldosterone in the adrenal cortex. By blocking angiotensin-II formation, ACE inhibi-tors generally reduce blood pressure in hypertensive patients and vascular re sistance in patients with congestive heart failure. When administered to dogs with heart failure at low dosages (0. 1 mg/kg q12h), benazepril improved clinical signs, but did not significantly affect blood pressure (Wu and Juany 2006) In cats with chronic renal failure, benazepril has been shown to reduc e systemic arterial pressure and glomerular capillary pressure while increasing renal plasma flow and glomerular filtration rates. It may also help improve appetite. Like enalapril and lisinopril, but not captopril, benazepril does not contain a sulfhydryl group. ACE inhibitors containing sulfhy-dryl groups (e. g., captopril) may have a greater tendency towards causing immune-mediate d reactions. Pharmacokinetics After oral dosing in healthy dogs, benazepril is rapidly absorbed and converted into the active metabolite benazeprilat with peak levels of benazeprilat occurring approximately 75 minutes after dosing. The elimination half-life of benazeprilat is approximately 3. 5 hours in healthy dogs. In cats, inhibition of ACE is long-lasting (half-life of 16-23 hours), despit e relatively quick elimination of free benazeprilat, due to high affinity of benazeprilat to ACE. Because enalaprilat exhibits nonlinear binding of benazeprilat to ACE, doses greater than 0. 25 mg/kg PO produced only small incremental increases in peak effect or durat ion of ACE inhibition. (King, Maurer et al. 2003) In humans, approximately 37% of an oral dose is absorbed after oral d osing and food apparently does not affect the extent of ab-sorption. About 95% of the parent drug and active metabolite are bound to serum proteins. Benazepril and benazeprilat are primarily eliminated via the kidneys and mild to moderate renal dysfunction apparently does not significantly alter elimination as biliary clear-ance may compensate somewhat for reductions in renal clearances. Hepatic dysfunction or age does not appreciably alter benazeprilat levels. Contraindications/Precautions/Warnings Benazepril is contraindicated in patients who have demonstrated hypersensitivity to the ACE inhibitors. ACE inhibitors should be used with caution in patients with hypo natremia or sodium depletion, coronary or cerebrovascular insufficiency, preexisting hematologic abnormalities or a collagen vascular disease (e. g., SLE). Patients with severe CHF should be monitored very closely upon initiation of therapy. Adverse Effects Benazepril's adverse effect profile in dogs is not well described, but other ACE inhibitors effects in dogs usually center around GI dis-tress (anorexia, vomiting, diarrhea). Potentially, hypotension, renal dysfunct ion and hyperkalemia could occur. Because it lacks a sulfhy-dryl group (unlike captopril), there is less likelihood that immune-mediated reactions will occur, but rashes, neutropenia and agranu-locytosis have been reported in humans. In healthy cats given mild overdoses (2 mg/kg PO once daily for 52 weeks ), only increased food consumption and weight were noted. Reproductive/Nursing Safety Benazepril apparently crosses the placenta. High doses of ACE inhibitors in rodents have caused decreased fetal weights and in-creases in fetal and maternal death rates; no teratogenic effects have been reported to date, but use during pregnancy should occur only when the potential benefits of therapy outweigh the risks to the offspring. In humans, the FDA categorizes this drug as category C for use during the first trimester of 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 ad-equate studies in humans. ) During the second and third trimesters, the FDA cat egorizes this drug 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. ) Benazepril is distributed into milk in very small amounts. Overdosage/Acute Toxicity In overdose situations, the primary concern is hypotension; sup-portive treatment with volume expansion with normal saline is reco mmended to correct blood pressure. Because of the drug's long duration of action, prolonged monitoring and treatment may be required. Recent massive overdoses should be managed using gut-emptying protocols as appropriate. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving benazepril and may be of significance in veterinary patients: T ! ASPIRIN : Aspirin may potentially negate the decrease in systemic vascular resistance induced by ACE inhibitors; however, one study in dogs using low-dose aspirin, the hemodynamic effects of enal-aprilat (active metabolite of enalapril, a related drug) were not affected

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T ! ANTIDIABETIC AGENTS (insulin, oral agents ): Possible increased risk for hypoglycemia; enhanced monitoring recommended T ! DIURETICS (e. g., furosemide, hydrochlorothiazide ): Potential for in-creased hypotensive effects; some veterinary clinicians recom-mend reducing furosemide doses (by 25-50%) when adding enalapril o r benazepril to therapy for heart failure T ! DIURETICS, POTASSIUM-SPARING (e. g., spironolactone, triamterene ): Increased hyperkalemic effects, enhanced monitoring of serum potassium T ! LITHIUM : Increased serum lithium levels possible; increased moni-toring required T ! POTASSIUM SUPPLEMENTS : Increased risk for hyperkalemia Laboratory Considerations T ! When using iodohippurate sodium I123/I134 or Technetium Tc99 pen-tentate renal imaging in patients with renal artery stenosis, ACE inhibitors may cause a reversible decrease in localization and ex-cretion of these agents in the affected kidney which may lead to confusion in t est interpretation. Doses T ! DOGS: For adjunctive treatment of heart failure: a) 0. 25-0. 5 mg/kg PO once daily (Miller and Tilley 1995); (Tre panier 1999), (Kittleson 2007) b) 0. 25-0. 5 mg/kg PO once to twice daily (Ware 1997) For adj unctive treatment of hypertension: a) 0. 25 mg/kg PO q12h (Brown and Henik 2000) b) 0. 25-0. 5 mg/kg q12-24h; Co-administ ration with a calcium channel antagonist may lower blood pressure when mono-therapy is not sufficient. In diabetic dogs, an ACE inhibitor may block adverse effects of calcium channel antagonists. (Brown 2003) c) For hypertension associated with protein-losing renal dis-ease: 0. 5 mg/kg PO once daily (q24h) Response may be vari-able in dogs with hypertension secondary to other diseases; ACE inhibit ors are usually well tolerated and can be tried in non-emergency hypertension. (Stepian 2006a) T ! CATS: For adjunctive treatment of heart failure: a) 0. 25-0. 5 mg/kg PO once daily (Trepanier 1999), (Kittleson 2007) b) For CHF or hypertension: 0. 25-0. 5 mg/kg PO once to twice daily (Atkins 2003b) For adj unctive treatment of hypertension: a) 0. 5-1 mg/kg PO once daily (Sparkes 2003b) b) 0. 25-1 mg/kg PO once to twice daily. Because of their an-tiproteinuric effects, ACE inhibitors are the drugs of first choice to treat hypertension in animals with proteinuria. (Langston 2003) c) 0. 25-0. 5 mg/kg PO once daily (q24h) (Stepian 2006a) d) For proteinuria, hypertension associated with chronic kidney disease: 0. 25-0. 5 mg/kg PO once to twice daily (q12-24h); rarely higher (Polzin 2006) Monitoring T ! Clinical signs of CHF T ! Serum electrolytes, creatinine, BUN, urine protein T ! Blood pressure (if treating hypertension or clinical signs associ-ated with hypotension arise) Client Information T ! Do not abruptly stop or reduce therapy without veterinarian's approval. Contact veterinarian if vomiting or diarrhea persist or is severe or if animal's condition deteriorates. Chemistry/Synonyms Benazepril HCl, an angiotensin converting enzyme inhibitor, oc-curs as white to off-white crystalline powder. It is soluble in water and ethanol. B enazepril does not contain a sulfhydryl group in its structure. Benazepril may also be known as: CGS-14824A (benazepril or benaze pril hydrochloride), Benace®, Boncordin®, Briem®, Cibace®, Cibacen®, Cibacen®, Cibacene®, Fortekor®, Labopal®, Lotensin®, Lotrel ®,Tensanil®, or Zinadril®. Storage/Stability/Compatibility Benazepril tablets (and combination products) should be stored at temperatures less than 86°F (30°C) and protected from moisture. They should be dispensed in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA In the UK (and elsewhere): Benazepril Tablets: 2. 5, 5, & 20 mg; Fortekor® (Novartis—UK); (POM-V) Labeled for use in cats for chronic renal insufficiency and for heart failure in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substanc e. See the appendix for more information. HUMAN-LABELED PRODUCTS: Benazepril HCl Tablets: 5 mg, 10 mg, 20 mg, & 40 mg; Lotensin® (Novartis); generic; (Rx) Also available in fixed dose combination products containing am-lodipine (Lotrel ®) or hy drochlorothiazide (Lotensin HCT®) BETAMETHASONE BETAMETHASONE ACETATE BETAMETHASONE SODIUM PHOSPHATE (bet-ta-meth-a-sone) Celestone® GLUCOCORTICOID Note : For more information on the pharmacology of glucocorticoids re-fer to the monograph: Glucocorticoids, General information. For topical or ot ic use, see the T opical Dermatology & Otic sections in the appendix. Prescriber Highlights TT Injectable (long-acting) & topical glucocorticoid TT Long acting; 25-40X more potent than hydrocortisone; no mineralocorticoid activity 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 are “Cushingoid” in nature with sustained use TT Many potential drug & lab interactions when used systemically

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Contraindications/Precautions/Warnings For the product Betasone® (Schering), the manufacturer states that the drug is “contraindicated in animals with acute or chronic bacte-rial infections unless therapeutic doses of an effective antimicrobial age nt are used. ” Systemic use of glucocorticoids is generally consid-ered contraindicated in systemic fungal infections (unless used for re placement therapy in Addison's), when administered IM in pa-tients with idiopathic thrombocytopenia and in patients hypersen-sitive to a particular compound. Use of sustained-release injectable gl ucocorticoids is contraindicated for chronic corticosteroid therapy of systemic diseases. Animals that have received glucocorticoids systemically other than w ith “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 return slow-ly. Should the animal undergo a “stressor” (e. g., surgery, trauma, ill-ness, etc. ) during the tapering process or until normal adrenal and pituitar y function resume, additional glucocorticoids should be ad-ministered. Corticosteroid therapy may induce parturition in large animal spe cies 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 alte rnate day regimen. Effects generally manifest as clinical signs of hyperadrenocorticism. When administered to young, growing ani-mals, glucocorticoids can retard growth. Many of the potential ef-fects, adverse and otherwise, are outlined in the Pharmacology sec-tion of the Glucocorticoids, General information monograph. In dogs, polydipsia (PD), polyphagia (PP) and polyuria (PU), may all be seen with short-term “burst” therapy as well as with alter-nate-day maintenance therapy on days when given the drug. Adverse eff ects in dogs associated with long-term use can include: dull, dry haircoat, weight gain, panting, vomiting, diarrhea, elevated liver enzymes, pancreatitis, GI ulceration, lipidemias, activation or wors-ening of diabetes mellitus, muscle wasting and behavioral changes (de pression, lethargy, viciousness). Discontinuation of the drug may be necessary; changing to an alternate steroid may also alleviate the problem. With the exception of PU/PD/PP, adverse effects as-sociated with antiinflammatory therapy are relatively uncommon. Ad verse effects associated with immunosuppressive doses are more common and potentially more severe. Cats generally require higher dosages than dogs for clinical effect bu t 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. Reproductive/Nursing Safety In addition to the contraindications, precautions and adverse effects outlined above, betamethasone has been demonstrated to cause de-creased sperm output and semen volume and increased percentages of abnormal sperm in dogs. Use with caution in nursing dams. Corticosteroids appear in milk and c ould suppress growth, interfere with endogenous corticoster-oid production or cause other unwanted effects in the nursing off-spring. However, in humans, several studies suggest that amounts ex creted in breast milk are negligible when prednisone or predni-solone doses in the mother are less than or equal to 20 mg/day or meth ylprednisolone doses are less than or equal to 8 mg/day. Larger doses for short periods may not harm the infant. 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. Chr onic 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 betamethasone systemi-cally and may be of significance in veterinary patients: !TAMPHOTERICIN B : When administered concomitantly with gluco-corticoids may cause hypokalemia !TANTICHOLINESTERASE AGENTS (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant glucocorticoid and anticholinesterase agent administration may lead to profound muscle weakness; if possible, discontinue anticholinesterase med-ication at least 24 hours prior to corticosteroid administration !TASPIRIN and OTHER SALICYLATES : Glucocorticoids may reduce sali-cylate blood levels !TBARBITURATES : May increase the metabolism of glucocorticoids !TCYCLOPHOSPHAMIDE : Glucocorticoids may inhibit the hepatic me-tabolism of cyclophosphamide; dosage adjustments may be re-quired !TCYCLOSPORINE : Concomitant administration of glucocorticoids and cyclosporine may increase the blood levels of each by mu-tually inhibiting hepatic metabolism; clinical significance is not clear !TDIGOXIN : When glucocorticoids are used concurrently with digi-talis glycosides, an increased chance of digitalis toxicity may occur should h ypokalemia develop; diligent monitoring of potassium and digitalis glycoside levels is recommended. !TDIURETICS, POTASSIUM-DEPLETING (e. g., furosemide, thiazides ): When administered concomitantly with glucocorticoids may cause hy-pokalemia !TESTROGENS : May decrease corticosteroid clearance !TINSULIN Requirements may increase in patients receiving gluco-corticoids !TISONIAZID : May have serum levels decreased by corticosteroids !TKETOCONAZOLE : Corticosteroid clearance may be reduced and the AUC increased !TMITOTANE : May alter the metabolism of steroids; higher than usual doses of steroids may be necessary to treat mitotane-induced ad-renal insufficiency !TRIFAMPIN : May increase the metabolism of glucocorticoids !TTHEOPHYLLINES : Alterations of pharmacologic effects of either drug can occur !TULCEROGENIC DRUGS (e. g., NSAIDs ): Use with glucocorticoids may increase the risk of gastrointestinal ulceration !TVACCINES : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live attenuated-virus va ccines as virus replication may be augmented; diminished im-mune response may occur after vaccine, toxoid, or bacterin ad-ministration in patients receiving glucocorticoids Laboratory Considerations !TGlucocorticoids may increase serum cholesterol and urine glucose levels !TGlucocorticoids may decrease serum potassium

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TT ! Glucocorticoids can suppress the release of thyroid stimulating hormone (TSH) and reduce T3 & T4 values; thyroid gland atrophy has been reported after chronic glucocorticoid administration T ! Uptake of I131 by the thyroid may be decreased by glucocorticoids T ! Reactions to skin tests may be suppressed by glucocorticoids T ! False-negative results of the nitroblue tetrazolium test for systemic bacterial infections may be induced by glucocorticoids T ! Betamethasone does not cross-react with the cortisol assay Doses T ! DOGS: For the control of pruritus: a) Betasone® Aqueous Suspension: 0. 25-0. 5 m L per 20 pounds bod y weight IM. Dose dependent on severity of condition. May repeat when necessary. Relief averages 3 weeks in dura-tion. Do not exceed more than 4 injections. (Package Insert; Betasone ®—Schering) Note : Product no longer marketed in the USA. T ! HORSES: Source of product an issue. Alternative is triamcinolone (see that monograph for additional information). ( Note : ARCI UCGFS Class 4 Drug) As a relatively short-acting corticosteroid for intraarticular administration: a) 6-15 mg per joint IA. Frequency of re-injection is limited to the minimum n umber needed to achieve soundness. (Fris-bee 2003) 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: T ! Weight, appetite, signs of edema T ! Serum and/or urine electrolytes T ! otal plasma proteins, albumin T ! Blood glucose T ! Growth and development in young animals T ! ACTH stimulation test if necessary Client Information T ! Clients should carefully follow the dosage instructions and should not discontinue the drug abruptly without consulting veterinar-ian beforehand T ! Clients should be briefed on the potential adverse effects that can be seen with these drugs and instructed to contact the veterinar-ian should these effects become severe or progress Chemistry/Synonyms A synthetic glucocorticoid, betamethason is available as the base and as the dipropionate, acetate and sodium phosphate salts. The base is used for oral dosage forms. The sodium phosphate and ac-etate salts are used in injectable preparations. The dipropionate salt is used in topical formulations and in combination with the sodium phosphate salt in a veterinary-approved injectable preparation. Betamethasone occurs as an odorless, white to practically white, crystalline powder. It is insoluble in water and practically insoluble in alcohol. The dipropionate salt occurs as a white or creamy-white, odorless powder. It is practically insoluble in water and sparingly soluble in alcohol. The sodium phosphate salt occurs as an odorless, white to practically white, hygroscopic powder. It is freely soluble in water and slightl y soluble in alcohol. Betamethasone may also be known as flubenisolone or Celestone ®. Storage/Stability/Compatibility Betamethasone tablets should be stored in well-closed containers at 2-30°C. The oral solution should be stored in well-closed contain-ers, protected from light and kept at temperatures less than 40°C. The sodi um phosphate injection should be protected from light and stored at room temperature (15-30°C); protect from freezing. The combination veterinary injectable product (Betasone®) should be stored between 2-30°C and protected from light and freezing. When betamethasone sodium phosphate was mixed with hepa-rin sodium, hydrocortisone sodium succinate, potassium chloride, vitamin B-co mplex with C, dextrose 5% in water (D 5W), D 5 in Ringer's, D 5 in lactated Ringer's, Ringer's lactate injection or nor-mal saline, no physical incompatibility was noted immediately or after 4 hours. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: The following product is apparently no longer marketed in the USA. Betamethasone Diproprionate Injection equivalent to 5 mg/m L of betamethasone and betamethasone sodium phosphate equivalent to 2 mg/m L betamethasone in 5 m L vials; Betasone® (Schering-Plough); (Rx). Approved for use in dogs. Betamethasone valerate is also found in Gentoc in® Otic, Gentocin® Topical Spray and Topa gen® Ointment, (Schering-Plough). There are several other otic and topical products containing betametha-sone and gentamicin on the veterinary market. See the appendix for more info rmation on these products. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substanc e. See the appendix for more information. HUMAN-LABELED PRODUCTS: Betamethasone Tablets: 0. 6 mg; Celestone® (Schering); (Rx) Betamethasone Solution: 0. 6 mg/5 m L in 118 m L; Celestone ® (Schering); (Rx) Betamethasone Injection: betamethasone (as sodium phosphate) 3 mg/m L and be tamethasone acetate 3 mg/m L injection in 5 m L vi-als; Celestone Soluspan® (Schering); (Rx) BETHANECHOL CHLORIDE (beh-than-e-kole) Urecholine® CHOLINERGIC Prescriber Highlights TT Cholinergic agent used primarily to increase bladder con-tractility; symptomatic treatment of dysautonomia TT Principle contraindications are GI or urinary tract obstruc-tions or if bladder wall integrity is in question TT Adverse Effects: “SLUD” (salivation, lacrimation, urination, defecation) TT Cholinergic crisis possible if injecting IV or SC, have atro-pine at the ready

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Uses/Indications In veterinary medicine, bethanechol is used primarily to stimulate bladder contractions in small animals. It also can be used as an esophageal or general GI stimulant, although metoclopramide and/ or neostigmine have largely supplanted it for these uses. Pharmacology/Actions Bethanechol directly stimulates cholinergic receptors. Its effects are principally muscarinic and at usual doses has negligible nicotinic activity. It is more resistant to hydrolysis than acetylcholine by cho-linesterase and, therefore, has an increased duration of activity. Pharmacologic effects include increased esophageal peristalsis and lo wer esophageal sphincter tone, increased tone and peristaltic activity of the stomach and intestines, increased gastric and pan-creatic secretions, increased tone of the detrusor muscle of the blad-der, and decreased bladder capacity. At high doses after parenteral administ ration, effects such as increased bronchial secretions and constriction, miosis, lacrimation, and salivation can be seen. When administered SC or orally, effects are predominantly on the GI and urinary tracts. Pharmacokinetics No information was located on the pharmacokinetics of this agent in veterinary species. In humans, bethanechol is poorly absorbed from the GI tract, and the onset of action is usually within 30-90 minutes after oral dosing. After subcutaneous administration, effects begin within 5-15 minutes and usually peak within 30 minutes. The duration of action after oral dosing may persist up to 6 hours after large doses and 2 hours after SC dosing. Subcutaneous administra-tion yields a more enhanced effect on urinary tract stimulation than do es oral administration. Bethanechol does not enter the CNS after usual doses; other dis-tribution aspects of the drug are not known. The metabolic or excre-tory fate of bethanechol has not been described. Contraindications/Precautions/Warnings Contraindications to bethanechol therapy include: bladder neck or other urinary outflow obstruction, when the integrity of the blad-der wall is in question (e. g., as after recent bladder surgery), hyper-thyroidism, peptic ulcer disease or when other inflammatory GI lesions are present, recent GI surgery with resections/anastomoses, GI obstruction or peritonitis, hypersensitivity to the drug, epilepsy, asthma, coronary artery disease or occlusion, hypotension, severe brady cardia or vagotonia or vasomotor instability. If urinary outflow resistance is increased due to enhanced urethral tone (not mechani-cal obstruction!), bethanechol should only be used in conjunction with another agent that will sufficiently reduce outflow resistance [e. g., diazepam, dantrolene (striated muscle) or phenoxybenzamine (smooth muscle). ] Adverse Effects When administered orally to small animals, adverse effects are usu-ally mild with vomiting, diarrhea, salivation, and anorexia being the most lik ely to occur. Cardiovascular (bradycardia, arrhythmias, hy-potension) and respiratory effects (asthma, dyspnea) are most likely onl y seen after overdosage situations or with high dose SC therapy. In horses, salivation, lacrimation and abdominal pain are poten-tial adverse effects. IM or IV use is not recommended except in emergencies when the IV route may be used. Severe cholinergic reactions are likely if given IV. If injecting the drug (SC or IV), it is recommended that atropine be immediately available. 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 fe tus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) It is unknown if bethanechol is distributed into milk. Overdosage/Acute Toxicity Clinical signs of overdosage are basically cholinergic in nature. Muscarinic effects (salivation, urination, defecation, etc. ) are usually seen with oral or SC administration. If given IM or IV, a full-blown cholinergic crisis can occur with circulatory collapse, bloody diar-rhea, shock and cardiac arrest possible. Treatment for bethanechol toxicity is atropine. Refer to the atro-pine monograph for more information on its use. Epinephrine may also be e mployed to treat clinical signs of bronchospasm. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bethanechol and may be of significance in veterinary patients: !TANTICHOLINERGIC D RUGS : (e. g., atropine, glycopyrrolate, propanthe-line): Can antagonize bethanechol's effects !TCHOLINERGIC D RUGS (e. g., neostigmine, physostigmine, pyridostigmine : Because of additional cholinergic effects, bethanechol should gen-erally not be used concomitantly with other cholinergic drugs !TGANGLIONIC BLOCKING DRUGS (e. g., mecamylamine ): Can produce se-vere GI and hypotensive effects !TQUINIDINE, PROCAINAMIDE : Can antagonize the effects of bethanechol Doses Note : The injectable product is no longer commercially marketed in the USA !TDOGS: For urinary indications: a) T o increase bladder contractility: 5-25 mg (total dose) PO q8h (Lane 2000) b) 5-15 mg (total dose) PO q8h (Lulich 2003) c) 5-25 mg (total dose) PO q8h (Bartges 2003a) d) 2. 5-25 mg (total dose) PO three times daily (Coates 2004) Fo r increased esophageal sphincter tone: a) 0. 5-1 mg/kg PO q8h (Jones 1985) Fo r symptomatic treatment of dysautonomia: a) 2. 5-7. 5 mg (total dose) PO divided q8-12h; ma y improve gastrointestinal motility and bladder emptying (Sisson 2004) b) 1. 25-5 mg (total dose) PO once daily (Willard 2003a) c) 0. 05 mg/kg SC q12h and slowly increase as necessary. While SC a dministration gives better results, can also use 1. 25-5 mg (total dose) q12h PO. (O'Brien 2003) !TCATS: T o increase bladder contractility: a) 1. 25-7. 5 mg (total dose) PO two to three times daily (Lane 2003) b) 1. 25-7. 5 mg per cat PO q8h (Osborne, Kruger et al. 2000), (Bartges 2003a) Fo r symptomatic treatment of dysautonomia: a) 2. 5-7. 5 mg (total dose) PO divided q8-12h; ma y improve gastrointestinal motility and bladder emptying (Sisson 2004) b) 1. 25-5 mg PO once daily (Willard 2003a) !THORSES: (Note : ARCI UCGFS Class 4 Drug) T o stimulate detrusor muscle activity:

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