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a) 0. 025-0. 075 mg/kg subcutaneously q8h. Dosage is variable and should be adjusted for each patient. (Jose-Cunilleras and Hinchcliff 1999) If bladder is capable of weak contractions: a) 0. 025-0. 075 mg/kg SC 2-3 times; o r 0. 25-0. 75 mg/kg PO 2-4 times a day. Note : Oral dose is 10X that of SC dose (Schott II and Carr 2003) T ! CATTLE: For adjunctive medical therapy (with fluids, mineral oil, and NSAIDs if needed) of cecal dilation/dislocation (CDD): a) Only if animal is “normal” or only slightly disturbed, defeca-tion is present, and rectal exam does not reveal torsion or retr oflexion. If these criteria are not met, or no improvement within 24 hours of medical therapy, surgical therapy is rec-ommended. Bethanechol at 0. 07 mg/kg SC three times daily for 2 days. Withhold feed for 24 hours and then gradually give increasing amounts of hay if defecation is present and CDD is resolved. (Meylan 2004) Monitoring T ! Clinical efficacy T ! Urination frequency, amount voided, bladder palpation T ! Adverse effects (see above section) Client Information T ! Give medication to animal with an empty stomach unless other-wise instructed by veterinarian T ! Contact veterinarian if salivation or GI (vomiting, diarrhea, or anorexia) effects are pronounced or persist Chemistry/Synonyms A synthetic cholinergic ester, bethanechol occurs as a slightly hygro-scopic, white or colorless crystalline powder with a slight, amine-like or “fishy” odor. It exhibits polymorphism, with one form melting at 211° and the other form at 219°. One gram of the drug is soluble in approximately 1 m L of water or 10 m L of alcohol. Bethanechol Chloride may also be known as: carbamylmethyl-choline chloride, Duvoid ®, Miotonachol®, Muscaran®, Myo Hermes®, Myocholine®, Myotonine®, Ucholine®, Urecholine®, Urocarb®, or Urotonine®. Storage/Stability Bethanechol tablets should be stored at room temperature in tight 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: Bethanechol Chloride Tablets: 5 mg, 10 mg, 25 mg, & 50 mg; Ure-choline®(Odyssey); generic; (Rx) An injectable product was formerly commercially available; a com-pounding pharmacy may be able to prepare a bethanechol inject-able form. Bicarbonate — see Sodium Bicarbonate BISACODYL (bis-a-koe-dill) Dulcolax® ORAL/RECTAL LAXATIVE Prescriber Highlights TT Stimulant laxative used in dogs & cats TT Contraindicated in GI obstruction TT GI cramping/diarrhea possible TT Don't give with milk products or antacids Uses/Indications Bisacodyl oral and rectal products are used as stimulant cathartics in dogs and cats. Pharmacology/Actions A stimulant laxative, bisacodyl's exact mechanism is unknown. It is thought to produce catharsis by increasing peristalsis by direct stimulation on the intramural nerve plexuses of intestinal smooth muscle. It has been shown to increase fluid and ion accumulation in the large intestine thereby enhancing catharsis. Pharmacokinetics Bisacodyl is minimally absorbed after either oral or rectal adminis-tration. Onset of action after oral administration is generally 6-10 hours and 15 minut es to an hour after rectal administration. Contraindications/Precautions/Warnings Stimulant cathartics are contraindicated in the following conditions: intestinal obstruction (not constipation), undiagnosed rectal bleed-ing, or when the patient is susceptible to intestinal perforation. Bisacodyl should only be used short-term as chronic use can damage mye nteric neurons. Adverse Effects Bisacodyl has relatively few side effects when used occasionally; cramping, nausea, or diarrhea may be noted after use. 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. ) Bisacodyl may be distributed into milk but at quantities unlikely to cause any pr oblems in nursing offspring. Overdosage/Acute Toxicity Overdoses may result in severe cramping, diarrhea, vomiting and potentially, fluid and electrolyte imbalances. Animals should be monitored and given replacement parenteral fluids and electrolytes as necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bisacodyl and may be of significance in veterinary patients: T ! ANTACIDS/MILK : Do not give milk or antacids within an hour of bisacodyl tablets as it may cause premature disintegration of the enteric coating.

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T ! ORAL DRUGS : Stimulant laxatives may potentially decrease GI tran-sit time thereby affecting absorption of other oral drugs. Separate BISMUTH SUBSALICYLATE doses by two hours if possible. (biz-mith sub-sal-iss-ih-layt) BSS, Pepto-Bismol® Doses ANTIDIARRHEAL Note : Bisacodyl enema products and pediatric suppositories are no longer available in the USA. Human pediatric suppositories were 5 Prescriber Highlights mg; the 10 mg “adult” suppositories can be cut lengthwise to ap-proximate one pediatric suppository. TT Used to treat diarrhea & as a component of “triple therapy” for treating Helicobacter GI infections T ! DOGS: TT High doses may cause salicylism, use with caution in cats As a cathartic: a) One 5 mg tablet PO for small dogs; one to two 5 mg tablets TT Constipation/impactions may occur (10-15 mg) for medium to large dogs. Do not break tablets. TT Refrigeration may improve palatability (Willard 2003a) b) 5-20 mg (1-4 tablets) PO once daily, or 1-3 pediatric sup-positories (Sherding 1994) T ! CATS: Uses/Indications In veterinary medicine, bismuth subsalicylate products are used to As a cathartic: treat diar rhea and as a component of “triple therapy” for treating a) One 5 mg tablet PO; do not break tablets. (Willard 2003a) Helico bacter GI infections. The drug is also used in humans for oth-b) 5 mg (1 tablet) PO once daily, or 1-3 pediatric suppositories er GI symptoms (indigestion, cramps, gas pains) and in the treat-(Sherding 1994) ment and prophylaxis of traveler's diarrhea. c) One 5 mg tablet PO q24h. May be given in combination with fiber s upplementation. Avoid daily use if used chronically as Pharmacology/Actions it may damage myenteric neurons. (Washabau 2001) Bismuth subsalicylate is thought to possess protectant, anti-endo-toxic and weak antibacterial properties. It is believed that the parent Client Information compound is cleaved in the small intestine into bismuth carbonate T ! If using oral tablets, do not crush or allow animal to chew; intense and salicylate. The protectant, anti-endotoxic and weak antibacterial cramping may occur. properties are thought to be because of the bismuth. The salicylate T ! Unless otherwise directed by veterinarian, bisacodyl should be component has antiprostaglandin activity that may contribute to its used on an “occasional” basis only. Chronic use can damage the effectiveness and reduce clinical signs associated with secretory diar-nerves in the colon and has lead to laxative dependence in hu-rheas. mans. Pharmacokinetics Chemistry/Synonyms No specific veterinary information was located. In humans, the A diphenylmethane laxative, bisacodyl occurs as white to off-white amount of bismuth absorbed is negligible while the salicylate com-crystalline powder. It is practically insoluble in water and sparingly ponent is rapidly and completely absorbed. Salicylates are highly soluble in alcohol. bound to plasma proteins and are metabolized in the liver to sali-Bisacodyl may also be known as bisacodylum; many trade names cylic acid. Salicylic acid, conjugated salicylate metabolites and any are available. absorbed bismuth are all excreted renally. Storage/Stability Contraindications/Precautions/Warnings Bisacodyl suppositories and enteric-coated tablets should be stored Salicylate absorption may occur; use with caution in patients with at temperatures less than 30°C. preexisting bleeding disorders. Because of the potential for adverse effec ts caused by the salicylate component, this drug should be used Dosage Forms/Regulatory Status cautiously, if at all, in cats. VETERINARY-LABELED PRODUCTS: None As bismuth is radiopaque, it may interfere with GI tract radio-HUMAN-LABELED PRODUCTS: logic examinations. Bisacodyl Enteric-coated Tablets: 5 mg; Alophen® (Numark); Bisa-Adverse Effects Lax® (Bergen Brunswig); Dulcolax® (Boehringer Ingelheim); Fleet® Antidiarrheal products are not a substitute for adequate fluid and Laxative (Fleet); Mo dane® (Savage Labs); Bisac-Evac® (G and W electrolyte therapy when required. May change stool color to a gray-Labs); Caroid® (Mentholatum Co); Corr ectol® (Schering-Plough); black or greenish-black; do not confuse with melena. In human Feen-a-mint® (Schering-Plough); generic; (OTC) infants and debilitated individuals, use of this product may cause Bisacodyl Delayed-Release Tablets: 10 mg; Doxidan ® (Pharmacia); impactions to occur. (OTC) Reproductive/Nursing Safety Bisacodyl Rectal Suppositories: 10 mg; Dulcolax® (Boehringer In-The FDA has not, apparently, given bismuth subsalicylate a preg-gelheim); Bisacody l Uniserts® (Upsher-Smith); Bisa-Lax® (Bergen nancy risk category. As it is a form of salicylate, refer to the aspirin Brunswig); Bisac-Evac® (G & W Labs), Fleet® Laxative (Fleet); ge-monograph for further guidance. Use with caution in pregnant ani-neric; (OTC) mals. Bisacodyl enema products and pediatric suppositories are no longer Use with caution in nursing dams. available in the USA. Pediatric suppositories were 5 mg and the 10 mg “ad ult” suppositories can be cut lengthwise to approximate a pe-diatric suppository.

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Overdosage/Acute Toxicity Bismuth subsalicylate liquid/suspension contains approximately 8. 7 mg/m L salicylate. Two tablespoonsful (30 m L) is approximately eq uivalent to one 325 mg aspirin tablet. See the Aspirin monograph for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bismuth subsalicylate and may be of significance in veterinary patients: !TTETRACYCLINE : Bismuth containing products can decrease the absorption of orally administered tetracycline products. If both agents are to be used, separate drugs by at least 2 hours and ad-minister tetracycline first. !TASPIRIN : Because bismuth subsalicylate contains salicylate, con-comitant administration with aspirin may increase salicylate se-rum levels; monitor appropriately. Laboratory Considerations !TAt high doses, salicylates may cause false-positive results for uri-nary glucose if using the cupric sulfate method (Clinitest®, Bene-dict's solution) and false-negative results if using the glucose oxi-dase 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 produced). !T5-HIAA determinations by the fluorometric method may be inter-fered by salicylates in the urine. !TFalsely elevated VMA (vanillylmandelic 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. !TUrinary excretion of xylose may be decreased if salicylates are given concurrently. !TFalsely elevated serum uric acid values may be measured if using colorimetric methods. Doses Note : Doses of liquids below are for the 17. 5 mg/m L (1. 75%) liquids (veterinary suspensions; original Pepto-Bismol® liquid, etc. ) unless otherwise specified. !TDOGS: For acute diarrhea: a) 1 m L per 5 kg of body weight PO 3 times a day; should prob-ably not exceed 5 days of therapy (Hall and Simpson 2000) b) Pepto-Bismol®: 0. 25 m L/kg PO q4-6h, up to 2 m L/kg q 6-8h (Cote 2000) Fo r eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 15. 4 mg/kg q8h, amoxi-cillin 11 mg/kg q8h and bismuth subsalicylate (original Pep-to-Bismo l®) 0. 22 m L/kg PO q4-6h. Give each for 3 weeks (Hall 2000) As a gastroprotectant/coating agent in the adjunctive treatment of uremic gastritis: a) 2 m L/kg PO q6-8h (Bar tges 2006d) !TCATS: For diarrhea: a) Pepto-Bismol® : 0. 25 m L/kg PO q4-6h; cats are sensitive to salicylates and probably should not receive frequent or high dosages (Cote 2000) b) Using “Pepto-Bismol® Re gular” or equivalent strength (17. 5 mg/m L) liquid: 0. 5-1 m L/kg PO q12h for 3 days. (Scherk 2005b) c) For diarrhea in kittens and young cats: 1-2 m L Pe pto-Bis-mol® 3-4 times a day. Refrigeration may increase palatability. ( Tams 1999) For eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 15. 4 mg/kg q8h, amoxi-cillin 11 mg/kg q8h and bismuth subsalicylate (original Pep-t o-Bismol®) 0. 22 m L/kg PO q4-6h. Gi ve each for 3 weeks (Hall 2000) !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 w eeks. (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; continue for 21 days. Used with famoti-dine (0. 5 mg/kg PO once daily) and sucralfate (25 mg/kg PO q8h) (J ohnson 2006c) !TCATTLE: For diarrhea: a) For calves: 60 m L two to four times a day for two days (Label Dir ections; Corrective Mixture® —Beecham). b) 2-3 ounces PO 2-4 times a da y (Braun 1986) !THORSES: For diarrhea: a) For foals: 3-4 ounces per 45 kg (100 lb. ) body weight PO q6-8h (Ma digan 2002a) b) For foals or adults: 1 ounce per 8 kg of body weight PO 3-4 times dail y (Clark and Becht 1987) c) For foals: 3-4 oz. PO q6-8h (M artens and Scrutchfield 1982) d) For foals: 60 m L two to four times a day for two days (Label Dir ections; Corrective Mixture® —Beecham). !TSWINE: For diarrhea in baby pigs: a) 2-5 m L PO two to four times a day for 2 days (Label Direc-tions; Corrective Mixture® — Beecham) Monitoring !TClinical efficacy !TFluid and electrolyte status in severe diarrhea Client Information !TShake product well before using. !TRefrigeration of the suspension may improve palatability. Do not mix with milk before administering. !TIf diarrhea persists, contact veterinarian. !TMay change stool color to a gray-black or greenish-black; contact veterinarian if stool becomes “tarry” black. Chemistry/Synonyms Bismuth subsalicylate occurs as white or nearly white, tasteless, odorless powder and contains about 58% bismuth. It is insoluble in water, glycerin and alcohol. Bismuth subsalicylate may also be known as: BSS, basic bis-muth salicylate, bismuth oxysalicylate, bismuth salicylate, bismuthi subsalicy las, Bismu-kote®, Bismukote®, Bismupaste®, Bismatrol®, Bismed®, Bismusal®, Bismylate®, Bisval®, Equi-Phar®, Gastrocote®, Jatrox®, Kalbeten®, Kaopectate®, Katulcin-R®, Pala BIS®, Peptic Relief®, Pink Biscoat®, Pink Bismuth Rose®, or Ulcolind Wismut®; many other human trade names are available.

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Storage/Stability/Compatibility Bismuth subsalicylate should be stored protected from light. Unless BLEOMYCIN SULFATE otherwise labeled store at room temperature; do not freeze. It is in-(blee-oh-mye-sin) Blenoxane®compatible with mineral acids and iron salts. When exposed to alkali bicarbonates, bismuth subsalicylate decomposes with effervescence. ANTINEOPLASTIC Dosage Forms/Regulatory Status Prescriber Highlights VETERINARY-LABELED PRODUCTS: TT Antibiotic antineoplastic agent infrequently used for a va-Bismuth Subsalicylate Paste: riety of neoplasms in dogs & cats; intralesional adminis-5% (50 mg/m L) in 15 m L tubes; Bismukote Paste for Small Dogs® tration may have promise (Vedco), (OTC). Labeled for use in small dogs. TT Two main toxicities: acute (fever, anorexia, vomiting, & al-10% (100 mg/m L) in 15 m L, 30 m L tubes; Bismukote Paste for Me-lergic reactions) & delayed (dermatologic effects, stomati-dium and Large Dogs® (Vedco), Bismupaste D® (Butler); (OTC). tis, pneumonitis & pulmonary fibrosis) Depending on product, labeled for use in small, medium and large TT Do not exceed total dosage recommendationsdogs. TT Intensive adverse effect monitoring required when used20% (200 mg/m L) in 60 m L tubes; Bismupaste E® (Butler), Equi-systemically Phar® (Vedco); (OTC). Labeled for use in horses. Bismuth Subsalicylate Oral Suspension: Bismuth subsalicylate Oral Suspension 1. 75% (17. 5 mg/m L; 262 mg/15 m L). Bismu-ko te® Suspension (Vedco), Bismusal® (Bimeda), Uses/Indications Bleomycin has occasionally been used as adjunctive treatment of rective Suspension® (Phoenix), Gastrocote® (Butler); generic; (OTC). Bismusal® Suspension (Agr i Pharm), Bismusol® (First Priority), Cor-lymphomas, squamous cell carcinomas, teratomas, and nonfunc-Availab le in gallons. Labeled for use in cattle, horses, calves, foals, tional thyroid tumors in both dogs and cats. Recent work has dem-dogs and cats. Each m L contains about 8. 7 mg salicylate. onstrated that bleomycin may be promising for intralesional treat-ment for a variety of localized tumors with or without concomitant Bismuth Subsalicylate Tablets: electropermeabilization. Bismuth Subsalicylate tablets (each tablet contains 262 mg of bis-muth subsalicylate). Labeled for use in dogs. Pala BIS® (Phar m X); Pharmacology/Actions (OTC). One tablet contains about 102 mg salicylate. Bleomycin is an antibiotic that has activity against a variety of gram-negative and gram-positive bacteria as well as some fungi. While its HUMAN-LABELED PRODUCTS: cytotoxicity prevents it from being clinically useful as an antimicro-Bismuth Subsalicylate (BSS) Liquid/Suspension: 87 mg/5 m L; 130 bial, it can be useful against a variety of tumors in small animals. mg/15 m L; 262 mg/15 m L; 524 mg/15 m L; 525 mg/15 m L; in 120 Bleomycin has both a DNA binding site and a site that binds to m L, 236 m L, 237 m L, 240 m L, 355 m L, 360 m L, or 480 m L; Kao-the ferrous form of iron. By accepting an electron from ferrous ion pectate®, Kaopectate® Children' s & Extra Strength (Pharmacia); to an oxygen atom in the DNA strand, DNA is cleaved. Pink Bismuth (various); Kao-T in® (Major); Peptic Relief® & K-Pek® Resistance to bleomycin therapy is via reduced cellular uptake (Rugby); Pepto-Bismol® & Maxim um Strength (Procter & Gamble); of the drug, reduced ability to damage DNA and increased rates of Kapectolin® (United Research Laboratories); Maalox® T otal Stom-DNA repair by the cell and, probably most importantly, via the en-ach Relief Liquid (Novar tis); (OTC). Note : Regular strength (262 mg/ zyme bleomycin hydrolase. m L) contains 8. 7 mg salicylate per m L; Extra-Strength (525 mg/m L) contains 15. 7 mg of salicylate per m L. Pharmacokinetics Bleomycin is not appreciably absorbed from the gut and must be Bismuth Subsalicylate Tablets and Caplets: 262 mg (regular & chew-administered parenterally. It is mainly distributed to the lungs, kid-able); Kaopectate® (Pfizer Consumer Health); Bismatr o l® (Major); neys, skin, lymphatics and peritoneum. In patients with normal re-Peptic Relief® (Rugby); Pept o-Bismol® (Major); (OTC). One tablet nal function, terminal half-life is about 2 hours. In humans, 60-70%contains about 102 mg salicylate. of a dose is excreted as active drug in the urine. Contraindications/Precautions/Warnings Because bleomycin is a toxic drug with a low therapeutic index, it should be used only by those having the facilities to actively monitor patients and handle potential complications. Bleomycin is contrain-dicated in patients with prior hypersensitivity reactions from the drug, p reexisting pulmonary disease, or adverse pulmonary effects from prior therapy. The drug should be used very cautiously in pa-tients with significant renal impairment and dosage reduction may be nec essary. Bleomycin can be teratogenic; it should only be used in pregnant animals when the owners accept the associated risks. Adverse Effects T oxicity falls into two broad categories: acute and delayed. Acute toxicities include fever, anorexia, vomiting, and allergic reactions (including anaphylaxis). Delayed toxic effects include dermatologic effects (e. g., alopecia, rashes, etc. ), stomatitis, pneumonitis and pul-monary fibrosis. These latter two effects have been associated with

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Tdrug-induced fatalities. Initial signs associated with pulmonary to xicity include pulmonary interstitial edema with alveolar hya-line membrane formation and hyperplasia of type II alveolar mac-rophages. Pulmonary toxicity is potentially reversible if treatment is sto pped soon enough. Unlike many other antineoplastics, bleomy-cin does not usually cause bone marrow toxicity but thrombocy-topenia, leukopenia and slight decreases in hemoglobin levels are possib le. Renal toxicity and hepatotoxicity are potentially possible. T o reduce the likelihood of pulmonary toxicity developing, a to-tal maximum dosage of 125-200 mg/m2 should not be exceeded. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the po-tential benefits from the use of the drug in pregnant women may be acc eptable despite its potential risks. ) It not known if bleomycin enters milk; it is not recommended to nur se while receiving the medication. Overdosage/Acute Toxicity No specific information was located. Because of the toxicity of the drug, it is important to determine dosages carefully. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bleomycin and may be of significance in veterinary patients: !TANESTHETICS, GENERAL : Use of general anesthetics in patients treated previously with bleomycin should be exercised with cau-tion. Bleomycin sensitizes lung tissue to oxygen (even to concen-trations of inspired oxygen considered to be safe) and rapid dete-rioration of pulmonary function with post-operative pulmonary fibrosis can occur. !TPRIOR OR CONCOMITANT CHEMOTHERAPY WITH OTHER AGENTS OR RA-DIATION THERAPY : Can lead to increased hematologic, mucosal and pulmonary toxicities with bleomycin therapy. 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 : T o reduce the likelihood of pulmonary toxicity developing, a total maximum dosage of 125-200 mg/m2 should not be exceeded. !TSMALL ANIMALS: For squamous cell carcinomas, lymphomas and other carcinomas: a) 10 U/m2 IV or SC once daily for 3-4 d oses, then 10 U/m2 every 7 days. Maximum accumulative dose: 200 U/m2 (Ja-cobs, Lumsden et al. 1992) b) 0. 3-0. 5 mg/kg IM, SC or IV (over 10 minutes) once weekly (Kit chell and Dhaliwal 2000) Monitoring !TEfficacy !TPulmonary T oxicity: Obtain chest films, (baseline and on a regu-lar basis—in humans they are recommended q1-2 w eeks); lung auscultation (dyspnea and fine rales may be early signs of toxici-ty); other initial signs associated with pulmonary toxicity include pulmonar y interstitial edema with alveolar hyaline membrane formation and hyperplasia of type II alveolar macrophages !TBlood chemistry (encompassing renal and hepatic function markers) and hematologic profiles (CBC) may be useful to mon-itor potential renal, hepatic and hematologic toxicities !Total dose accumulation Client Information !TClients must be informed of the potential toxicities associated with therapy and urged to report any change in pulmonary func-tion (e. g., shortness of breath, wheezing) immediately Chemistry/Synonyms An antibiotic antineoplastic agent, bleomycin sulfate is obtained from Streptomyces verticullis. It occurs as a cream colored, amor-phous powder that is very soluble in water and sparingly soluble in alc ohol. After reconstitution, the p H of the solution ranges from 4. 5-6. Bleomycin is assayed microbiologically. One unit of bleomycin is equivalent to one mg of the reference Bleomycin A 2 standard. Bleomycin sulfate may also be known as: bleomycin sulphate, ble omycini sulfas, Bileco®, Blanoxan®, Blenamax®, Blenoxane®, Bleo®, Bleo-S®, Bleo-cell®, Bleocin®, Bleolem®, Blio®, Blocamicina®, Bonar®, Oil Bleo®, or Tecnomicina®. Storage/Stability/Compatibility Powder for injection should be kept refrigerated. After reconsti-tuting with sterile saline, water, or dextrose, the resulting solution is stab le for 24 hours. Bleomycin is less stable in dextrose solutions than in saline. After reconstituting with normal saline, bleomycin is reportedly stable for at least two weeks at room temperature and for 4 weeks when refrigerated; however, since there are no preserva-tives in the resulting solution, the product is recommended for use within 24 hour s. Bleomycin sulfate is reported to be compatible with the following drugs: amikacin sulfate, cisplatin, cyclophosphamide, dexametha-sone sodium phosphate, diphenhydramine HCl, doxorubicin, hep-arin sodium, metoclopramide HCl, vinblastine sulfate, and vincris-tine sulfate. Compatibility is dependent upon factors such as p H, co ncentration, 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: Bleomycin Sulfate Powder for Injection: 15 and 30 units per vial; Blenoxane® (Bristol-Myers Oncology); generic; (Rx)

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BOLDENONE UNDECYLENATE (bole-di-nohn un-de-sil-en-ate) Equipoise® ANABOLIC STEROID Prescriber Highlights TT Long-acting anabolic steroid labeled for horses; possibly useful in cats to stimulate appetite TT Not recommended for use in stallions or pregnant mares TT May cause androgenic effects, including aggressiveness; potentially a hepatotoxin TT Potentially a drug of abuse by humans, watch for diver-sion scams Uses/Indications Boldenone is labeled for use as adjunctive therapy “... as an aid for treating debilitated horses when an improvement in weight, haircoat, or general physical condition is desired” (Package Insert; Equipoise®—Fort Dodge). Boldenone may possibly be useful to stimulate appetite in cats. Pharmacology/Actions In the presence of adequate protein and calories, anabolic steroids promote body tissue building processes and can reverse catabolism. As these agents are either derived from or are closely related to tes-tosterone, the anabolics have varying degrees of androgenic effects. Endoge nous testosterone release may be suppressed by inhibiting luteinizing hormone (LH). Large doses can impede spermatogenesis by negative feedback inhibition of FSH. Anabolic steroids can also stimulate erythropoiesis possibly by stimulatio n of erythropoietic stimulating factor. Anabolics can cause nitrogen, sodium, potassium and phosphorus retention and decrease the urinary excretion of calcium. Pharmacokinetics No specific information was located for this agent. It is considered a long-acting anabolic, with effects persisting up to 8 weeks. It is unknown if the anabolic agents cross into milk. Contraindications/Precautions/Warnings The manufacturer (Solvay) recommends not using the drug on stal-lions or pregnant mares. Other clinicians state that anabolic steroids should not be used in either stallions or non-pregnant mares in-tended for reproduction. Boldenone should not be administered to horses inte nded for food purposes. In humans, anabolic agents are contraindicated in patients with hepatic d ysfunction, hypercalcemia, patients with a history of myo-cardial infarction (can cause hypercholesterolemia), pituitary insuf-ficiency, prostate carcinoma, in selected patients with breast carci-noma, benign prostatic hypertrophy and during the nephrotic stage of nep hritis. Adverse Effects In the manufacturer's (Equipoise®—Solvay) package insert, only an-drogenic (over aggressiveness) effects are listed. However, in work repo rted in both stallions and mares (Squires and Mc Kinnon 1987), boldenone caused a detrimental effect in testis size, and sperm pro-duction and quality in stallions. In mares, the drug caused fewer total and larg e follicles, smaller ovaries, increased clitoral size, short-ened estrus duration, reduced pregnancy rates and severely altered sexual beha vior. Although not reported in horses, anabolic steroids have the po-tential to cause hepatic toxicity. Reproductive/Nursing Safety The anabolic agents are category X (Risk of use outweighs any possible benefit) agents for use in pregnancy and are contraindicated because of possible fetal masculinization. Overdosage/Acute Toxicity No information was located for this specific agent. In humans, so-dium and water retention can occur after overdosage of anabolic stero ids. It is suggested to treat supportively and monitor liver func-tion should an inadvertent overdose be administered. Drug Interactions No drug interactions were located for boldenone specifically. The following drug interactions have either been reported or are theo-retical in humans or animals receiving anabolic steroids and may be of significance in veterinary patients: T ! ANTICOAGULANTS (warfarin ): Anabolic agents as a class may potenti-ate the effects of anticoagulants; monitoring of INR and dosage adju stment of the anticoagulant (if necessary) are recommended T ! CORTICOSTEROIDS, ACTH : Anabolics may enhance the edema that can be associated with ACTH or adrenal steroid therapy T ! INSULIN : Diabetic patients receiving insulin may need dosage ad-justments if anabolic therapy is added or discontinued; anabolics may decr ease blood glucose and decrease insulin requirements Laboratory Considerations T ! Concentrations of protein bound iodine (PBI) can be decreased in patients receiving androgen/anabolic therapy, but the clinical sig-nificance of this is probably not important T ! Androgen/anabolic agents can decrease amounts of thyroxine-binding globulin and decrease total T 4 concentrations and increase resin uptake of T 3 and T 4; free thyroid hormones are unaltered and, clinically, there is no evidence of dysfunction. T ! Both creatinine and creatine excretion can be decreased by anabolic steroids T ! Anabolic steroids can increase the urinary excretion of 17-ketos-teroids T ! Androgenic/anabolic steroids may alter blood glucose levels. T ! Androgenic/anabolic steroids may suppress clotting factors II, V, VII, and X. T ! Anabolic agents can affect liver function tests (BSP retention, SGOT, SGPT, bilirubin, and alkaline phosphatase) Doses T ! HORSES: (Note : ARCI UCGFS Class 4 Drug) a) 1. 1 mg/kg IM; may repeat in 3 week intervals (most horses will r espond with one or two treatments) (Package Insert; Equipoise®—Fort Dodge) b) 1 mg/kg IM; repeated at 3 week intervals (Robinson 1987) T ! CATS: a) As an appetite stimulant: 5 mg (total dose) IM/SC every 7 days; anab olic steroids not as effective as many other appetite stimulants and may be associated with hepatotoxicity (Bart-ges 2003b)

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Monitoring T ! Androgenic side effects T ! Fluid and electrolyte status, if indicated T ! Liver function tests if indicated T ! Red blood cell count, indices, if indicated T ! Weight, appetite Client Information T ! Because of the potential for abuse by humans, anabolic steroids are controlled drugs. Boldenone should be kept in a secure area and out of the reach of children. T ! Contact veterinarian of patient develops yellowing of whites of the eyes, or develops a decreased appetite or lethargy. Chemistry/Synonyms An injectable anabolic steroid derived from testosterone, boldenone undecylenate has a chemical name of 17 beta-hydroxyandrosta-1, 4-dien-3-one. The commercially available product is in a sesame oil vehicle. Boldenone undecylenate may also be known as: Ba-29038, bold-enone undecenoate, Equipoise ®, or Vebonol®. Storage/Stability/Compatibility Boldenone injection should be stored at room temperature; avoid freezing. Because it is in an oil vehicle, it should not be physically mixed with any other medications. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Boldenone Undecylenate for Injection: 25 mg/m L in 10 m L vials; 50 mg/m L in 10 m L and 50 m L vials; Equipoise®(Fort Dodge); (Rx, C-III). Approved for use in horses not to be used for food. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substanc e. See the appendix for more information. HUMAN-LABELED PRODUCTS: None BROMIDES POTASSIUM BROMIDE SODIUM BROMIDE (broe-mide) ANTICONVULSANT Prescriber Highlights TT Primary or adjunctive therapy for seizure disorders in dogs; 2nd or 3rd line agent for cats TT Very long half-life, must give loading dose to see steady-state therapeutic levels within a month TT Most prevalent adverse effect in dogs is sedation, espe-cially when used with phenobarbital TT Cats may develop adverse respiratory effects TT Therapeutic levels in dogs approximately 1-2 mg/m L TT Toxic effects include profound sedation to stupor, ataxia, tremors, hind limb paresis, or other CNS manifestations TT If using sodium bromide (vs. potassium bromide), dosage adjustments must be made Uses/Indications Bromides are used both as primary therapy and as adjunctive ther-apy to control seizures in dogs that are not adequately controlled by phenobar bital (or primidone) alone (when steady state trough phe-nobarbital levels are >30 mcg/m L for at least one month). While historical ly bromides were only recommended for use alone in pa-tients suffering from phenobarbital (or primidone) hepatotoxicity, they are mor e frequently used as a drug of first choice. Although not frequently used, bromides are also considered suitable b y some for use in cats with chronic seizure disorders, but cats may be more susceptible to the drug's adverse effects. Pharmacology/Actions Bromide's anti-seizure activity is thought to be the result of its generalized depressant effects on neuronal excitability and activity. Bromide ions compete with chloride transport across cell mem-branes resulting in membrane hyperpolarization, thereby raising seizure threshold and limit ing the spread of epileptic discharges. Pharmacokinetics Bromides are well absorbed after oral administration, primarily in the small intestine. Bromides are also well absorbed after solutions are administered rectally in dogs (bioavailability of 60-100%). Bromide is distributed in the extracellular fluid and mimics the vol-ume of distribution of chloride (0. 2-0. 4 L/Kg). It is not bound to plasma proteins and readily enters the CSF (in dogs: 87% of serum concentration; in humans: 37%). Bromides enter maternal milk (see Reproductive Safety below). Bromides are principally excreted by the kidneys. The half-life in dogs has been reported to be from 16-25 days; cats, 10 days; and humans, 12 days. Contraindications/Precautions/Warnings Older animals and those with additional diseases, may be prone to intolerance (see Adverse Effects below) at blood levels that are easily tolerable by younger, healthier dogs. Patients with renal dysfunc-tion may need dosage adjustments. Adverse Effects A transient sedation (lasting up to 3 weeks) is commonly seen in dogs receiving bromides. Serum concentrations of bromide above 15 m Mol/L (150 mg/d L) are considered “toxic” by some, but many dogs apparently tolerate levels of up to 30 m Mol/L. T oxicity gener-ally presents as profound sedation to stupor, ataxia, tremors, hind limb paresis, o r other CNS manifestations. Pancreatitis has been reported in dogs receiving combination therapy of bromides with either primidone or phenobarbital; however, since this effect has been reported with both primidone and phenobarbital, its direct re-lationship with bromide is unknown. Additional potential adverse effec ts reported include: polyphagia, polydipsia, polyuria, anorexia, vomiting, and constipation. Pruritic dermatitis and paradoxical hy-peractivity are rarely reported. If administering an oral loading dose of potassium bromide, acute GI upset may occur if given too rapidly. Potentially, large loading doses could affect serum potassium levels in patients re-ceiving potassium bromide. If the patient cannot tolerate the gastrointestinal effects (vomit-ing) of potassium bromide and divided doses with food do not al-leviate the problem, switching to sodium bromide may be tried. Lower respiratory effects (cough, dyspnea) have been associated with bromide therapy in cats. Peribronchial infiltrates may be seen on radiographs and dyspnea may be serious or fatal. Signs appear to be reversible in most cats once bromides are discontinued. Other adverse effects in cats include polydipsia, sedation, and weight gain.

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Reproductive/Nursing Safety Reproductive safety has not been established. Human infants have suffered bromide intoxication and growth retardation after mater-nal ingestion of bromides during pregnancy. Bromide intoxication has also be en reported in human infants breastfeeding from moth-ers taking bromides. Use with caution in pregnancy or lactation. Overdosage/Acute Toxicity T oxicity is more likely with chronic overdoses, but acute overdoses are a possibility. In addition to the adverse effects noted above, ani-mals that have developed bromism (whether acute or chronic) may deve lop signs of muscle pain, conscious proprioceptive deficits, ani-socoria, and hyporeflexia. Standard gut removal techniques should be employed af-ter a known acute overdose. Death after an acute oral ingestion is appare ntly rare as vomiting generally occurs spontaneously. Administration of parenteral (0. 9% sodium chloride) or oral sodi-um chloride, parenteral glucose and diuretics (e. g., furosemide) may be help ful in reducing bromide loads in either acutely or chronically intoxicated individuals. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bromides and may be of significance in veterinary patients: !TCNS SEDATING DRUGS : Because bromides can cause sedation, other CNS sedating drugs may cause additive sedation !TDIURETICS (furosemide, thiazides ): May enhance the excretion of bromides thereby affecting dosage requirements !TLOW/HIGH S ALT D IETS: Bromide toxicity can occur if chloride ion ingestion is markedly reduced. Patients put on low salt diets may be at risk. Conversely, additional sodium chloride in the diet (in-cluding prescription diets high in chloride) could reduce serum bromid e levels, affecting seizure control. Keep chloride content of diet relatively constant while bromides are being administered. If chloride content must be altered, monitor bromide levels more frequently. !TDRUGS T HAT C AN LOWER S EIZURE T HRESHOLD (e. g., acepromazine, xy-lazine ): These drugs may potentially reduce efficacy of antiseizure medications Laboratory Considerations !TSee drug interactions above regarding chloride. Bromide may interfere with serum chloride determinations yielding falsely high results. Doses Note : Doses are listed for potassium bromide. If using sodium bro-mide reduce dose by approximately 15%. !TDOGS: Because of the extraordinarily long serum half-life in dogs, (it may take up to 4-5 months for blood levels to reach steady state concen-trations), many dosing regimens include an initial oral bolus load-ing dose to reduce the period to attain therapeutic concentrations. Detailed protocols for using bromide in treating seizures in dogs can be found in the chapter by Quesnel in Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); the entry on Epilepsy, Idiopathic by Parent in The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004); and the chapter on Seizures by Taylor in Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003). a) Give a loading dose (or steady-state levels will not occur for 2-3 months) di vided over 5 days. T o achieve a serum level of 1 mg/m L (minimum) give 120 mg/kg PO per day for 5 days and then reduce dose to 30 mg/kg PO once daily. T o achieve a ser um level of 1. 5 mg/m L give 160 mg/kg PO for 5 days and then reduce to 40 mg/kg PO once daily. Measure plasma levels 2-3 days after loading is completed to document if target se-rum level is met. Re-measure levels at 3 weeks and adjust dose as req uired. (Boothe 1999) Note : See Dr. Boothe's bromide level monitoring recommendations below in Monitoring. b) For seizures: Loading dose: 400-600 mg/kg/day divided and give n with food. May be given over 24 hours or more gradu-ally over 5 days. Then go to initial maintenance dose: 20-30 mg/kg PO once daily (M unana 2004a) c) For idiopathic epilepsy: Loading dose: 100 mg/kg q6h for the first 24 hour s, or 100 mg/kg q24h for 4 days. Maintenance dose: 35-40 mg/kg PO once daily (q24h). Serum KBr con-centrations at 8 weeks, 12 weeks and every 6 months thereaf-ter (Berry 2003) d) A good starting dose is 35 mg/kg PO once daily, but the au-thor often uses a loading dose: 125 mg/kg/day for 5 days PO divide d q12h and then resume at 35 mg/kg PO once daily. For dogs where oral administration is not possible (e. g., status epilepticus), may give rectally at 100 mg/kg body weight every 4 hours for 6 total doses. (Dewey 2005b) e) Using an intravenous sodium bromide loading dose to rap-idly achieve minimum therapeutic concentration (1-1. 5 mg/ m L): Intr avenous, 600-1200 mg/kg, diluted in a solution and administered over eight hours. If target serum bromide con-centrations are not reached, additional intravenous sodium bromid e may be administered. (USPC 2005) ( Note : It has been anecdotally reported that a 3% solution of sodium bromide can be used intravenously. T o prepare a 3% solution: add 30 grams of sodium bromide to 1000 m L of sterile water for in-jection; use an in-line IV filter. Use with caution—Plumb) !TCATS: a) As third choice (after phenobarbital and diazepam) therapy of re fractory seizures: 10-20 mg/kg/day PO. Follow same guideline as dogs (Quesnel 2000) b) As second line therapy for epilepsy: 30 mg/kg PO once daily (Munana 2004c) Monitoring !TEfficacy/T oxicity !TSerum Levels. In dogs, therapeutic bromide concentrations are generally agreed to be 1-3 mg/m L; lower range may be effective for dogs on phenobarbital therapy and the higher range for dogs on bromide alone. Actual monitoring recommendations vary and depend on whether the patient received a loading dose or not. One recommendation (Boothe 2004) based upon pharmacokinetic principles is: If no load was given and maintenance dose was used initially, monitor at 3-4 weeks and then at steady-state (2. 5-3 months). The first sample indicates about 50% of what will be achieved at steady-state and allows adjustment of the dosage early. If a loading dose was used, an immediate level after the load (day 6 or 7 after a 5 day loading protocol), followed by a sample at 1 month and then 3 months. The immediate sample indicates what was achieved with loading; the 1 month level indicates the success of the maintenance dose, maintains what was achieved with the loading dose and allows dosage adjustment, if required; and the 3 month level establishes the new baseline.

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TClient Information T ! Clients must be committed to administering doses of anticon-vulsant medications on a regular basis. Lack of good compliance with d osing regimens is a major cause of therapeutic failures with anti-seizure medications. If a dose is missed, give it when remem-bered; a dose may be doubled the next day, but should preferably be separ ated by several hours to reduce the chance for gastroin-testinal upset. T ! Clients should also understand and accept that this treatment in-volves using a non-approved “drug. ” T ! Dose measurements of bromide solutions should be done with a needle-less syringe or other accurate measuring device. The dose may either be sprinkled on the dog's food (assuming he/she con-sumes it entirely) or squirted in the side of the mouth. T ! oxic effects (e. g., profound sedation, ataxia, stupor, GI effects) should be explained to the owner and if they occur, they should be reported to the veterinarian. T ! Dogs that cannot tolerate the gastrointestinal effects (vomiting) of potassium chloride with single daily doses may better tolerate doses divided through the day given with food. Clients should not alter diet without first consulting with veterinarian and to avoid giving dogs salty treats (e. g., pig ears). Chemistry Potassium bromide occurs as white, odorless, cubical crystals or crystalline powder. One gram will dissolve in 1. 5 m L of water. Potassium bromide contains 67. 2% bromide. Each gram contains 8. 4 m Eq (m Mol) of potassium and bromide. Sodium bromide occurs as white, odorless, cubic crystals or granular powder. One gram will dissolve in 1. 2 m L of water. Sodium bromide contains 77. 7% bromide. Because of the different molecular weights of sodium and po-tassium, with respect to actual bromide content, sodium bromide solutio ns of 250 mg/m L contain about 20% more bromide than potassium bromide 250 mg/m L solution. This is generally not clini-cally significant unless changing from one salt to another for a given patient. Storage/Stability/Compatibility Store in tight containers. Solutions may be stored for up to one year in clear or brown, glass or plastic containers at room temperature. Refrigerating the solution may help reduce the change for micro-bial growth, but may cause crystals or precipitants to form. Should precipitat ion occur, warming the solution should resolubolize the bromide. Bromides can precipitate out alkaloids in solution. Mixing with strong oxidizing agents can liberate bromine. Metal salts can pre-cipitate solutions containing bromides. Sodium bromide is hygro-scopic; potassium bromide is not. Dosage Forms/Regulatory Status Neither potassium or sodium bromide are available in approved dosage forms in North America. Reagent grade or USP grade may be obtained from various chemical supply houses to compound an acceptable oral product. If purchasing a reagent grade, specify American Chemical Society (ACS) grade. At a concentration of 250 mg/m L, 25 grams of potassium bromide are weighed and add a sufficient amount of distilled water to a final volume of 100 m L; potassium bromide dissolves easily in water, sodium bromide may take longer to dissolve. Flavoring agents are not usually necessary for patient acceptance. BROMOCRIPTINE MESYLATE (broe-moe-krip-teen) Parlodel® DO PAMINE AGONIST/PROLACTIN INHIBITOR Prescriber Highlights TT Dopamine agonist & prolactin inhibitor occasionally used in dogs for pregnancy termination or pseudopregnancy; in horses for pituitary adenomas; in cats for acromegaly TT Many adverse effects possible; GI, CNS depression & hypotension are most likely; much more likely to cause emesis in dogs than cabergoline TT Interferes with lactation Uses/Indications Bromocriptine may potentially be of benefit in treating acromega-ly/pituitary adenomas or pseudopregnancy in a variety of species. Howe ver, because of adverse effects, its potential value for treating hyperadrenocorticism in dogs is low. It has been used in dogs for pregnancy termination and pseudopregnancy. Pharmacology/Actions Bromocriptine exhibits multiple pharmacologic actions. It inhibits prolactin release from the anterior pituitary thereby reducing se-rum prolactin. The mechanism for this action is by a direct effect on the pit uitary and/or stimulating postsynaptic dopamine recep-tors in the hypothalamus to cause release of prolactin-inhibitory facto r. Bromocriptine also activates dopaminergic receptors in the neostriatum of the brain. Pharmacokinetics In humans, only about 28% of a bromocriptine dose is absorbed from the gut and, due to a high first-pass effect, only about 6% reaches the systemic circulation. Distribution characteristics are not well described but in humans, it is highly bound (90-96%) to serum albumin. Bromocriptine is metabolized by the liver to inac-tive and non-toxic metabolites. It has a biphasic half-life; the alpha phase is ab out 4 hours and the terminal phase is about 15 hours, but one source says 45-50 hours. Contraindications/Precautions/Warnings Bromocriptine is generally contraindicated in patients with hyper-tension. It should be used with caution in patients with hepatic dis-ease as metabolism of the drug may be reduced. Adverse Effects Bromocriptine may cause a plethora of adverse effects that are usually dose related and minimized with dosage reduction. Some more likely possibilities include: gastrointestinal effects (nausea, vomiting), nervous system effects (sedation, fatigue, etc. ), and hy-potension (particularly with the first dose, but it may persist). At dosages used in d ogs, more likely to cause emesis than cabergoline. Reproductive/Nursing Safety Usage during pregnancy is contraindicated in humans, although documented teratogenicity has not been established. Because bromocriptine interferes with lactation, it should not be used in animals that are nur sing.

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Overdosage/Acute Toxicity Overdosage may cause vomiting, severe nausea, and profound hy-potension. Standardized gut removal techniques should be employed when a pplicable and cardiovas cular support instituted as needed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bromocriptine and may be of significance in veterinary patients: T ! ALCOHOL : Use with alcohol may cause a disulfiram-type reaction T ! BUTYROPHENONES (e. g., haloperidol, azaperone ), AMITRIPTYLINE, PHENOTHIAZINES, and RESERPINE : May increase prolactin con-centrations and bromocriptine doses may need to be increased T ! CYCLOSPORINE : May elevate cyclosporine levels T ! ERYTHROMYCIN, CLARITHROMYCIN : May increase bromocriptine levels T ! ESTROGENS or PROGESTINS : May interfere with the effects of bromocriptine T ! ERGOT ALKALOIDS : Use of bromocriptine and ergot alkaloids is not recommended; some human patients receiving both have devel-oped severe hypertension and myocardial infarction T ! HYPOTENSIVE MEDICATIONS : May cause additive hypotension if used with bromocriptine T ! MAO INHIBITORS (including amitraz, and maybe selegiline ): Avoid use of bromocriptine with these compounds T ! OCTREOTIDE : May increase bromocriptine levels T ! SYMPATHOMIMETICS (e. g., phenylpropanolamine ): Enhanced bro-mocriptine effects have been reported in humans (rare), includ-ing ventricular tachycardia and cardiac dysfunction Doses T ! DOGS: For treatment of pseudocyesis (pseudopregnancy): a) 10-100 mcg/kg PO daily in divided doses until lactation ceases. Vo miting, depression and anorexia are common side effects, usually more problematic than the lactation. (David-son and Feldman 2005) b) 10-100 mcg/kg PO twice daily for 10-14 days. Vomiting is very common; reducing dose and administering after meals may help. (Johnson 2003a) c) 30 mcg/kg PO once daily for 16 days (Root Kustritz 2003) For pr egnancy termination after mismating: a) From day 35-45 after LH surge 50-100 mcg/kg PO or IM twice daily for 4-7 days. Not uniformly effective and may cause vomiting at this dosage (a peripheral acting antiemetic 30 minutes before dose may be helpful) (Verstegen 2000) b) As an abortifacient 25 days after LH surge: Cloprostenol at 1 mcg/kg SC q48 hour s (every other day) plus bromocriptine at 30 mcg/kg PO q24h (every day) (Johnson 2003a) T ! CATS: For adjunctive treatment of acromegaly: a) Initial dose of 0. 2 mg (total dose); may reduce insulin require-ments (Jones 2004a) T ! HORSES: (Note : ARCI UCGFS Class 2 Drug) For treatment of pituitary adenoma: a) 0. 03-0. 09 mg/kg (30-90 mcg/kg) twice daily PO or SC, but its use is limited (T oribio 2004b) b) 5 mg IM q12h. T o prepare an injectable formulation for IM use from oral dosage forms: Bromocriptine mesylate 70 mg is added to 7 m L of a solution of 80% normal saline and 20% absolute alcohol (v/v). Final concentration is 1% (10 mg/m L) (Beck 1992) Monitoring T ! Monitoring is dependent upon the reason for use to evaluate ef-ficacy. However, blood pressures should be evaluated if patients have clinical signs associated with hypotension. Client Information T ! Have client administer drug with food to reduce GI adverse ef-fects. Chemistry/Synonyms A dopamine agonist and prolactin inhibitor, bromocriptine mesy-late is a semisynthetic ergot alkaloid derivative. It occurs as a yel-lowish-white powder and is slightly soluble in water and sparingly soluble in alcohol. B romocriptine mesylate may also be known as: bromocryptine, brom-e rgocryptine, 2-bromergocryptine, bromocriptine methane-sulphonate, bromocriptini mesilas, 2-bromo-alpha-ergocryptine mesylate, 2-b romoergocryptine monomethanesulfonate, or CB-154 (bromocriptine); many trade names are available. Storage/Stability Tablets and capsules should be protected from light and stored in tight containers at temperatures less than 25°C. 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: Bromocriptine Mesylate Capsules: 5 mg (as base); Parlodel® (San-doz); Bromocriptine Mesylate (Mylan); (Rx) Bromocriptine Mesylate Tablets: 2. 5 mg (as base); Parlode l® Snap Tabs (Sandoz); Bromocriptine Mesylate (Mylan) (Rx) BUDESONIDE (bue-des-oh-nide) Entocort EC® GLUCOCORTICOID Prescriber Highlights TT Orally administered glucocorticoid with limited systemic glucocorticoid effects; may be useful in treating IBD in small animals that are either refractory to, or intolerant of, systemic steroids TT Limited veterinary experience TT Drug interactions (CYP3A inhibitors, antacids) TT Expense may be an issue; may need to be compounded to smaller dosage strengths Uses/Indications While there are inhalational forms of the medication for treating asthma or allergic rhinitis, most veterinary interest involves its po-tential oral use to treat inflammatory intestinal diseases in small ani-mals that are either refractory to, or intolerant of, systemic steroids. In humans, o ral budesonide is indicated for Crohn's disease. Pharmacology/Actions Budesonide is a potent glucocorticoid (15X more potent than pred-nisolone) with high topical activity. It has weak mineralocorticoid acti vity. By delaying dissolution until reaching the duodenum and

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Tsubsequent controlled release of the drug, the drug can exert its to pical antiinflammatory activity in the intestines. While the drug is absorbed from the gut into the portal circulation, it has a high first-pass metabolism effect through the liver that reduces sys-temic blood levels and resultant glucocorticoid effects of the drug. Ho wever, significant suppression of the HPA-axis does occur in pa-tients taking the drug. Pharmacokinetics Budesonide's pharmacokinetics have been reported in dogs. The drug has a bioavailability of 10-20%. When dosed at 10 mcg/kg, half-life is about 2 hours and clearance 2. 2 l/hr/kg. At 100 mcg/kg, half-life is slightly prolonged to 2-3 hours. Upon oral administration of the commercially available product in h umans, budesonide is nearly completely absorbed from the gut, but time to achieve peak concentrations are widely variable (30-600 minutes). The presence of food in the gut may delay absorption, but does not impact the amount of drug absorbed. Because of a high first-pass effect, only about 10% of a dose is systemically bio-available in healthy adults. In patients with Crohn's disease, oral bioavailability may be twice that initially, but with further dosing, reduces to amounts similar to healthy subjects. Budesonide's mean volume of distribution in humans ranges from 2. 2-3. 9 L/kg. The drug is completely metabolized and these metabolites are excreted in the feces and urine. Budesonide's terminal half-life is about 4 hours. Contraindications/Precautions/Warnings Budesonide is contraindicated in patients hypersensitive to it. Because budesonide can cause systemic corticosteroid effects, it should be used with caution in any patient where glucocorticoid therapy may be problematic including those with GI ulcers, active infections, diabetes mellitus, or cataracts. Adverse Effects There are limited reports of the clinical use of budesonide in small animals and the determination of the drug's adverse effect profile is ongoing. Steroid hepatopathy is possible. In humans, oral budes-onide is generally well tolerated and glucocorticoid adverse effects oc cur infrequently when the drug is used for courses of therapy of no more than 8 weeks duration. Patients with moderate to severe hepatic dysfunction may be more likely to develop signs associated with hypercorticism. Because budesonide does suppress the HPA-axis, animals un-dergoing stressful procedures such as surgery, should be considered fo r exogenous steroid administration. Reproductive/Nursing Safety In humans, the FDA categorizes budesonide 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). Like other corticosteroids, budesonide has been demon-strated to be embryocidal and teratogenic in rats and rabbits. Specific data on budesonide levels in maternal milk are not avail-able and the manufacturer warns against use by nursing women; how ever, because of the drugs high first pass effect, the amounts are unlikely to be of clinical significance to nursing animal offspring. Overdosage/Acute Toxicity Acute, oral overdoses are unlikely to be of much concern although doses of 200 mg/kg were lethal in mice. Gut evacuation should be considered for massive overdoses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving budesonide and may be of significance in veterinary patients: !TERYTHROMYCIN, CIMETIDINE, KETOCONAZOLE, ITRACONAZOLE, FLUCON-AZOLE, DILTIAZEM, GRAPEFRUIT JUICE POWDER, etc: Because the he-patic enzyme CYP3A extensively metabolizes budesonide, drugs that inhib it this isoenzyme can significantly increase the amount of drug that enters the systemic circulation. Ketoconazole given with budesonide may increase the area under the curve (AUC) of budesonide by eight fold. !TORAL ANTACIDS : Because the dissolution of the drug's coating is p H dependent, oral antacids should not be given at the same time as the drug. Other drugs that potentially would increase gastric p H (e. g., omeprazole, ranitidine, etc. ) apparently do not signifi-cantly impact the oral pharmacokinetics of the drug. Laboratory Considerations !TWhile no specific laboratory interactions were located, budes-onide could potentially alter laboratory test results similarly to othe r c orticosteroids. Doses !TDOGS For treatment of IBD: a) 1 mg PO once daily for small dogs and 2 mg PO once daily fo r large dogs (Mackin 2002) b) 3 mg/m2 (0. 5-3 mg per dog depending on body weight) PO onc e daily or every other day (Gaschen 2006) !TCATS: For treatment of IBD: a) 1 mg PO once daily (Mackin 2002) Monitoring !TEfficacy !TAdverse effects Client Information !TDo not open the capsule unless your veterinarian instructs you to do so; do not crush or allow animal to chew capsules !This drug must be given as prescribed to be effective, do not stop therapy without contacting your veterinarian !TIf animal exhibits increased thirst or appetite or their coat chang-es, contact your veterinarian Chemistry/Synonyms Budesonide, a non-halogenated glucocorticoid, occurs as a white to off-white, odorless, tasteless powder. It is practically insoluble in water, freely soluble in chloroform and sparingly soluble in alcohol. The commercially available capsules contain a granulized micron-ized form of the drug that is coated to protect from dissolution in gast ric juice, but will dissolve at p H >5. 5. In humans, this p H usu-ally corresponds with the drug reaching the duodenum. Budesonide may also be known as S 1320, Ent ocord®, Entocort EC®, Pulmicort®, and Rhinocort®. Storage/Stability Budesonide oral capsules should be stored in tight containers at room temperature. Exposures to temperatures as low as 15°C (59°F) and as high as 30°C (86°F) are permitted. If reformulating into smaller capsules, do not alter (damage) the micronized enter-ic-coated sugar spheres inside of the capsules.

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Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None. HUMAN-LABELED PRODUCTS: Budesonide Capsules: 3 mg (micronized); Entocort EC® (Pro-metheus); (Rx) Human budesonide capsules may need to be compounded into dos-age strengths suitable for dogs or cats, but the enteric-coated sugar spheres f ound inside the capsule should not be altered or damaged. There are also budesonide products (powder and suspension for oral inhalat ion, and nasal sprays) for the treatment of asthma or allergic rhinitis. Trade names for these products include Pulmicort® and Rhinocort®. BUPRENORPHINE HCL (byoo-pre-nor-feen) Buprenex®, Subutex® OPIATE PARTIAL AGONIST Prescriber Highlights TT Partial mu opiate agonist used primarily as an injectable & buccal analgesic in small animals (but has been used in horses) TT Buccal administration in cats well tolerated & effective TT Rarely, may cause respiratory depression Uses/Indications Buprenorphine is most often used as an analgesic for mild to mod-erate pain in small animals. While it is not as an effective analgesic as pure mu-ago nists (morphine, hydromorphone, etc. ), it generally causes fewer adverse effects. In cats, buccal (oral) administration is often a practical, effective method for helping to control post-oper-ative pain. More experience is occurring using opiates with short-term NSAIDs f or post-op pain control. Buprenorphine has been used in horses, but its short duration of actio n and expense relative to other opiates limit its usefulness. Pharmacology/Actions Buprenorphine has partial agonist activity at the mu-receptor. This is in contrast to pentazocine that acts as an antagonist at the mu-receptor. Buprenorphine is considered 30 times as potent as mor-phine and exhibits many of the same actions as the opiate agonists. It pr oduces a dose-related analgesia but at higher dosages analgesic effects may actually decrease. Buprenorphine appears to have a high affinity for mu-receptors in the CNS, which may explain its relatively long duration of action. Analgesia may persist for 12 hours, but usu-ally a 6-8 hour duratio n of analgesic effect is typical. The cardiovascular effects of buprenorphine may cause a decrease in both b lood pressure and cardiac rate. Rarely, human patients may exhibit increases in blood pressure and cardiac rate. Respiratory de-pression is a possibility, and decreased respiratory rates have been noted in horses treated with buprenorphine. Gastrointestinal effects appear to be minimal with buprenorphine, but further studies are needed to clarify this. Pharmacokinetics Buprenorphine is rapidly absorbed following IM injection, with 40-90% absorbed systemically when tested in humans. The drug is also absorbed sublingually (bioavailability≈55%) in people. Oral doses appear to undergo a high first-pass effect with metabolism oc-curring in the GI mucosa and liver. The distribution of the drug has not been well studied. Data from w ork done in rats reflects that buprenorphine concentrates in the liver, but is also found in the brain, GI tract, and placenta. It is highly bound (96%) to plasma proteins (not albumin), crosses the placenta, and it and its metabolites are found in maternal milk at concentrations equal to or greater than those found in plasma. Buprenorphine is metabolized in the liver by N-dealkylation and glucuro nidation. These metabolites are then eliminated by biliary excretion into the feces (≈70%) and urinary excretion (≈27%). In the horse, onset of action is approximately 15 minutes after IV dosing. T he peak effect occurs in 30-45 minutes and the duration of action may last up to 8 hours. Because acepromazine exhibits a similar onset and duration of action, many equine clinicians favor using this drug in combination with buprenorphine. In cats, buprenorphine has a volume of distribution [Vd(ss)] of app roximately 8 L/kg and a clearance of about 20 m L/kg/min. Elimination half-life is about 6-7 hours. When administered via oral mucosa (liquid placed into the side of cat's mouth), absorption was comparable to that seen with IM or IV administration. Contraindications/Precautions/Warnings All opiates should be used with caution in patients with hypothy-roidism, severe renal insufficiency, adrenocortical insufficiency (Addison' s), and in geriatric or severely debilitated patients. Rarely, patients may develop respiratory depression from bu-prenorphine; it, therefore, should be used cautiously in patients with co mpromised cardiopulmonary function. Like other opiates, buprenorphine must be used with extreme caution in patients with head trauma, increased CSF pressure or other CNS dysfunction (e. g., coma). Patients with severe hepatic dysfunction may eliminate the drug more slo wly than normal patients. Buprenorphine may increase bile duct pressure and should be used cautiously in patients with biliary tract disease. The drug is contraindicated in patients having known hypersen-sitivity to it. Adverse Effects Although rare, respiratory depression appears to be the major ad-verse effect to monitor for with buprenorphine; other adverse effects (sedation) may be noted. The primary side effect seen in humans is sedation with an incidence of approximately 66%. Reproductive/Nursing Safety Although no controlled studies have been performed in domestic animals or humans, the drug has exhibited no evidence of terato-genicity or causing impaired fertility in laboratory animals. In hu-mans, 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 The intraperitoneal LD 50 of buprenorphine has been reported to be 243 mg/kg in rats. The ratio of lethal dose to effective dose is at least 1000:1 in rodents. Because of the apparent high index of safety, acute overdoses should be a rare event in veterinary medi-cine. Treatment with naloxone and doxapram have been suggested in ca ses of acute overdoses causing respiratory or cardiac effects. Secondary to buprenorphine's high affinity for the mu receptor, high doses of naloxone may be required to treat respiratory depression.

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TDrug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving buprenorphine and may be of significance in veterinary patients: !TANESTHETICS, LOCAL (mepivacaine, bupivacaine ): May be potenti-ated by concomitant use of buprenorphine !TANTICONVULSANTS (phenobarbital, phenytoin ): May decrease plasma buprenorphine levels !TBENZODIAZEPINES : Case reports of humans developing respira-tory/cardiovascular/CNS depression; use with caution !TCNS DEPRESSANTS (e. g., anesthetic agents, antihistamines, phenoth-iazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with buprenorphine !TERYTHROMYCIN : Can increase plasma buprenorphine levels !TFENTANYL (and other pure opiate agonists ): Buprenorphine may potentially antagonize some analgesic effects ( Note : This is con-troversial), but may also reverse some of the sedative and respira-tory depressant effects of pure agonists !THALOTHANE : Potentially can increase buprenorphine effects !TKETOCONAZOLE, ITRACONAZOLE, FLUCONAZOLE : Can increase plasma buprenorphine levels !TMONAMINE OXIDASE (MAO) INHIBITORS (e. g., selegiline, amitraz ): Pos-sible additive effects or increased CNS depression !TNALOXONE : May reduce analgesia associated with high dose buprenorphine !TPANCURONIUM : If used with buprenorphine may cause increased conjunctival changes !TRIFAM PIN: Potentially decrease plasma buprenorphine concentrations Doses !TDOGS: For analgesia: a) 0. 005-0. 02 mg/kg IM, IV or SC q6-12h (H endrix and Han-sen 2000) b) 0. 01-0. 015 mg/kg IM,IV (may also be given orally) (Mathews 1999) c) 0. 005-0. 03 mg/kg IV, IM, SC, epidural (Boothe 1999) d) 0. 006-0. 02 mg/kg IV, IM, SQ; duration of effect 6-12 hour s and is a relatively effective analgesic, but may be difficult to reverse with naloxone if untoward effects are seen. (Perkows-ki 2006b) !TCATS: For analgesia: a) 0. 005-0. 01 mg/kg IM, IV or SC q6-12h (H endrix and Han-sen 2000) b) 0. 01-0. 03 mg/kg PO transmucosally (squirted directly into the mouth) q8h (Lic htenberger 2006e) c) 0. 01-0. 03 mg/kg IM, IV, SC q6-8h; 0. 01-0. 03 mg/kg PO q6-12h (Hansen 2003a) d) 0. 01-0. 03 mg/kg IM, IV, Buccal. Effects may last up to 6 hours. Buccal use is well accepted by cats. (Robertson and Lascelles 2003) !TFERRETS: a) 0. 01-0. 05 mg/kg SC or IM 2-3 times dail y (Williams 2000) !THORSES: (Note : ARCI UCGFS Class 2 Drug) For neuroleptanalgesia: a) 0. 004 mg/kg IV (given with acepromazine 0. 02 mg/kg) (T hurmon and Benson 1987) b) 0. 006 mg/kg IV (given with xylazine 0. 07 mg/kg) (Thurmon and Be nson 1987) !TRABBITS/RODENTS/SMALL MAMMALS: As an analgesic (for control of acute or chronic visceral pain): a) Rabbits: 0. 02-0. 05 mg/kg SC or IM q6-12h; 0. 5 mg/kg per rectum q12h Ro dents: 0. 1-3 mg/kg IM or SC q6-12h (Huerkamp 1995) b) Rabbits: 0. 01-0. 05 mg/kg SC, IM or IV q6-12h; 0. 5 mg/kg rectally q12h (Ivey and Morrisey 2000) c) Guinea pigs: 0. 05 mg/kg SC or IV q8-12h Mic e: 0. 05-0. 1 mg/kg SC q12h. Rats: 0. 01-0. 05 mg/kg SC or IV q8-12h or 0. 1-0. 25 mg/kg PO q8-12h. (Adamcak and Otten 2000) Monitoring !TAnalgesic efficacy !TRespiratory status !TCardiac status Client Information !This agent should be used parenterally in an inpatient setting or with direct professional supervision !TBuccal/SL dosing may be performed at home, but pre-measur-ing dosages in syringes (if using the injection orally) should be considered Chemistry/Synonyms A thebaine derivative, buprenorphine is a synthetic partial opiate agonist. It occurs as a white, crystalline powder with a solubility of 17 mg/m L in water and 42 mg/m L in alcohol. The commercially available injectable product (Buprenex®—Norwich Eaton) has a p H of 3. 5-5 and is a sterile solution of the drug dissolved in D 5W. T erms of potency are expressed in terms of buprenorphine. The commercial product contains 0. 324 mg/m L of buprenorphine HCl, which is equivalent to 0. 3 mg/m L of buprenorphine. Buprenorphine HCl may also be known as:buprenorphini hydro-chloridum, CL-112302, NIH-8805, UM-952; Anorfin ®, Buprenex®, Buprine®, Finibron®, Magnogen®, Nopan®, Norphin®, Pentorel®, Prefin®, Suboxone®, Subutex®, Temgesic®, or Temgesic-n X®. Storage/Stability/Compatibility Buprenorphine should be stored at room temperature (15-30° C). T emperatures above 40° C or below freezing should be avoided. Buprenorphine products should be stored away from bright light. Autoclaving may considerably decrease drug potency. The drug is stable between a p H of 3. 5-5. Buprenorphine is reported to be compatible with the following IV solutions and drugs: acepromazine, atropine, diphenhydramine, D5W, D 5W and normal saline, droperidol, glycopyrrolate, hy-droxyzine, lactated Ringer's, normal saline, scopolamine, and xyla-zine. Buprenorphine is reportedly incompatible with diazepam and lorazepam. 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: Buprenorphine HCl for Injection: 0. 324 mg/m L (equivalent to 0. 3 mg/m L buprenorphine); 1 m L amps & Carp uject; Buprenex® (Reckitt Benkhiser); Buprenorphine Hydrochloride (Abbott); (Rx, C-III)

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Buprenorphine HCl Sublingual Tablets: 2 mg (as base), & 8 mg (as base); Subutex® (Reckitt Benkhiser); (Rx, C-III) Buprenorphine HCl Combinations: Sublingual Tablets: 2 mg bu-prenorphine base/0. 5 mg naloxone; 8 mg buprenorphine base/2 mg naloxone; S uboxone® (Reckitt Benkhiser); (C-III) BUSPIRONE HCL (byoo-spye-rone) Bu Spar® ANXIOLYTIC Prescriber Highlights TT Non-benzodiazepine anxiolytic agent used in dogs & cats TT May take a week or more to be effective; not appropriate for acute treatment of situational anxieties TT Use with caution in patients with severe hepatic or renal disease TT Adverse Effects relatively uncommon; cats may exhibit behavior changes Uses/Indications Buspirone may be effective in treating certain behavior disorders in dogs and cats, principally those that are fear/phobia related and especially those associated with social interactions. Buspirone may also be useful for urine spraying or treatment of motion sickness in cats. Pharmacology/Actions Buspirone is an anxioselective agent. Unlike the benzodiazepines, buspirone does not possess any anticonvulsant or muscle relaxant activity and little sedative or psychomotor impairment activity. Buspirone does not share the same mechanisms as the benzodiaz-epines (does not have significant affinity for benzodiazepine recep-tors and does not affect GABA binding). It appears to act as a partial agonist at serotonin (5-HT1A) receptors and as an agonist/antago-nist of dopamine (D2) receptors in the CNS. In neurons, buspirone slows the neur onal flow depletion of serotonin stores. Pharmacokinetics In humans, buspirone is rapidly and completely absorbed but a high first pass effect limits systemic bioavailability to approximately 5%. Binding to plasma proteins is very high (95%). In rats, high-est tissue concentrations are found in the lungs, kidneys, and fat. Lowe r levels are found in the brain, heart, skeletal muscle, plasma and liver. Both buspirone and its metabolites are distributed into maternal milk. The elimination half-life (in humans) is about 2-4 hours. Buspirone is hepatically metabolized to several metabolites (including one that is active: 1-PP). These metabolites are excreted primarily in the urine. Contraindications/Precautions/Warnings Buspirone should be used with caution with either significant renal or hepatic disease. Because buspirone may reduce disinhibition, it should be used with caution in aggressive animals. While buspirone has far less sedating properties than many other anxiolytic drugs, it should be used with caution in working dogs. Because buspirone often takes a week or more for effect, it should not be used as the sole ther apy for situational anxieties. Adverse Effects Adverse effects are usually minimal in animals with buspirone and it is generally well tolerated. Bradycardia, GI disturbances and ste-reotypic behaviors are possible. Cats may demonstrate increased affect ion. In multi-cat households, cats that have previously been extremely timid in the face of repeated aggression from other cats may, after receiving buspirone begin turning on their attacker. The most likely adverse effect profile seen with buspirone in hu-mans includes dizziness, headache, nausea/anorexia, and restless-ness; other neurologic effects (including sedation) may be noted. Rarel y, tachycardias and other cardiovascular clinical signs may be present. Reproductive/Nursing Safety While the drug has not been proven safe during pregnancy, doses of up to 30 times the labeled dosage in rabbits and rats demonstrated no teratogenic effects. 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. ) Buspirone and its metabolites have been detected in the milk of lactating r ats; avoid use during nursing if possible. Overdosage/Acute Toxicity Limited information is available. The oral LD 50 in dogs is 586 mg/ kg. Oral overdoses may produce vomiting, dizziness, drowsiness, miosis and gastric distention. Standard overdose protocols should be followed after ingestion has been determined. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving buspirone and may be of significance in veterinary patients: T ! CNS DEPRESSANTS : Potentially could cause increased CNS depression T ! DILTIAZEM : May cause increased buspirone plasma levels and ad-verse effects T ! ERYTHROMYCIN : May cause increased buspirone plasma levels and adverse effects T ! GRAPEFRUIT J UICE (powder ): May cause increased buspirone plasma levels and adverse effects T ! KETOCONAZOLE, ITRACONAZOLE : May cause increased buspirone plasma levels and adverse effects T ! MONOAMINE OXIDASE I NHIBITORS (e. g., selegiline, amitraz ): Use with buspirone is not recommended because dangerous hypertension may occur T ! RIFAMPIN : May cause decreased buspirone plasma levels T ! TRAZODONE : Use with buspirone may cause increased ALT T ! VERAPAMIL : May cause increased buspirone plasma levels Doses T ! DOGS: For low-grade anxieties and fears: a) 1 mg/kg PO q8-24h (mild anxiet y); 2. 5-10 mg per dog PO q8-24h (mild anxiety); 10-15 mg per dog PO q8-12h (more severe anxiety, thunderstorm phobia) (Overall 2000) b) 1-2 mg/kg PO q12h; 5-15 mg per dog PO q8-12h (Sieb ert 2003c) c) 5-10 mg (total dose) PO q8-12h (Reisner and H oupt 2000)

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d) For global anxiety: 0. 5-2 mg/kg PO q8-12h; may tak e 2-4 weeks until effect. (Horwitz 2006) e) 1 mg/kg PO q8-12h; most useful in social phobias; may also be useful for panic disorders (Virga 2005b) T ! CATS: For adjunctive treatment of low-grade anxieties/fears, spraying, overgrooming: a) 0. 5-1 mg/kg PO q8-12h; 2. 5-5 mg per cat PO q8-12h for 6-8 weeks; some cats do well on once daily dosing (Overall 2000) b) 2. 5-5 mg (total dose) PO once a day to 3 times a day (Seksel 2003) c) 2. 5-5 mg per cat PO twice daily (Reisner and Houpt 2000), (Crow ell-Davis 1999) d) 0. 5-1 mg/kg PO q12h; 2. 5-7. 5 mg per cat PO q12h (Siebert 2003c) e) 0. 5-1 mg/kg PO q8-12h; most useful in social phobias; may also be useful for panic disorders (Virga 2005b) Monitoring T ! Efficacy T ! Adverse effect profiles Chemistry/Synonyms An arylpiperazine derivative anxiolytic agent, buspirone HCl dif-fers structurally from the benzodiazepines. It occurs as a white, crystalline powder with solubilities at 25°C of 865 mg/m L in water and about 20 mg/m L in alcohol. Buspirone HCl may also be known as MJ-9022; many trade names are availab le. Storage/Stability/Compatibility Buspirone HCl tablets should be stored in tight, light-resistant con-tainers at room temperature. After manufacture, buspirone tablets have an expir ation date of 36 months. 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: Buspirone HCl Tablets: 5 mg (4. 6 mg as base), 7. 5 mg (6. 85 mg as base), 10 mg (9. 1 mg as base), 15 mg (13. 7 mg as base) and 30 mg (27. 4 mg as base); Bu Spar® (Bristol-Myers Squibb); generic; (Rx) BUSULFAN (byoo-sul-fan) Myleran®, Busulfex® ANTINEOPLASTIC Prescriber Highlights TT Antineoplastic used in treating chronic granulocytic leu-kemias in small animals TT Myelosuppression; may be severe TT May increase uric acid levels Uses/Indications Busulfan may be useful in the adjunctive therapy of chronic granu-locytic leukemias or polycythemia vera in small animals. Not com-monly used in veterinary medicine. Pharmacology/Actions Busulfan is a bifunctional alkylating agent antineoplastic and is cell cycle-phase nonspecific. The exact mechanism of action has not been determined but is thought to be due to its alkylating, cross-linking of strands of DNA and myelosuppressive proper-ties. Busulfan's primary activity is against cells of the granulocytic series. Pharmacokinetics Busulfan is well absorbed after oral administration. Distribution characteristics are not well described but in humans, drug concen-trations in the CSF are nearly equal to those found in plasma. It is unknown w hether the drug enters maternal milk. Busulfan is rap-idly, hepatically metabolized to at least 12 different metabolites that are slow ly excreted into the urine. In humans, serum half-life of busulfan averages about 2. 5 hours. Contraindications/Precautions/Warnings Busulfan is contraindicated in patients who have shown resistance to the drug in the past or are hypersensitive to it. Only veterinar-ians with the experience and resources to monitor the toxicity of this agent should administer this drug. The risk versus benefits of therapy must be carefully considered in patients with preexisting bone marrow depression or concurrent infections. Additive bone marrow depression may occur in patients undergoing concomitant radiation therapy. Adverse Effects The most commonly associated adverse effect seen with busulfan therapy is myelosuppression. In humans, anemia, leukopenia, and thrombocytopenia may be observed. Onset of leukopenia is gen-erally 10-15 days after initiation of therapy and leukocyte nadirs occurring on average around 11-30 days. Severe bone marrow de-pression can result in pancytopenia that may take months to years for r ecovery. In humans, bronchopulmonary dysplasia with pulmo-nary fibrosis, uric acid nephropathy, and stomatitis have been re-ported. These effects are uncommon and generally associated with chronic, higher dose therapy. Reproductive/Nursing Safety Busulfan's teratogenic potential has not been well documented, but it is mutagenic in mice and may potentially cause a variety of fetal abnormalities. It is generally recommended to avoid the drug dur-ing pregnancy, but because of the seriousness of the diseases treated with bus ulfan, the potential benefits to the mother must be consid-ered. In humans, the FDA categorizes this drug as category D for use d uring pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is unknown if busulfan enters milk; avoid nursing if the dam is rece iving the drug. Overdosage/Acute Toxicity There is limited experience with busulfan overdoses. The LD50 in mice is 120 mg/kg. Chronic overdosage is more likely to cause se-rious bone marrow suppression than is an acute overdose; how-ever, any overdose, should be treated seriously with standard gut empty ing protocols used when appropriate and supportive therapy initiated when required. There is no known specific antidote for busulfan intoxication.

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Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving busulfan and may be of significance in veterinary patients: T ! ACETAMINOPHEN : Use within 72 hours prior to busulfan can reduce busulfan clearance by reducing glutathione concentrations in tis-sues and blood T ! CYCLOPHOSPHAMIDE : Can potentially reduce clearance of busulfan, probably by competing for available glutathione T ! ITRACONAZOLE : Potential decreased busulfan clearance T ! MYELOSUPPRESSANT AGENTS : Concurrent use with other bone mar-row depressant medications may result in additive myelosuppres-sion T ! PHENYTOIN : Possible increased clearance of busulfan T ! THIOGUANINE : Used concomitantly with busulfan may result in hepatotoxicity Laboratory Considerations T ! Busulfan may raise serum uric acid levels. Drugs such as allopurinol may be required to control hyperuricemia. Doses For more information on cancer chemotherapy, refer to the pro-tocols found in the appendix or other dosages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). T ! SMALL ANIMALS: a) For chronic granulocytic leukemias (not during “blastic” phase—of no benefit): 3-4 mg/m2 PO once daily. Discontin-ue when total white blood cell count reaches approximately 15,000. Rep eat as necessary. May require up to two weeks to observe a positive response. If there is too rapid a decline in total WBC's, discontinue drug. (Jacobs, Lumsden et al. 1992) b) For chronic myelogenous leukemia or polycythemia vera: 2 mg/m2 PO once daily ; rarely used (Kitchell 2005) Monitoring T ! CBC T ! Serum uric acid T ! Efficacy Client Information T ! Clients must understand the importance of both administering busulfan as directed and reporting immediately any signs asso-ciated with toxicity (e. g., abnormal bleeding, bruising, urination, depr ession, infection, shortness of breath, etc. ). Chemistry/Synonyms An alkylsulfonate antineoplastic agent, busulfan occurs as white, crystalline powder. It is slightly soluble in alcohol and very slightly soluble in water. Busulfan may also be known as: bussulfam, busulfanum, busul-phan, CB-2041, GT-41, myelosan, NSC-750, WR-19508, Bussulfam®, Busulfan um®, Busulivex®, Mielucin®, Misulban®, or Myleran®. Storage/Stability Busulfan tablets should be stored in well-closed containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Busulfan Tablets: 2 mg; Myleran® (Glaxo Smith Wellcome); (Rx) Busulfan Injection: 6 mg/m L in 10 m L amps with syringe filters; Busulfex ® (Orphan Medical); (Rx) BUTORPHANOL TA RTRATE (byoo-tor-fa-nol) Stadol®, Torbutrol®, Torbugesic® OPIATE PARTIAL AGONIST Prescriber Highlights TT Partial opiate agonist/antagonist used in a variety of spe-cies as an analgesic, premed, antitussive, or antiemetic TT Not a good choice as an analgesic for moderate to se-vere pain in small animals TT Contraindicated or caution in patients with liver disease, hypothyroidism, or renal insufficiency, Addison's, head trauma, increased CSF pressure or other CNS dysfunction (e. g., coma) & in geriatric or severely debilitated patients TT Potential adverse effects in DOGS/CATS: Sedation, atax-ia, anorexia or diarrhea (rarely) TT HORSES (at usual doses) may include a transient ataxia & sedation, but CNS excitement possible TT Controlled substance (C-IV) Uses/Indications Approved indication for dogs is “... for the relief of chronic non-productive cough associated with tracheobronchitis, tracheitis, tonsillit is, laryngitis and pharyngitis originating from inflamma-tory conditions of the upper respiratory tract” (Package Insert; Torbut rol®—Fort Dodge). It is also used in practice in both dogs and cats as a preanesthetic medication, analgesic, and as an antiemetic prior to cisplatin treatment (although not very effective in cats for this indication). Compared with other opiate analgesics, butorpha-nol is not very useful in small animals (particularly dogs) for treat-ing pain and has to be dosed frequently. The approved indication for horses is “... for the relief of pain associated with colic in adult horses and yearlings” (Package Insert; Torbugesic®—Fort Dodge). It has also been used clinically as an anal-gesic in cattle. Pharmacology/Actions Butorphanol is considered to be, on a weight basis, 4-7 times as potent an analgesic as morphine, 15-30 times as pentazocine, and 30-50 times as meperidine; however a ceiling effect is reached at higher dosages, where analgesia is no longer enhanced and may be reduced. Its agonist activity is thought to occur primarily at the kappa and sigma receptors and the analgesic actions at sites in the limbic system (sub-cortical level and spinal levels). Its use as an an-algesic in small animals has been disappointing, primarily because of its v ery short duration of action and ability to alleviate only mild to moderate pain. The antagonist potency of butorphanol is considered to be ap-proximately 30 times that of pentazocine and 140th that of naloxone and will antagonize the effect of true agonists (e. g., morphine, mep-eridine, oxymorphone).

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Besides the analgesic qualities of butorphanol, it possesses sig-nificant antitussive activity. In dogs, butorphanol has been shown to elevate CNS respiratory center threshold to CO 2 but, unlike opi-ate agonists, not depress respiratory center sensitivity. Butorphanol, unlike morphine, apparently does not cause histamine release in dogs. CNS depression may occur in dogs, while CNS excitation has been noted (usually at high doses) in horses and dogs. Although possessing less cardiovascular effects than the classical opiat e agonists, butorphanol can cause a decrease in cardiac rate secondary to increased parasympathetic tone and mild decreases in arterial blood pressures. The risk of causing physical dependence seems to be minimal whe n butorphanol is used in veterinary patients. Pharmacokinetics Butorphanol is absorbed completely in the gut when administered orally but, because of a high first-pass effect, only about 1/6th of the administered dose reaches the systemic circulation. The drug has also been shown to be completely absorbed following IM admin-istration. Butorphanol is well distributed, with highest levels (of the par-ent compound and metabolites) found in the liver, kidneys, and intest ine. Concentrations in the lungs, endocrine tissues, spleen, heart, fat tissue and blood cells are also higher than those found in plasma. Approximately 80% of the drug is bound to plasma pro-teins (human data). Butorphanol will cross the placenta and neo-natal plasma levels have been roughly equivalent to maternal levels. The dr ug is also distributed into maternal milk. Butorphanol is metabolized in the liver, primarily by hydroxy-lation. Other methods of metabolism include N-dealkylation and co njugation. The metabolites of butorphanol do not exhibit any analgesic activity. These metabolites and the parent compound are mainly excreted into the urine (only 5% is excreted unchanged), but 11-14% of a dose is excreted into the bile and eliminated with the feces. Following IV doses in horses, the onset of action is approximate-ly 3 minutes with a peak analgesic effect at 15-30 min utes. The du-ration of action in horses may be up to 4 hours after a single dose. Contraindications/Precautions/Warnings The drug is contraindicated in patients having known hypersensi-tivity to it. All opiates should be used with caution in patients with hy pothyroidism, severe renal insufficiency, adrenocortical insuffi-ciency (Addison's), and in geriatric or severely debilitated patients. Like other opiates, butorphanol must be used with extreme caution in patients with head trauma, increased CSF pressure or other CNS dysfunction (e. g., coma). Dogs with MDR1 mutations (many Collies, Australian shep-herds, etc. ) may develop a more pronounced sedation that persists long er 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. The manufacturer states that butorphanol “should not be used in d ogs with a history of liver disease” and, because of its effects on suppressing cough,“it should not be used in conditions of the lower respiratory tract associated with copious mucous production. ” The drug should be used cautiously in dogs with heartworm disease, as safety for butorphanol has not been established in these cases. Adverse Effects Adverse effects reported in dogs/cats include sedation, excitement, respiratory depression, ataxia, anorexia or diarrhea (rarely). Adverse effects may be less severe than those seen with pure agonists. Adverse effects seen in horses (at usual doses) may include a tr ansient ataxia and sedation, but excitement has been noted as well (see below). Although reported to have minimal effects on the GI, butorphanol has the potential to decrease intestinal motility and ileus can occur. Horses may exhibit CNS excitement (tossing and jerking of head, increased ambulation, augmented avoidance re-sponse to auditory stimuli) if given high doses (0. 2 mg/kg) IV rap-idly. Very high doses IV (1-2 mg/kg) may lead to the development of nystagmus, salivation, seizures, hyperthermia and decreased GI motility. These effects are considered transitory in nature. Reproductive/Nursing Safety Although no controlled studies have been performed in domestic animals or humans, the drug has exhibited no evidence of terato-genicity or of causing impaired fertility in laboratory animals. The ma nufacturer, however, does not recommend its use in pregnant bitches, foals, weanlings (equine), and breeding horses. In hu-mans, the FDA categorizes this drug as category C f o r u s e d u r-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. ) 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. ) Butorphanol can be distributed into milk, but not in amounts that w ould cause c oncern in nursing offspring. Overdosage/Acute Toxicity Acute life-threatening overdoses with butorphanol should be un-likely. The LD 50 in d ogs is reportedly 50 mg/kg. However, because butorphanol injection is available in two dosage strengths (0. 5 mg/ m L and 10 mg/m L) for veterinary use, the possibility exists that inadvertent overdoses may occur in small animals. It has been sug-gested that animals exhibiting clinical signs of overdose (CNS ef-fects, cardiovascular changes, and respiratory depression) be treat-ed immediately with intravenous naloxone. Additional supportive measur es (e. g., fluids, O 2, vasopressor agents, and mechanical ven-tilation) may be required. Should seizures occur and persist, diaz-epam may be used for control. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving butorphanol and may be of significance in veterinary patients: !TOTHER CNS DEPRESSANTS (e. g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with butor-phanol; dosage may need to be decreased !TERYTHROMYCIN : Could potentially decrease metabolism of butor-phanol !TFENTANYL (and other pure opiate agonists ): Butorphanol may po-tentially antagonize some analgesic effects ( Note : this is contro-versial), but may also reverse some of the sedative and respiratory depressant effects of pure agonists !TPANCURONIUM If used with butorphanol may cause increased con-junctival changes !TTHEOPHYLLINE : Could potentially decrease metabolism of butorphanol

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Doses Note : All doses are expressed in mg/kg of the base activity. If using the human pro duct (Stadol®), 1 mg of tartrate salt = 0. 68 mg base. !TDOGS: As an antitussive: a) 0. 055-0. 11 mg/kg SC q6-12h; treat ment should not nor-mally be required for longer than 7 days; or 0. 55 mg/kg PO q6-12h; may incr ease dose to 1. 1 mg/kg PO q6-12h (The oral doses correspond to one 5 mg tablet per 20 lbs. and 10 lbs. of body weight, respectively); treatment should not nor-mally be required for longer than 7 days (Package Insert; Tor-butr ol®—Fort Dodge) b) 0. 05-1 mg/kg PO q6-12h; goal is to suppress coughing with-out causing excessive sedation (Johnson 2000) c) 0. 55-1. 1 mg/kg PO as needed (Johnson 2004d) As an analgesic: a) 0. 1-1 mg/kg IM, IV or SC q1-3h (Hendr ix and Hansen 2000) b) 0. 2-0. 4 mg/kg SC, IM or IV (use lower dose if given IV); Ef-ficacy is 1-2 hours f or moderate pain and 2-4 hours for mild pain. May give orally at 0. 4 mg/kg to the nearest quarter tablet 3 times a day (Mathews 1999) c) 0. 5-1 mg/kg PO q6-8h (Hardie 2000) d) 0. 1- 0. 5 mg/kg IV, IM, SQ; provides only mild to moderate analgesia (go od visceral analgesia); duration of sedative ac-tion 2-4 hours, but analgesic action may be 1 hour or less (Per kowski 2006b) e) As a constant rate infusion: 0. 1-0. 4 mg/kg/hr; occasionally used for abdominal pain (Hellyer 2006) As a preanesthe tic: a) 0. 05 mg/kg IV or 0. 4 mg/kg SC, IM (Morgan 1988) b) 0. 2-0. 4 mg/kg IM (with acepromazine 0. 02-0. 04 mg/kg IM) (Reidesel) As an anti-eme tic prior to cisplatin treatment: a) 0. 4 mg/kg IM H hour pr ior to cisplatin infusion (Klausner and Bell 1988) !TCATS : As an analgesic: a) 0. 1-1 mg/kg IM, IV or SC q1-3h (Hendr ix and Hansen 2000) b) 0. 2-0. 4 mg/kg SC, IM or IV (use lower dose if given IV); Ef-ficacy is 1-2 hours f or moderate pain and 2-4 hours for mild pain. May give orally at 0. 4 mg/kg to the nearest quarter tablet 3 times a day (Mathews 1999) c) 0. 5-1 mg/kg PO q6-8h (Hardie 2000) d) 0. 1- 0. 5 mg/kg IV, IM, SQ; provides only mild to moderate analgesia (go od visceral analgesia); duration of sedative ac-tion 2-4 hours, but analgesic action may be 1 hour or less (Per kowski 2006b) e) As a postoperative CRI (usually in combination with ket-amine) for mild to moderate pain: Loading dose of 0. 1-0. 2 mg/kg IV, the n a CRI of 0. 1-0. 2 mg/kg/hr; Ketamine is used at a loading dose of 0. 1 mg/kg IV with a CRI of 0. 4 mg/kg/hr. When used with an opioid CRI may allow reduction in dosage of both. (Lichtenberger 2006d) As a preanesthetic: a) 0. 2-0. 4 mg/kg IM (with glycopyrrolate 0. 01 mg/kg IM and ketamine 4- 10 mg/kg IM) (Reidesel) !TFERRETS: a) As a sedative/analgesic: Butorphanol alone 0. 05-0. 1 mg/kg IM, SC. Butorphanol/Xy-lazine: Butorphanol 0. 2 mg/kg + Xylazine 2 mg/kg IM For injec table anesthesia: Butorphanol 0. 1 mg/kg, Ketamine 5 mg/kg, medetomidine 80 mcg/kg. Combine in one syringe and give IM. May need to suppleme nt with isoflurane (0. 5-1. 5%) for abdominal sur-gery. (Finkler 1999) b) Xylazine (2 mg/kg) plus butorphanol (0. 2 mg/kg) IM; T elazol (1. 5 mg/kg) plus xylazine (1. 5 mg/kg) plus butorph-anol (0. 2 mg/kg) IM; may reverse xylazine with yohimbine (0. 05 mg/kg IM) (Williams 2000) As an analgesic: a) 0. 05- 0. 5 mg/kg SC or IM q4h (Williams 2000) b) For post-op analgesia: 0. 1-0. 2 mg/kg loading dose, then a constant r ate infusion of 0. 1-0. 2 mg/kg/hr (Lichtenberger 2006a) !TRABBITS/RODENTS/SMALL MAMMALS: For chemical restraint in rabbits: a) 0. 1-0. 5 mg/kg IV (Burke 1999); (Ivey and Morrisey 2000) For analgesia: a) F or postsurgical analgesia in rabbits: 0. 1-0. 5 mg/kg IV or SC q2-4h; lowe r dosages may be more effective due to “ceiling effect” (Ivey and Morrisey 2000) b) Rabbits: As an analg esic (post-operative pain): 0. 4 mg/kg SC q4-6h; for surgical procedures (in combo with xylazine/ket-amine): 0. 1 mg/kg once IM or SC (Huerkamp 1995) c) Rabbits for post-op analgesia: 0. 1-0. 2 mg/kg loading dose, then a c onstant rate infusion of 0. 1-0. 2 mg/kg/hr (Lichten-berger 2006a) !TBIRDS: As an analgesic: a) Psittacines: 2-4 mg/kg IM; frequent re-dosing every 2-4 hours is ne eded to maintain analgesia. If adverse effects are an issue (e. g., respiratory or cardiovascular depression), may re-verse with naloxone (0. 05-0. 25 mg/kg IM or slow IV) (Clyde and Paul-Murp hy 2000) b) 1-2 mg/kg IM (Lichtenberger 2006a) c) 1-4 mg/kg q4h IM, IV, PO (Bays 2006) d) Parrots: 1-3 mg/kg IM (Carpenter 2006) !TCATTLE: As an analgesic: a) For surgery in adult cattle: 20-30 mg IV (jugular) (may wish to pre treat with 10 mg xylazine) (Powers 1985) b) 0. 02-0. 25 mg/kg IV, SQ; 20-30 mg (total dose) IV for an adult animal. Duration of effect is 4 hours. An appropriate withdrawal period is 72 hours for milk, and 4 days for meat. (Walz 2006b) !THORSES: (Note : ARCI UCGFS Class 3 Drug) As an analgesic: a) 0. 1 mg/kg IV q3-4h; not to exceed 48 hours (Package Insert; Torbugesic®—Fort Dodge) b) For moderate to marked abdominal pain: 0. 01-0. 02 mg/kg IV alone o r in combination with xylazine (0. 02-0. 1 mg/kg IM) (Moore 1999)--

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c) For colic pain: 5-10 mg (total dose for a 450-500 kg horse) IV combined with 100-200 mg xylazine (total dose). Com-pared to IV bolus, a constant rate infusion of butorphanol at 23. 7 mcg/kg/hr induces fewer GI side effects while providing analgesia. (Zimmel 2003) d) Foals: 0. 1-0. 2 mg/kg IV or IM (Robertson 2003) e) Two studies have looked at butorphanol CRI in horses for post-o p pain. 1) Loading dose of 0. 0178 mg/kg (17. 8 mcg/ kg), then a constant rate infusion of 23. 7 mcg/kg/hr; 2) Con-stant rate infusion of 13 mcg/kg/hr (Mogg 2006) As a preanesthetic, outpatient surgery, or chemical restraint: a) 0. 01-0. 04 mg/kg IV (with xylazine 0. 1-0. 5 mg/kg IV) (Ors-ini 1988) b) For field anesthesia: Sedate with xylazine (1 mg/kg IV; 2 mg/ kg IM) given 5-10 minutes (longer for IM route) before induction of anesthesia with ketamine (2 mg/kg IV). Horse must be adequately sedated (head to the knees) before giving the ketamine (ketamine can cause muscle rigidity and sei-zures). If adequate sedation does not occur, either 1) Redose xylazine: up to half the original dose, 2) Add butorphanol (0. 02-0. 04 mg/kg IV). Butorphanol can be given with the o riginal xylazine if you suspect that the horse will be difficult to tranquilize (e. g., high-strung Thoroughbreds) or added before the ketamine. This combination will improve induc-tion, increase analgesia and increase recumbency time by abou t 5-10 minutes. 3) Diazepam (0. 03 mg/kg IV). Mix the diazepam with the ketamine. This combination will improve induction when sedation is marginal, improve muscle re-laxation during anesthesia and prolong anesthesia by about 5-10 min utes. 4) Guaifenesin (5% solution administered IV to effect) can also be used to increase sedation and muscle relaxation. (Mathews 1999) As an antitussive: a) 0. 02 mg/kg IM two to three times daily (Orsini 1988) !TREPTILES/AMPHIBIANS: As an analgesic: a) 0. 05-1 mg/kg q12h IM, IV, PO, SC (up to 20 mg/kg in tor-toises) (Bays 2006) Monitoring !TAnalgesic and/or antitussive efficacy !TRespiratory rate/depth !TAppetite and bowel function !TCNS effects Client Information !TClients should report any significant changes in behavior, appe-tite, bowel or urinary function in their animals Chemistry/Synonyms A synthetic opiate partial agonist, butorphanol tartrate is related structurally to morphine but exhibits pharmacologic actions simi-lar to other partial agonists such as pentazocine or nalbuphine. The co mpound occurs as a white, crystalline powder that is sparingly soluble in water and insoluble in alcohol. It has a bitter taste and a p Ka of 8. 6. The commercial injection has a p H of 3-5. 5. One mg of the tartrate is equivalent to 0. 68 mg of butorphanol base. Butorphanol tartrate may also be known as: levo-BC-2627 (bu-torphanol), Do lorex®, Equanol®, Stadol®, Torbutrol®, Torbugesic®, and Verstadol®. Storage/Stability/Compatibility The injectable product should be stored out of bright light and at room temperature; avoid freezing. The injectable product is reported to be compatible with the fol-lowing IV fluids and drugs: acepromazine, atropine sulfate, chlo-rpromazine, diphenhydramine HCl, droperidol, fentanyl citrate, hydro xyzine HCl, meperidine, morphine sulfate, pentazocine lac-tate, perphenazine, prochlorperazine, promethazine HCl, scopol-amine HBr, and xylazine. The drug is reportedly incompatible with the following agents: dimenhydrinate, and pentobarbital sodium. Dosage Forms/Regulatory Status Note : Butorphanol is a class IV controlled substance. The veterinary products (Torbutrol®, Torbugesic®) strengths are listed as base activ-ity. The human product (Stadol®) strength is labeled as the tartrate salt. !TVETERINARY-LABELED PRODUCTS: Butorphanol Tartrate Injection: 0. 5 mg/m L (activity as base) in 10 m L vials; Torbutrol® (Fort-Dodge); (Rx, C-IV). Approved for use in dogs. Butorphanol Tartrate Injection: 2 mg/m L (activity as base) in 10 m L v ials. Torbugesic-SA® (Fort Dodge); (Rx, C-IV). Approved for use in cats. Butorphanol Tartrate Injection: 10 mg/m L (activity as base) in 10 m L, 50 m L vials; Torbugesic® (Fort-Dodge), Dolorex®(Intervet), Bu-torject® (Phoenix), Tor phaject® (Butler); Equanol® (Vedco) generic; (Rx, C-IV). Approved for use in horses not intended for food. Butorphanol Tartrate Tablets: 1 mg, 5 mg, and 10 mg (activity as base) tab lets; bottles of 100; Torbutrol® (Fort-Dodge); (Rx, C-IV). Approved for use in dogs. The ARCI (Racing Commissioners International) has designated this drug as a c lass 3 substance. See the appendix for more information. !THUMAN-LABELED PRODUCTS: Butorphanol Tartrate Injection: 1 mg/m L (as tartrate salt; equiva-lent to 0. 68 mg base) in 1 m L & 2 m L vials; 2 mg/m L (as tartrate salt) in 1 m L, 2 m L, and 10 m L vials; Stadol®(Bristol-Myers Squibb); generic; (Rx, C-IV) Butorphanol Nasal Spray: 10 mg/m L in 2. 5 m L metered dose); ge-neric; (Rx, C-IV) n-Butylscopolammonium Bromide — See the monograph found in the “N's” before neomycin

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When using to induce estrus, it is recommended to wait at least 4 months after the prior cycle to allow the uterus to recover. CABERGOLINE Adverse Effects (ka-ber-go-leen) Dostinex® Cabergoline is usually well tolerated by animal patients. Vomiting PRO LACTIN INHIBIT OR/DO PAMINE ( D2) AGO NIST has been reported, but may be alleviated by administering with food. Dogs receiving cabergoline for more than 14 days may exhibit changes in coat color. Human patients have reported postural hypotension, dizziness, Prescriber Highlights TT Ergot derivative that may be useful in inducing/ headache, nausea and vomiting while receiving cabergoline. synchronizing estrus in dogs & as an abortifacient in dogs or cats Reproductive/Nursing Safety This drug can cause spontaneous abortion in pregnant dogs or TT Limited clinical experience & published references cats. In pregnant humans, cabergoline is designated by the FDA available as a category B drug ( Animal studies have not demonstrated risk to TT Appears to be well tolerated in dogs & cats; vomiting the fetus, but there are no adequate studies in pregnant women; or has been reported animal studies have shown an adverse effect, but adequate studies in TT Potentially very expensive, particularly in large dogs, pregnant women have not demonstrated a risk to the fetus during the but generic tablets now available; must usually be first trimester of pregnancy, and there is no evidence of risk in later compounded trimesters. ) Because cabergoline suppresses prolactin, it should not be used in nursing mother s. Uses/Indications Overdosage/Acute Toxicity For dogs, cabergoline may be useful for inducing estrus, treatment Overdose information is not available for dogs or cats, and remains of primary or secondary anestrus, pseudopregnancy, and pregnancy very limited for humans. It is postulated that cabergoline overdoses termination in the second half of pregnancy. Cabergoline may be in people could cause hypotension, nasal congestion, syncope or useful in treating some cases of pituitary-dependent hyperadreno-hallucinations. Treatment is basically supportive and primarily fo-corticism (Cushing's). cuses on supp orting blood pressure. In cats, cabergoline, with or without a prostaglandin, may be use-Drug Interactions ful for pregnancy termination, particularly earlier in pregnancy. The following drug interactions have either been reported or are Preliminary work has been done in psittacines (primarily theoretical in humans or animals receiving cabergoline and may be Cockatiels) for adjunctive treatment of reproductive-related disor-of significance in veterinary patients: ders, particularly persistent egg laying. In humans, cabergoline is indicated for the treatment of disorders T ! HYPOTENSIVE DRUGS : Because cabergoline may have hypotensive associated with hyperprolactenemia or the treatment of Parkinson's effects, concomitant use with other hypotensive drugs may cause disease. additive hypotension T ! METOCLOPRAMIDE : Use with cabergoline may reduce the efficacy Pharmacology/Actions of both drugs and should be avoided Cabergoline has a high affinity for dopamine2 (D2) receptors and T ! PHENOTHIAZINES (e. g., acepromazine, chlorpromazine ): Use of caber-has a long duration of action. It exerts a direct inhibitory effect on goline with dopamine (D2) antagonists may reduce the efficacy of the secretion of prolactin from the pituitary. When compared to both drugs and should be avoided bromocriptine it has greater D2 specificity, a longer duration of ac-tion, and less tendency to cause vomiting. Laboratory Considerations T ! No particular laboratory interactions or considerations were lo-Pharmacokinetics cated for this drug. The pharmacokinetics of cabergoline have apparently not been re-ported for dogs or cats. In humans, the drug is absorbed after oral Doses dosing but its absolute bioavailability is not known. Food does not Because of the dosage differences in animals versus human patients appear to significantly alter absorption. The drug is only moderately and the strength of the commercially available product, a com-bound to plasma proteins (≈ 50%). Cabe rgoline is extensively me-pounding pharmacist must usually reformulate this medication. tabolized in the liver via hydrolysis; these metabolites and about 4% T ! DOGS: of unchanged drug are excreted into the urine. Half-life is estimated For estrus induction: to be around 60 hours. Duration of pharmacologic action may per-a) 5 mcg/kg PO once daily induces fertile proestrus in 4-25sist for 48 hours or more. Renal dysfunction does not appear to sig-days. (Davidson 2004c) nificantly alter elimination characteristics of the drug. b) 5 mcg/kg PO once daily until an induced proestrus is pro-Contraindications/Precautions/Warnings nounced for 2 days or until onset of estrus (Concannon Cabergoline is contraindicated in dogs and cats that are pregnant 2005) unless abortion is desired (see indications). Cabergoline should c) 0. 6 mcg/kg PO once daily. Make a 10 mcg per m L solution by not be used in patients who are hypersensitive to ergot derivatives. dissolving commercial tablets in warm distilled water (One Patients that do not tolerate bromocriptine may or may not tolerate 0. 5 mg tablet (500 mcg) per 50 m L of distilled water. ) Give the cabergoline. In humans, cabergoline is contraindicated in patients appropriate dose for the patient within 15 minutes of prepa-who have uncontrolled hypertension. ration and discard the remaining solution. Continue until day Patients with significantly impaired liver function should receive 2 after the onset of the first signs of proestrus, or until day 42 the drug with caut ion, and if required, possibly at a lower dosage. without signs of proestrus. 81% (22 of 27) of dogs treated at

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this low dose showed proestrus between days 4 and 48. (Cirit, Bacinoglu et al. 2006) For treatment of pseudocyesis (pseudopregnancy): a) 5 mcg/kg once a day PO for 5-10 days. (Gobello, Concan-non et al. 2001) b) 5 mcg/kg once a day or every other day SC (likely needs to be compounded). (Davidson 2004c) For pr egnancy termination: a) Administer after day 40: 5 mcg/kg PO for 5 days; approxi-mately 50% effective (Romagnoli 2006a) b) Between days 35-45: Cabe rgoline 5 mcg/kg PO once daily for 7 days in food and cloprostenol at 1 mcg/kg SC (after a tenfold dilution with physiologic saline) on days 1 and 3 given at least 8 hours after food. If pregnancy not terminated by day 8, cabergoline continued (at same dose) until day 12. (Corrada, Rodriguez et al. 2006) For pituitary-dependent hyperadrenocorticism (Cushing's Dis-ease): a) 0. 1 mg/kg PO every 3 days. Effective in 70% of dogs treated. Dogs with tumor sizes greater than 5 mm did not respond. (Castillo, Lalia et al. 2005) T ! CATS: For pregnancy termination: a) At 30 days post-coitus, cabergoline at 5 mcg/kg PO q24h and clopr ostenol 5 mcg/kg SC q48h in 7-13 days was used to induce abortion. (Davidson 2004c) T ! BIRDS: For persistent egg laying in psittacines combination with remov-al of males, altered light cycle: a) Initially 10-20 mcg/kg PO daily; higher dosages were also used. Fur ther work needed to determine the dose rate, etc. (Chitty, Raftery et al. 2006) Monitoring T ! Efficacy T ! Adverse effects Client Information T ! Give this medication with food; contact veterinarian if vomiting persists Chemistry/Synonyms Cabergoline, a synthetic, ergot-derivative, dopamine agonist sim-ilar to bromocriptine, occurs as a white powder that is insoluble in water, and soluble in ethanol or chloroform. The commercially available tablets also contain the inactive ingredients, leucine and lactose. Cabergoline may also be known as FCE-21336, cabergolina, Cabasar®, Ac tualene®, Sostilar®, Dostinex® or Galastop®. Storage/Stability/Compatibility The commercially available tablets should be stored at controlled room temperature (20°-25°C; 68°-77°F). It has been reported that the drug is unstable or degrades in aqueous suspensions and if com-pounded into a liquid that will not be used immediately, should be compound ed into a lipid-based product. Preparing a fresh aque-ous solution for immediate use should be stable (see Dog dose “c” above). T he veterinary (Europe) product Galastop ® should be stored below 25°C and protected from light. Do not refrigerate. Once opened, it should be used within 28 days. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in USA. Cabergoline is available in Europe as Galastop® (Ceva) 50 mcg/m L oral liquid (miglyol base). HUMAN-LABELED PRODUCTS: Cabergoline Tablets: 0. 5 mg (500 mcg); Dostinex® (Pfizer); generic; (Rx) CALCITONIN SALMON (kal-si-toe-nin sam-in) Miacalcin®, Calcimar® OSTEOCLAST INHIBITING HORMONE Prescriber Highlights TT Hormone used primarily to control hypercalcemia in small animals (esp. dogs) TT Hypersensitivity possible TT Young animals may be extremely sensitive to effects TT May cause GI effects TT Do not confuse with calcitriol Uses/Indications In small animals, calcitonin has been used as adjunctive therapy to control hypercalcemia. Its use has been limited by expense, avail-ability and resistance development to its effects after several days of tr eatment. Pharmacology/Actions Calcitonin has a multitude of physiologic effects. It principally acts on bone inhibiting osteoclastic bone resorption. By reducing tubu-lar reabsorption of calcium, phosphate, sodium, magnesium, po-tassium and chloride, it promotes their renal excretion. Calcitonin also increases je junal secretion of water, sodium, potassium and chloride (not calcium). Pharmacokinetics Calcitonin is destroyed in the gut after oral administration and therefore must be administered parenterally. In humans, the onset of effect after IV administration of calcitonin salmon is immedi-ate. After IM or SC administration, onset occurs within 15 minutes with maximal e ffects occurring in about 4 hours. Duration of ac-tion is 8-14 hours aft er IM or SC injection. The drug is thought to be rapidly metabolized by the kidneys, in the blood and peripheral tissues. Contraindications/Precautions/Warnings Calcitonin is contraindicated in animals hypersensitive to it. Patients with a history of hypersensitivity to other proteins may be at risk. Y oung animals are reportedly up to 100 times more sensitive to calcitonin than are older animals (adults). Adverse Effects There is not a well-documented adverse effect profile for calcitonin in domestic animals. Anorexia and vomiting have been reported to occur in dogs. Overmedicating can lead to hypocalcemia. The fol-lowing effects are documented in humans and potentially could be seen in animals: diarrhea, anorexia, vomiting, swelling and pain at injection site, redness and peripheral paresthesias. Rarely, allergic reactions may occur. Tachyphylaxis (resistance to drug therapy with time) may occur in some dogs treated.

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Reproductive/Nursing Safety There is little information on the reproductive safety of calcitonin; however, it does not cross the placenta. Very high doses have de-creased birth weights in laboratory animals, presumably due to the metabolic e ffects of the drug. 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 ad-equate studies in humans. ) Calcitonin has been shown to inhibit lactation. Safe use during nursing has not be en established. Overdosage/Acute Toxicity Very limited data is available. Nausea and vomiting have been re-ported after accidental overdose injections. Chronic overdosing can lead to hy pocalcemia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcitonin and may be of significance in veterinary patients: T ! VITAMIN D ANALOGS or CALCIUM products: May interfere with the efficacy of calcitonin Doses T ! DOGS: For hypervitaminosis D (toxicity)/hypercalcemia: a) 4-6 IU/kg SC q12h to q8h (Carothers, Chew et al. 1994) b) In animals with severe hypercalcemia (>16 mg/d L) calcitonin may be beneficial when used in combination with furosemide, IV fluids, and prednisone. Initially, give 4 U/kg IV, followed by 4-8 mg/kg SC once or twice daily (dose extrapolated from human information) (Carothers, Chew et al. 1994) c) 4-6 IU/kg SC q2-3 hours unt il serum calcium levels are nor-malized (Firth 2000) d) For adjunctive therapy if fluid deficit replacement, saline di-uresis, furosemide and prednisone have failed to control cal-cium: 4 Units/kg IV, then 4-8 U/kg SC q12-24h (Nelson and Elliott 2003b) e) 4-6 Units/kg SC q8-12h (Davies 2005) T ! REPTILES: For hypercalcemia: a) Green iguanas in combination with fluid therapy: 1. 5 IU/kg SC q8h for several weeks if necessary (Gauvin 1993) For se condary nutritional hyperparathyroidism or nutritional secondary hyperparathyroidism (NSHP): a) If reptile is not hypocalcemic: 50 Units/kg IM once weekly for 2-3 doses. (He rnandez-Divers 2005) b) Correct husbandry problems and correct hypocalcemia with calcium and v itamin D. Once calcium level is normal and patient is on oral calcium supplementation (usually about 7 days after starting therapy) give calcitonin at 50 Units/kg IM weekly for 2-3 doses. Supportive care can be tapered off once patient becomes stable. (Johnson 2004a) Monitoring T ! Serum Calcium Chemistry/Synonyms A polypeptide hormone, calcitonin is a 32-amino acid polypeptide having a molecular weight of about 3600. Calcitonin is available commercially as either calcitonin human or calcitonin salmon, both of which are synthetically prepared. Potency of calcitonin salmon is expressed in international units (IU). Calcitonin salmon is approx-imately 50X more potent than calcitonin human on a per weight basis. Calcitonin salmon may also be known as calcitonin-salmon, cal-citoninum salmonis, salmon calcitonin, SCT-1, or Calcimar®; man y other trade names are available internationally. Storage/Stability Calcitonin salmon for injection should be stored in the refrigerator (2-8°C). The nasal solution should be stored in the refrigerator but protected from freezing. Once in use it should be stored at room temperature in an upright position; use within 35 days. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Calcitonin Salmon for Injection: 200 IU/m L in 2 m L vials; Miacal-cin® (Novartis); (Rx) Calcitonin Salmon Intranasal Spray: 200 Units/activation (0. 09 m L/ dose) in 2 m L (Miacalcin®) and 3. 7 m L (Fortical®) glass bottles with pump; Miacalcin® (Novartis); Fortical® (Upsher-Smith); (Rx) CALCITRIOL (kal-si-trye-ole) Rocaltrol®, Calcijex® VITAMIN D ANALOG Prescriber Highlights TT Vitamin D analog may be useful in dogs (& possibly cats) for treatment of hypocalcemia, chronic renal disease or idiopathic seborrhea. TT Contraindications: Hypercalcemia, hyperphosphatemia, malabsorption syndromes TT Adverse Effects: Hypercalcemia, hypercalcuria or hyper-phosphatemia greatest concerns TT May need to have oral dosage forms compounded TT Do not confuse with calcitonin Uses/Indications Calcitriol may be potentially beneficial in the adjunctive treatment of chronic renal disease in dogs and cats but its use is somewhat controversial, particularly the decision on how soon in the course of chronic renal insufficiency it should employed. It may also be of benefit in treating some types of dermatopathies (primary idiopath-ic seborrhea). Pharmacology/Actions Calcitriol is a vitamin D analog. Vitamin D is considered a hormone and, in conjunction with parathormone (PTH) and calcitonin, reg-ulates calcium homeostasis in the body. Active analogues (or metab-olites) of vitamin D enhance calcium absorption from the GI tract, promot e reabsorption of calcium by the renal tubules, and increase the rate of accretion and resorption of minerals in bone. Calcitriol has a rapid onset of action (approximately 1 day) and a short dura-

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tion of action. Unlike other forms of vitamin D, calcitriol does not require renal activation for it to be effective. Pharmacokinetics If fat absorption is normal, vitamin D analogs are readily absorbed from the GI tract (small intestine). Bile is required for adequate absorption and patients with steatorrhea, liver or biliary disease will have diminished absorption. Calcitriol has a rapid onset of biologic action and has a short duration of action (<1 day to 2-3 days). Dogs and cats appear to require much smaller doses of calcitriol than do humans. Contraindications/Precautions/Warnings Calcitriol is contraindicated in patients with hypercalcemia, vita-min D toxicity, malabsorption syndrome, or abnormal sensitivity to the effects of vitamin D. It should be used with extreme caution in patients with hyperphosphatemia (many clinicians believe hy-perphosphatemia or a combined calcium/phosphorous product of >70 is a co ntraindication to the use of vitamin D analogs). Adverse Effects While hypercalcemia is a definite concern, calcitriol administered in low dosages to dogs with chronic renal disease infrequently causes hypercalcemia, unless it is used with a calcium-containing phos-phorus binder, particularly calcium carbonate. Signs of hypercalce-mia include polydipsia, polyuria and anorexia. Hyperphosphatemia may also occur and patients' serum phosphate levels should be nor-malized before therapy is begun. Monitoring of serum calcium lev-els is mandatory while using this drug. Reproductive/Nursing Safety Calcitriol has proven to be teratogenic in laboratory animal when given at doses several times higher than those used therapeutically. 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. ) Safe use during lactation has not been established. Overdosage/Acute Toxicity Overdosage can cause hypercalcemia, hypercalciuria, and hyperphosphatemia. Intake of excessive calcium and phosphate may also cause the same effect. Acute ingestions should be man-aged using established protocols for removal or prevention of the drug being absorbed from the GI. Orally administered mineral oil may reduce absorption and enhance fecal elimination. Hypercalcemia secondary to chronic dosing of the drug should be treated by first temporarily discontinuing (not dose reduction) calcitriol and exogenous calcium therapy. If the hypercalcemia is severe, furosemide, calcium-free IV fluids (e. g., normal saline), urine acidification, and corticosteroids may be employed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcitriol and may be of significance in veterinary patients: !TCALCIUM-CONTAINING PHOSPHORUS BINDING AGENTS (e. g., calcium carbonate ): Use with calcitriol may induce hypercalcemia !TCORTICOSTEROIDS : Can nullify the effects of vitamin D analogs !TDIGOXIN or VERAPAMIL : Patients on verapamil or digoxin are sen-sitive to the effects of hypercalcemia; intensified monitoring is required !TPHENYTOIN, BARBITURATES or PRIMIDONE : May induce hepatic en-zyme systems and increase the metabolism of Vitamin D analogs thus decreasing their activity !TTHIAZIDE D IURETICS : May cause hypercalcemia when given in con-junction with Vitamin D analogs Laboratory Considerations !TSERUM CHOLESTEROL levels may be falsely elevated by vitamin D analogs when using the Zlatkis-Zak reaction for determination Doses !TDOGS: T o suppress secondary hyperparathyroidism in CRF: a) Decision to use calcitriol must be made with caution because hy percalcemia is potentially a serious complication that if prolonged can result in a reduction (reversible or irrevers-ible) of GFR. Hypercalcemia is an uncommon side effect (unless use d with a calcium-containing phosphorus binding agent) if calcitriol is dosed at 2. 5-3. 5 ng/kg/day PO. (Polzin, Osborne et al. 2005) b) 2. 5-3. 5 ng/kg PO once daily. Dogs with refractory hyper-parathyroidism may require up to 6 ng/kg/day. (Chew 2003) c) 1) Confirm the diagnosis of chronic renal failure (serum creatinine >2 mg/dl); 2) Reduce hyperphosphatemia to <6 mg/dl; 3) If serum creatinine between 2-3 mg/dl and serum phosphorus <6 mg/dl, start calcitriol at 2. 5-3. 5 ng/kg/day PO (so-called “preventative” dose); if serum creatinine >3 mg/dl and serum phosphorus <6 mg/dl, obtain a baseline PTH level and start calcitriol at 3. 5 ng/kg/day. Monitoring of preventative dose: assess serum calcium on days 7 and 14 after starting calcitriol and then every 6 months. Serum creatinine should be measured every 1-3 months. If hypercalcemia occurs, stop calcitriol for one week to determine if the drug is causing the hypercalcemia or if it's due to another cause (e. g., too little calcitriol). Monitoring patients with elevated PTH: monitor as above, bu t also determine PTH levels at 4-6 weeks after starting calcitriol. If still elevated increase dose by 1-2 ng/kg/day, but do not exceed 6. 6 ng/kg/day unless monitoring ionized calcium. If higher daily doses are required (5-7 ng/kg/day), a pulsed-dosing strategy may be considered. This is usually about 20 ng/kg given twice weekly PO at bedtime on an emp-ty stomach. (Nagode 2005) For subacute and chronic maintenance treatment of hyp ocalcemia: a) Initially, 20-30 ng/kg/day PO divided twice a day for 3-4 day s, then 5-15 ng/kg/day divided twice a day (Chew and Nagode 2000) For primary idiopathic seborrhea (especially in spaniel breeds): a) 10 ng/kg PO once daily. Give as far away from the main meal as possib le. (Kwochka 1999) !TCATS: T o suppress secondary hyperparathyroidism in CRF: a) 1. 65-3. 63 ng/kg PO daily (Polzin, Osborne et al. 2000) b) 2. 5-3. 5 ng/kg PO once daily (Chew 2003) c) See the dog dose in “c” above (Nagode 2005) Monitoring !TSerum calcium, phosphate, creatinine. Baseline and at one week and 1 month after starting treatment; then monthly thereafter !TUrine calcium baseline and as needed !TSerum PTH levels !TClinical efficacy ( e. g., improved appetite, activity level, slowed progression of disease)

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Client Information T ! Clients should be briefed on the signs of hypercalcemia (poly-dipsia, polyuria, anorexia) and hypocalcemia (muscle tremors, twitc hing , tetany, weakness, stiff gait, ataxia, behavioral changes, and seizures) and instructed to report these signs to the veterinar-ian T ! If using lower doses (<3. 5 ng/kg/day) give with the morning meal; if using doses of >5 ng/kg/day; administer at bedtime on an emp-ty stomach to reduce chance for hypercalcemia Chemistry/Synonyms Calcitriol, a vitamin D analog is synthesized for pharmaceutical use. It is a white crystalline compound and is insoluble in water. Calcitriol may also be known as: calcitrolo, calcitriolum, 1,25-di-hydroxycholecalciferol, 1-alpha,25 dihydrocholecalciferol, 1alpha, 25-Dihydr oxyvitamin D3 or 1,25-DHCC, 1,25-dihidroxyvitamin D3, Ro 21-5535, U 49562, Acuode®, Alpha D3®, Bocatriol®, Calci jex®, Calcitriol Kyra Med®, Calcitriol Purissimus®, Calcitriol-Nefro®, Calcitriolo®, Decostriol®, Dexiven ®, Difix®, Hitrol ®, Kalcytriol®, Kolkatriol®, Lotravel ®, Osteotriol®, Renatriol®, Rexamat®, Rocaltrol®, Roical®, Rolsical®, Silkis®, Sitriol®, or Tirocal®. Storage/Stability Protect from light. Store in tight, light resistant containers at room temperature. The injection does not contain preservatives and re-maining drug should be discarded after opening ampule. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Note : Most doses are expressed in nanograms/kg (ng/kg); to convert mcg to ng: 1 mcg = 1000 ng, 0. 25 mcg = 250 ng, etc. Reformulation by a compounding pharmacy is usually required to assure accurate dosing. Calcitriol Capsules: 0. 25 mcg, 0. 5 mcg; Rocaltro l®(Roche); Calcitriol (T eva); (Rx) Calcitriol Oral Solution: 1 mcg/m L in 15 m L btls; Rocaltro l®(Roche); Calcitriol (T eva); (Rx) Calcitriol Injection: 1 mcg/m L & 2 mcg/m L in 1 m L amps & vials; Calcije x® (Abbott); Calcitriol Injection (aai Pharma); (Rx) CALCIUM ACETATE (kal-see-um ass-a-tate) Phos Lo® ORAL PHOSPHATE BINDER Prescriber Highlights TT Oral phosphorus binding agent for use in treating hyper-phosphatemia associated with chronic renal failure TT Must monitor serum phosphorus & calcium Uses/Indications Calcium acetate can be used for oral administration to treat hyper-phosphatemia in patients with chronic renal failure. Secondary to its phosphor us binding efficiency and lower concentration of elemental calcium, calcium acetate is considered the most effective and having the lowest potential for causing hypercalcemia of the calcium-based phosphorus-binding agents. When compared to calcium carbonate, calcium acetate binds approximately twice as much phosphorus per gram of elemental calcium administered. Unlike calcium citrate, cal-cium acetate does not promote aluminum absorption. Pharmacology/Actions When calcium acetate is given with meals it binds to dietary phos-phorus and forms calcium phosphate, an insoluble compound that is eliminate d in the feces. Calcium acetate is soluble over a range of p H and, therefore, available for binding phosphorus in the stomach and proximal small intestine. Pharmacokinetics No information was located on the pharmacokinetics of calcium ac-etate in dogs and cats. In humans, approximately 30% is absorbed when gi ven with food. Contraindications/Precautions/Warnings This agent should not be used when hypercalcemia is present. Because hypercalcemia can result from administering oral calcium products to animals with renal failure, adequate monitoring of se-rum ionized calcium and phosphorus is required. Use calcium containing phosphate binders with caution in pa-tients having a serum calcium and phosphorus product greater than 60. Using calcium-based phosphate binders and calcitriol together is contr oversial. Some authors state the combination is contraindicat-ed; while others state that intensified monitoring for hypercalcemia is requir ed. Adverse Effects Hypercalcemia is the primary concern associated with using high dosages of this agent; adequate monitoring is required. In humans, GI intolerance (nausea) has been reported. Reproductive/Nursing Safety No reproductive safety studies were located and the human label states that it is not known whether the drug can cause fetal harm. However, it would be surprising if calcium acetate caused terato-genic effects. In humans, the FDA categorizes calcium acetate as cat-egory 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 would be expected that calcium acetate would be safe to ad-minister during lactation. Overdosage/Acute Toxicity Potentially, acute overdoses could cause hypercalcemia. Patients should be monitored and treated symptomatically. If dosage was massive and recent, consider using standard protocols to empty the gut. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcium acetate and may be of significance in veterinary patients: T ! CALCITRIOL : If administered with calcium acetate, may lead to hy-percalcemia; if calcitriol is used concomitantly, intensified moni-toring for hypercalcemia is mandatory T ! DIGOXIN : Calcium acetate is not recommended for use in human patients that are on digoxin therapy, as hypercalcemia may cause serious arrhythmias T ! FLUOROQUINOLONES, TETRACYCLINES : Oral calcium-containing products can reduce absorption of fluoroquinolones; if both cal-cium acetate and one of these antibiotics are required, separate dosages by at least two hours

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TLaboratory Considerations No specific concerns noted; see Monitoring Doses T ! DOGS /CATS: For hyperphosphatemia associated with chronic renal failure: a) In conjunction with a low-phosphorus diet: Initial therapy at 60-90 mg/kg/da y, with food or mixed with food, or just pri-or to each meal. Individualize dose to achieve desired serum phosphor us concentrations. Perform serial serum phospho-rus evaluations at 2-4 week intervals. Decrease dose if serum calcium exceeds normal limits; additional aluminum-based phosphate binders should be used if hyperphosphatemia persists. (Polzin, Osborne et al. 2005) Monitoring Initially at 10-14 day intervals; once “stable”, at 4-6 week intervals: T ! Serum phosphorus (after a 12-hour fast) T ! Serum ionized calcium Client Information T ! Give with meals; either just before or mixed into food T ! he veterinarian may prescribe additional doses to be adminis-tered between meals if additional calcium is required, give only with meals unless the ve t erinarian instructs to do so T ! Use of this medication will require ongoing laboratory monitoring Chemistry/Synonyms Calcium acetate is a white, odorless, hygroscopic powder that is freely soluble in water and slightly soluble in alcohol. Each gram contains approximately 254 mg of elemental calcium. Calcium acetate may also be known as: calcii acetas, acetato de calcio, kalcio ac etates, kalciumacetat, or kalciumasetaatti, Phos Lo®. Storage/Stability The commercially available tablets, capsules and gelcaps should be stored at room temperature (25°C); excursions are permitted to 15-30°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Calcium Acetate Tablets: 667 mg (169 mg elemental calcium); Phos-Lo® (Nabi); (Rx) Calcium Acetate Capsules: 333. 5 mg (half-size; 84. 5 mg elemental calcium), 667 mg (169 mg elemental calcium); Phos Lo® (Nabi); (Rx) Calcium Acetate Gelcaps: 667 mg (169 mg elemental calcium); Phos Lo® (N abi); (Rx) Calcium EDTA — see Edetate Calcium Disodium CALCIUM SALTS CALCIUM GLUCONATE CALCIUM GLUCEPTATE CALCIUM CHLORIDE CALCIUM LACTATE (kal-see-um) ESSENTIAL CATION NUTRIENT Prescriber Highlights TT Used to treat or prevent hypocalcemia; or as an oral antacid TT Contraindicated in V-fib or hypercalcemia TT Must NOT give IV too rapidly TT Must monitor therapy carefully depending on condition, etc. TT Drug interactions & incompatibilities prevalent Uses/Indications Calcium salts are used for the prevention or treatment of hypocal-cemic conditions. Pharmacology/Actions Calcium is an essential element that is required for many functions within the body, including proper nervous and musculoskeletal sys-tem function, cell membrane and capillary permeability, and acti-vation of enzymatic reactions. Pharmacokinetics Calcium is absorbed in the small intestine in the ionized form only. Presence of vitamin D (in active form) and an acidic p H is nec-essary for oral absorption. Parathormone (parathyroid hormone) increases with resultant increased calcium absorption in calcium deficiency states and decreases as serum calcium levels rise. Dietary factors (high fiber, phytates, fatty acids), age, drugs (corticoster-oids, tetracyclines), disease states (steatorrhea, uremia, renal osteo-dystrophy, achlorhydria), or decreased serum calcitonin levels may all cause red uced amounts of calcium to be absorbed. After absorption, ionized calcium enters the extracellular flu-id and then is rapidly incorporated into skeletal tissue. Calcium administrat ion does not necessarily stimulate bone formation. Approximately 99% of total body calcium is found in bone. Of cir-culating calcium, approximately 50% is bound to serum proteins or co mplexed with anions and 50% is in the ionized form. T otal se-rum calcium is dependent on serum protein concentrations. T otal serum calci um changes by approximately 0. 8 mg/dl for every 1. 09 g/dl change in serum albumin. Calcium crosses the placenta and is distributed into milk. Calcium is eliminated primarily in the feces, contributed by both unabsorbe d calcium and calcium excreted into the bile and pancre-atic juice. Only small amounts of the drug are excreted in the urine as most of the cation filtered by the glomeruli is reabsorbed by the tubules and ascending loop of Henle. Vitamin D, parathormone, and thiazide diuretics decrease the amount of calcium excreted by the kidneys. Loop diuretics (e. g., furosemide), calcitonin, and so-matotropin increase calcium renal excretion.

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Contraindications/Precautions/Warnings Calcium is contraindicated in patients with ventricular fibrillation or hypercalcemia. Parenteral calcium should not be administered to patients with above normal serum calcium levels. Calcium should be used very cautiously in patients receiving digitalis glycosides, or having cardiac or renal disease. Calcium chloride, because it can be acidifying, should be used with caution in patients with respiratory failure, respiratory acidosis, or renal disease. In dogs, calcium gluconate diluted 1:1 has been regarded as safe to administer subcutaneously for the treatment of primary hy-poparathyroidism in the past, but there are now several case reports of severe tissue reactions (pyogranulomatous panniculitis, adipocyte mineralization, etc. ) at the injection site; use with caution, particu-larly when using with calcitriol. Adverse Effects Hypercalcemia can be associated with calcium therapy, particularly in patients with cardiac or renal disease; animals should be ade-quately monitored. Other effects that may be seen include GI irrita-tion and/or constipation after oral administration, mild to severe tiss ue reactions after IM or SC administration of calcium salts and venous irritation after IV administration. Calcium chloride may be more irritating than other parenteral salts and is more likely to cause hypotension. T oo rapid intravenous injection of calcium can cause hypotension, cardiac arrhythmias and cardiac arrest. Should calcium salts be infused perivascularly, stop the infusion; tr eatment then may include: infiltrating the affected area with nor-mal saline, corticosteroids administered locally, applying heat and elev ating the area, and infiltrating the affected area with 1% pro-caine and hyaluronidase. Reproductive/Nursing Safety Although parenteral calcium products have not been proven safe to use during pregnancy, they are often used before, during, and after parturition in cows, ewes, bitches, and queens to treat parturient pa-resis secondary to hypocalcemia. 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. ) Overdosage/Acute Toxicity Unless other drugs are given concurrently that enhance the absorp-tion of calcium, oral overdoses of calcium containing products are unlike ly to cause hypercalcemia. Hypercalcemia can occur with par-enteral therapy or oral therapy in combination with vitamin D or increase d parathormone levels. Hypercalcemia should be treated by withholding calcium therapy and other calcium elevating drugs (e. g., vitamin D analogs). Mild hypercalcemia generally will resolve without further intervention when renal function is adequate. More serious hypercalcemia (>12 mg/dl) should generally be tr eated by hydrating with IV normal saline and administering a loop diuretic (e. g., furosemide) to increase both sodium and calcium excretion. Potassium and magnesium must be monitored and re-placed as necessary. ECG should also be monitored during treat-ment. Corticosteroids, and in humans calcitonin and hemodialysis, hav e also been employed in treating hypercalcemia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcium and may be of significance in veterinary patients: !TCALCIUM CHANNEL BLOCKERS (e. g., diltiazem, verapamil, etc. ): Intra-venous calcium may antagonize the effects of calcium-channel blocking agents !TDIGOXIN : Patients on digitalis therapy are more apt to develop ar-rhythmias if receiving IV calcium—use with caution !TMAGNESIUM (oral): With oral calcium may lead to increased serum magnesium and/or calcium, particularly in patients with renal failure. !TMAGNESIUM SULFATE : Parenteral calcium can neutralize the effects of hy permagnesemia or magnesium toxicity secondary to paren-teral magnesium sulfate !TNEUROMUSCULAR BLOCKERS (e. g., tubocurarine, metubine, gallamine, pancuronium, atracurium, and vecuronium ): Parenteral calcium may reverse the effects of nondepolarizing neuromuscular blocking agents; calcium has been reported to prolong or enhance the ef-fects of tubocurarine !TTETRACYCLINES, FLUOROQUINOLONES (oral): Oral calcium can reduce the amount of tetracyclines or fluoroquinolones absorbed from the GI tract; separate dosages by two hours if possible !TPOTASSIUM SUPPLEMENTS : Patients receiving both parenteral cal-cium and potassium supplementation may have an increased chanc e of developing cardiac arrhythmias—use cautiously !TTHIAZIDE D IURETICS : Used in conjunction with large doses of cal-cium may cause hypercalcemia !TVITAMIN A : Excessive intake of vitamin A may stimulate calcium loss from bone and cause hypercalcemia. !TVITAMIN D : Concurrent use of large doses of vitamin D or its analogs may cause enhanced calcium absorption and induce hypercalcemia Laboratory Considerations !TSERUM AND URINARY MAGNESIUM : Parenteral calcium may cause false-negative results for serum and urinary magnesium when us-ing the Titan yellow method of determination. Doses !TDOGS For hypocalcemia: a) Calcium gluconate injection: 94-140 mg/kg IV slowly to ef-fect (intraperitoneal route may also be used). Monitor respi-rations and cardiac rate and rhythm during administration. (USPC 1990) b) For acute hypocalcemia: Calcium gluconate 10% injection: War m to body temperature and give IV at a rate of 50-150 mg/kg (0. 5-1. 5 m L/kg) over 20-30 minutes. If bradycardia develops, halt infusion. Following acute crisis, infuse 10-15 m L (of a 10% solution) per kg over a 24-hour period. Long-term therapy may be accomplished by increasing dietary calcium and using vitamin D. Calcium lactate may be given orally at a rate of 0. 5-2 g/day. (Seeler and Thurmon 1985) c) Calcium gluconate 10% 0. 5-1. 5 m L/kg or calcium chloride 10% 1. 5 -3. 5 m L (total) IV slowly over 15 minutes; monitor heart rate or ECG during infusion. If ST segment elevation or Q-T interval shortening occur, temporarily discontinue infu-sion and reinstate at a slower rate when resolved. Maintenance ther apy is dependent on cause of hypocalcemia. Hypopara-thyroidism is treated with vitamin D analogs (refer to DHT mono graph) with or without oral calcium supplementation. (Russo and Lees 1986) d) For emergency treatment of tetany and seizures secondary to hy poparathyroidism: Calcium gluconate 10%: 0. 5-1. 5 m L/ kg (up to 20 m L) over 15-30 minutes. May repeat at 6-8 hour intervals or give as continuous infusion at 10-15 mg/ kg/hour. Monitor ECG and stop infusion if S-T segment el-evates, Q-T interval shortens, or arrhythmias occur. For long-term therapy (with DHT—refer to that monograph), calcium

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supplementation may occasionally be useful. Calcium glu-conate at 500-750 mg/kg/day divided three times daily, or calcium lactate at 400-600 mg/kg/day divided three times daily, or calcium carbonate 100-150 mg/kg/day divided twice daily. Monitor serum calcium and adjust as necessary. (Kay and Richter 1988) e) For emergency treatment: Calcium gluconate 10% 5-15 mg/ kg (0. 5 -1. 5 m L/kg) slowly to effect over a ten minute period, or calcium chloride 10% (extremely caustic if administered extravascularly) 5-15 mg/kg (0. 15-0. 5 m L/kg); dose is the same but volume is N that of calcium gluconate; monitor heart rate or ECG (if possible) during infusion. If brady-cardia or Q-T interval shortening occurs, temporarily dis-continue infusion. Short-term treatment immediately after co rrection of tetanty: Either give a constant rate infusion of calcium gluconate 10% at 60-90 mg/kg/day (6. 5-9. 75 m L/ kg/day) added to the fluids or give the daily dosage SC in 3-4 divided doses per day after diluting with an equal volume of saline. (Crystal 2004) For hyperkalemic cardiotoxicity: a) Secondary to uremic crisis: Correct metabolic acidosis, if pr esent, with sodium bicarbonate (bicarbonate may also be beneficial even if acidosis not present). Calcium gluconate (10%) indicated if serum K+ is >8 m Eq/L. Give at an approx-imate dose of 0. 5-1 m L/kg over 10-20 min utes; monitor ECG. Rapidly corrects arrhythmias but effects are very short (10-15 minutes). IV glucose (0. 5-1 g/kg body weight with or without insulin) also beneficial in increasing intracellular K+ concentrations. (Polzin and Osborne 1985) !TCATS : For hypocalcemia: a) Calcium gluconate injection: 94-140 mg/kg IV slowly to ef-fect (intraperitoneal route may also be used). Monitor respi-rations and cardiac rate and rhythm during administration. (USPC 1990) b) For acute hypocalcemia secondary to hypoparathyroidism: Using 10% calcium gluconate injection, give 1-1. 5 m L/kg IV slowly over 10-20 minutes. Monitor ECG if possible. If bradycardia, or Q-T interval shortening occurs, slow rate or temporarily discontinue. Once life-threatening signs are controlled, add calcium to IV fluids and administer as a slow infusion at 60-90 mg/kg/day (of elemental calcium). This converts to 2. 5 m L/kg every 6-8 hours of 10% cal-cium gluconate. Carefully monitor serum calcium (once to twic e daily) during this period and adjust dose as required. Begin oral calcium initially at 50-100 mg/kg/day divided 3-4 times daily of elemental calcium and dihydrotachysterol once animal can tolerate oral therapy. Give DHT initially at 0. 125-0. 25 mg PO per day for 2-3 da ys, then 0. 08-0. 125 mg per day for 2-3 days and finally 0. 05 mg PO per day un-til further dosage adjustments are necessary. As cat's serum calcium is stabilized, intravenous calcium may be reduced and discontinued if tolerated. Stable serum calcium levels (8. 5-9. 5 mg/dl) are usually achieved in about a week. Con-t inue to monitor and adjust dosages of DHT and calcium to lowest levels to maintain normocalcemia. (Peterson and Randolph 1989) ( Note: refer to the DHT monograph for fur-ther information. ) c) For hypocalcemia secondary to phosphate enema toxicity or puer peral tetany: follow the guidelines for use of intravenous calcium in “b” above. (Peterson and Randolph 1989) d) For emergency treatment: Calcium gluconate 10% 5-15 mg/ kg (0. 5 -1. 5 m L/kg) slowly to effect over a ten minute period, or calcium chloride 10% (extremely caustic if administered ext ravascularly) 5-15 mg/kg (0. 15-0. 5 m L/kg); dose is the same but volume is N that of calcium gluconate; monitor heart rate or ECG (if possible) during infusion. If brady-cardia or Q-T interval shortening occurs, temporarily dis-continue infusion. Short-term treatment immediately after co rrection of tetanty: Either give a constant rate infusion of calcium gluconate 10% at 60-90 mg/kg/day (6. 5-9. 75 m L/ kg/day) added to the fluids or give the daily dosage SC in 3-4 divided doses per day after diluting with an equal volume of saline. (Crystal 2004) !TCATTLE For hypocalcemia: a) Calcium gluconate injection: 150-250 mg/kg IV slowly to eff ect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 250-500 m L IV slowly, or IM o r SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Gluc. Inje ction 23%—T ech America) c) 8-12 grams of calcium IV infused over a 5-10 min ute pe-riod; use a product containing magnesium during the last month of pregnancy if subclinical hypomagnesemia is de-tected. (Allen and Sansom 1986) !THORSES For hypocalcemia: a) Calcium gluconate injection: 150-250 mg/kg IV slowly to eff ect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 250-500 m L IV slowly, or IM o r SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Glucon-ate Injection 23%—T ech America) c) For lactation tetany: 250 m L per 450 kg body weight of a standard commercially available solution that also contains magnesium and phosphorous IV slowly while auscultating heart. If no improvement after 10 minutes, repeat. Intensity in heart sounds should be noted, with only an infrequent ex-trasystole. Stop infusion immediately if a pronounced change in rat e or rhythm is detected. (Brewer 1987) !TSHEEP & GOATS: For hypocalcemia: a) Sheep: Calcium gluconate injection: 150-250 mg/kg IV slow ly to effect (intraperitoneal route may also be used). Monitor respirations and cardiac rate and rhythm during administration. (USPC 1990) b) Sheep: Calcium gluconate 23% injection: 25-50 m L IV slow ly, or IM or SC (divided and given in several locations, with massage at sites of injection) (Label directions; Calcium Gluconate Injection 23%—T ech America) !TSWINE: For hypocalcemia: a) Calcium gluconate injection: 150-250 mg/kg IV slowly to eff ect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 25-50 m L IV slowly, or IM o r SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Glu-conate Injection 23%—T ech America)

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!TBIRDS: For hypocalcemic tetany: a) Calcium gluconate: 50-100 mg/kg IV slowly to effect; may be diluted and given IM if a vein cannot be located (Clubb 1986) For egg-bound birds: a) Initially, calcium gluconate 1% solution 0. 01-0. 02 m L/g IM. Pr ovide moist heat (80-85°F) and allow 24 hours for bird to pass egg. (Nye 1986) !TREPTILES: For egg binding in combination with oxytocin (oxytocin: 1-10 IU/kg IM. ): a) Calcium glubionate: 10-50 mg/kg IM as needed until calci-um levels back to normal or egg binding is resolved. Use care whe n giving multiple injections. Calcium/oxytocin is not as effective in lizards as in other species. (Gauvin 1993) Monitoring !TSerum calcium !TSerum magnesium, phosphate, and potassium when indicated !TSerum PTH (parathormone) if indicated !TRenal function tests initially and as required !TECG during intravenous calcium therapy if possible !TUrine calcium if hypercalcuria develops Chemistry Several different salts of calcium are available in various formula-tions. Calcium gluceptate and calcium chloride are freely soluble in wate r; calcium lactate is soluble in water; calcium gluconate and cal-cium glycerophosphate are sparingly soluble in water, and calcium phosp hate and carbonate are insoluble in water. Calcium gluconate for injection has a p H of 6-8. 2 and calcium chloride for injection has a p H of 5. 5-7. 5. T o determine calcium content per gram of various calcium salts: Calcium Acetate: 253 mg (12. 7 m Eq) Calcium Carbonate: 400 mg (20 m Eq) Calcium Chloride: 270 mg (13. 5 m Eq) Calcium Citrate: 211 mg (10. 6 m Eq) Calcium Gluceptate: 82 mg (4. 1 m Eq) Calcium Gluconate: 90 mg (4. 5 m Eq) Calcium Glycerophosphate: 191 mg (9. 6 m Eq) Calcium Lactate: 130 mg (6. 5 m Eq) Calcium Phosphate Dibasic Anhydrous: 290 mg (14. 5 m Eq) Dihydrate: 230 mg (11. 5 m Eq) Calcium Phosphate Tribasic: 400 mg (20 m Eq) Storage/Stability/Compatibility Calcium gluconate tablets should be stored in well-closed containers at room temperature. Calcium lactate tablets should be stored in tight containers at room temperature. Calcium gluconate injection, calcium gluceptate injection, and calcium chloride injection should be stored at room temperature and protected from freezing. Calcium chloride for injection is reportedly compatible with the fol-lowing intravenous solutions and drugs: amikacin sulfate, ascorbic acid, bretylium tosylate, cephapirin sodium, chloramphenicol so-dium succinate, dopamine HCl, hydrocortisone sodium succinate, isop roterenol HCl, lidocaine HCl, methicillin sodium, norepineph-rine bitartrate, penicillin G potassium/sodium, pentobarbital so-dium, phenobarbital sodium, sodium bicarbonate, verapamil HCl, and vitamin B-c omplex with C. Calcium chloride for injection compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: fat emulsion 10%, dobutamine HCl, oxytetracy-cline HCl, and tetracycline HCl. Compatibility is dependent upon fac tors such as p H, concentration, temperature and diluent used. Calcium chloride for injection is reportedly incompatible with the fol-lowing solutions or drugs: amphotericin B, cephalothin sodium, and chlo rpheniramine maleate. Calcium gluconate for injection is reportedly compatible with the fol-lowing intravenous solutions and drugs: sodium chloride for injec-tion 0. 9%, lactated Ringer's injection, dextrose 5%-20%, dextrose-lac tated Ringer's injection, dextrose-saline combinations, amikacin sulfate, aminophylline, ascorbic acid injection, bretylium tosylate, cephapirin sodium, chloramphenicol sodium succinate, corticotro-pin, dimenhydrinate, erythromycin gluceptate, heparin sodium, hy-drocortisone sodium succinate, lidocaine HCl, methicillin sodium, nor epinephrine bitartrate, penicillin G potassium/sodium, pheno-barbital sodium, potassium chloride, tobramycin sulfate, vancomy-cin HCl, verapamil and vitamin B-complex with C. Calcium gluconate compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or so-lutions: phosphate salts, oxytetracycline HCl, prochlorperazine edi-sylate, and tetracycline HCl. Compatibility is dependent upon fac-tors such as p H, concentration, temperature and diluent used. Calcium gluconate is reportedly incompatible with the following so-lutions or drugs: intravenous fat emulsion, amphotericin B, cefa-mandole naftate, cephalothin sodium, dobutamine HCl, methyl-prednisolone sodium succinate, and metoclopramide HCl. Consult specialized references or a hospital pharmacist for more spe cific information. Dosage Forms/Regulatory Status VETERINARY-APPROVED PRODUCTS: (not necessarily a complete list) Parenteral Products: Calcium Gluconate (as calcium borogluconate) 23% [230 mg/m L; 20. 7 mg (1. 06 m Eq) calcium per m L]; in 500 m L bottles; Am T ech® Calcium Gluconate 23% Solution (Phoenix Scientific); (OTC), Cal-cium Gluconate 23% (Ag ri Pharm, Agri Labs, Aspen, Bimeda, Durvet, Phoenix Pharmaceutical, Vet T ek, Vetus); (OTC), Cal-Nate 1069® (Butler); (OTC). Depending on the product, approved for use in cattle, horses, swine, sheep, cats, and dogs. No withdrawal times are required. Calcium Gluconate oral 40 g-42 g calcium/300 m L tube. Supple-ment for use pre and post calving. Cal S upreme Gel® (Bimeda); (OTC) Calcium Chloride 35% w/w or 47% w/v equivalent to 170 mg cal-cium/m L (127 mg per gm) in 300 m L (400 g) tube. Clearcal 50® (Vedco); (OTC) Products are also available that include calcium, phosphorus, po-tassium and/or dextrose; refer to the individual product's labeling fo r specific dosage information. Trade names for these products include: Norcalciphos®—Pfizer, and Cal-Dextro ® Special, #2, C, and K—Fort Dodge; (Rx). Oral Products : No products containing only calcium (as a salt) are available commercially with veterinary labeling. There are several products (e. g., Pet-Cal® and Osteoform® Improved ) that contain cal-cium with phosphorous and vitamin D (plus other ingredients in some p reparations).

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HUMAN-APPROVED PRODUCTS: (not a complete list) Parenteral Products : Calcium Gluconate Injection 10% [100 mg/m L; 9 mg (0. 47 m Eq) calcium per m L] in 10 m L amps, 10 and 50 m L, 100 m L, and 200 m L vials; ge neric; (Rx) Calcium Chloride Injection 10% [100 mg/m L; 27. 2 mg (1. 36 m Eq) calcium per m L] in 10 m L amps, vials, and syringes; generic; (Rx) Oral Products : Calcium Gluconate (9. 3% calcium) Tablets: 500 mg (45 mg cal-cium), 650 mg (58. 5 mg calcium), 975 mg (87. 75 mg calcium), 1 gram (90 mg of calcium); generic; (OTC) Calcium Lactate (13% calcium) Tablets: 325 mg (42. 25 mg calci-um), 650 mg (84. 5 mg calcium); Capsules (13% calcium), 500 mg (96 mg calcium), Cal-Lac® (Bio T ech); generic; (OTC) Also available are calcium carbonate tablets, suspension and cap-sules, calcium acetate tablets, calcium citrate tablets, and tricalcium phosphate tab lets. Camphorated Tincture of Opium — See Paregoric CAPTOPRIL (kap-toe-pril) Capoten® ANGIOTENSIN-CO NVERTING ENZYME (ACE) INHIBITOR Prescriber Highlights TT First available ACE inhibitor; use largely supplanted by enalapril & other newer ACE inhibitors TT Shorter duration of activity & more adverse effects than other newer ACE inhibitors Uses/Indications The principle uses of captopril in veterinary medicine, at present, are as a vasodilator in the treatment of CHF and in the treatment of hypertension. Because of fewer adverse effects, enalapril and benazepril have largely supplanted the use of this drug in veteri-nary medicine. Pharmacology/Actions Captopril prevents the formation of angiotensin-II (a potent va-soconstrictor) by competing with angiotensin-I for the enzyme angiotensin-c onverting enzyme (ACE). ACE has a much higher af-finity for captopril than for angiotensin-I. Because angiotensin-II conce ntrations are decreased, aldosterone secretion is reduced and plasma renin activity is increased. The cardiovascular effects of captopril in patients with CHF include decreased total peripheral resistance, pulmonary vascular resistance, mean arterial and right atrial pressures, and pulmonary capillary wedge pressure; no change or decrease in heart rate; and increased cardiac index and output, stroke volume, and exercise tolerance. Renal blood flow can be increased with little change in hepatic blood flow. Pharmacokinetics In dogs, approximately 75% of an oral dose is absorbed but food in the GI tract reduces bioavailability by 30-40%. It is distributed to most tissues (not the CNS) and is 40% bound to plasma proteins in dogs. The half-life of captopril is about 2. 8 hours in dogs and less than 2 hours in humans. Its duration of effect in dogs may only persist for 4 hours. The drug is metabolized and renally excreted. More than 95% of a dose is excreted renally, both as unchanged (45-50%) drug and as metabolites. Patients with significant renal dysfunction can have significantly prolonged half-lives. Contraindications/Precautions/Warnings Captopril is contraindicated in patients who have demonstrated hypersensitivity with ACE inhibitors. It should be used with cau-tion and under close supervision in patients with renal insufficien-cy; doses may need to be reduced. Captopril should also 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 o f therapy. Adverse Effects There have been some reports of hypotension, renal failure, hyper-kalemia, vomiting and diarrhea developing in dogs after captopril administrat ion. Captopril may have a higher incidence of gastro-intestinal effects in dogs than other available ACE inhibitors. Al-though seen in people, skin rashes (4-7% incidenc e) and neutro-penia/agranulocytosis (rare) have not been reported in dogs. Reproductive/Nursing Safety Captopril apparently crosses the placenta. High doses of ACE in-hibitors in rodents have caused decreased fetal weights and increas-es in fetal and maternal death rates; no teratogenic effects have been repo rted 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 dur-ing the first trimester of pregnancy (Animal studies have shown an adver se effect on the fetus, but there are no adequate studies in hu-mans; or there are no animal reproduction studies and no adequate studies in humans. ) During the second and third trimesters, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is catego-rized as in class: C (These dr ugs 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. ) Captopril enters milk in concentrations of about 1% of that found in mater nal plasma. Overdosage/Acute Toxicity In overdose situations, the primary concern is hypotension; sup-portive treatment with volume expansion with normal saline is rec-ommended to correct blood pressure. Dogs given 1. 5 gm/kg orally deve loped emesis and decreased blood pressure. Dogs receiving doses greater than 6. 6 mg/kg q8h may develop renal failure. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving captopril and may be of significance in veterinary patients: T ! ANTACIDS : Reduced oral absorption of captopril may occur if giv-en concomitantly with antacids; it is suggested to separate dosing by at least two hours

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T ! CIMETIDINE: Used concomitantly with captopril has caused neuro-logic dysfunction in two human patients T ! DIGOXIN : Levels may increase 15-30% when captopril is added, automatic reduction in dosage is not recommended, but monitor-ing of serum digoxin levels should be performed T ! DIURETICS : Concomitant diuretics may cause hypotension if used with captopril; titrate dosages carefully T ! NON-STEROIDAL ANTIINFLAMMATORY AGENTS (NSAIDs ): May reduce the clinical efficacy of captopril when it is being used as an anti-hypertensive agent T ! POTASSIUM or POTASSIUM SPARING DIURETICS (e. g., spironolactone ): Hyperkalemia may develop with captopril T ! PROBENECID : Can decrease renal excretion of captopril and pos-sibly enhance the clinical and toxic effects of the drug T ! VASODILATORS (e. g., prazosin, hydralazine, nitrates ): Concomitant va-sodilators may cause hypotension if used with captopril; titrate dosages care fully Laboratory Considerations T ! Captopril may cause a false positive urine acetone test (sodium nitroprusside reagent). T ! When using iodohippurate sodium I123/I134 or Technetium Tc99 penten-tate renal imaging in patients with renal artery stenosis, ACE inhib-itors may cause a reversible decrease in localization and excretion of these ag ents in the affected kidney which may lead confusion in test interpretation. Doses Note : Because of fewer adverse effects in dogs, longer duration of ac-tivity, and/or veterinary labeling/dosage forms, enalapril and other newer ACE inhibitors have largely supplanted the use of this drug in veterinary medicine. T ! DOGS: a) 1-2 mg/kg PO q8h (Kittleson 2000) b) 0. 5-2 mg/kg PO q8-12h (Bonagura and M uir 1986) T ! CATS: a) 1/4 to one-half 12. 5 mg tablet PO q8-12h (Bonagura 1989) b) F or dilative, restrictive or hypertrophic cardiomyopathy: 0. 55-1. 54 mg/kg PO q8-12h (Kittleson 2000) Monitoring T ! Clinical signs of CHF T ! Serum electrolytes, creatinine, BUN, urine protein T ! CBC with differential; periodic T ! Blood pressure (if treating hypertension or signs associated with hypotension arise). Client Information T ! Give medication on an empty stomach unless otherwise instruct-ed. Do not abruptly stop or reduce therapy without veterinarian's appr o val. Contact veterinarian if vomiting or diarrhea persist or are severe, or if animal's condition deteriorates. Chemistry/Synonyms Related to a peptide isolated from the venom of a South American pit viper, captopril occurs as a slightly sulfurous smelling, white to off-white, crystalline powder. It is freely soluble in water or alcohol. Captopril may also be known as: captoprilum, or SQ-14225; many tra de names are available. Storage/Stability Captopril tablets should be stored in tight containers at tempera-tures not greater than 30°C. Dosage Forms/Regulatory Status T ! VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. T ! HUMAN-LABELED PRODUCTS: Captopril Tablets 12. 5 mg, 25 mg, 50 mg, and 100 mg; Capoten® (PAR); generic; (Rx) Captopril and Hydrochlorothiazide Tablets: 15 mg hydrochlorothi-azide and 25 mg captopril; 15 mg hydrochlorothiazide and 50 mg captop ril; 25 mg hydrochlorothiazide and 25 mg captopril; 25 mg hydrochlorothiazide and 50 mg captopril. Captopril and Hydro-chlorothiazide Tablets (Teva); Capozide® 25/25 Table ts, Capozide® 50/25 Tablets, Capozide® 50/15 Tablets, Capozide® 25/15 Tablets (B-M Squibb); (Rx) CARBENICILLIN INDANYL SODIUM (kar-ben-i-sill-in in-da-neel) Geocillin® EXTENDED-ACTION ORAL PENICILLIN Prescriber Highlights TT “Antipseudomonal” oral carboxypenicillin that may be useful for treating susceptible UTI's or bacterial prostati-tis in small animals TT Blood levels too low to treat other systemic infections TT Inactivates aminoglycosides in vitro; may have ramifica-tions when used together for UTI Uses/Indications Carbenicillin was used parenterally in the treatment of systemic Pseu domonas aeruginosa infections in small animals, usually in com-bination with an appropriate aminoglycoside agent, but in the USA the injectab le is no longer available and most clinicians use ticarcillin or piperacillin in its place. Because the oral form is poorly absorbed and the drug has a rapid elimination half-life, oral therapy is only indicated for the treatment of susceptible urinary tract (and possibly prostate) infections as levels are too low in serum and other tissues for adequate therapy in other systemic Pseudomonas infections. Pharmacology/Actions The alpha-carboxypenicillins, sometimes called anti-pseudomonal penicillins, include both carbenicillin and ticarcillin. These agents have similar spectrums of activity as the aminopenicillins (ampicil-lin, etc. ) including increased activity against many strains of gram-negati ve aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus. Additionally, they have activity against several gram-negative organisms of the family Enterobacteriaceae in-cluding many strains of Pseudomonas aeruginosa and Acinetobacter. 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 some activity against many anaerobic bacteria including Clostridial organisms.

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Pharmacokinetics The oral form (indanyl sodium) of the drug is rapidly, but incom-pletely, absorbed (see above) with only 30-40% of an oral dose ab-sorbed in humans. Peak levels of the indanyl sodium salt are at-tained in humans about 30 minutes after administration, but it is rapid ly hydrolyzed into the base. Attainable serum levels after oral therapy are generally too low to treat systemic infections, but high levels are achieved in the urine. The volume of distribution is reportedly 0. 18-0. 2 L/kg in dogs and cats, and 0. 29-0. 4 L/kg in the horse. The drug is 29-60% bound to serum proteins (human). Carbenicillin is thought to cross the placenta and is found in small quantities in milk. In cattle, mastitic milk levels of carbenicillin are approximately twice those found in normal milk, but are too low to treat most causal organisms. Carbenicillin is eliminated primarily by the kidneys, via both tu-bular secretion and glomerular filtration. Concurrent probenecid administ ration can slow elimination and increase blood levels. In humans, about 2-5% of the drug is metabolized by hydrolysis to inactive compounds. The half-life in dogs and cats is reportedly 45-75 minutes and 60-90 minutes in the horse. Clearance is 1. 8 m L/kg/min in the dog and 4. 6 m L/kg/min in the horse. 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). 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. In humans, it is esti-mated that up to 15% of patients hypersensitive to cephalosporins wil l also be hypersensitive to penicillins. The incidence of cross-re-activity in veterinary patients is unknown. When given orally, penicillins may cause GI effects (anorexia, 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 and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems associ-ated with these drugs. In humans, the FDA categorizes this drug as cate gory 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 Acute oral carbenicillin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carbenicillin and may be of significance in veterinary patients: !TAMINOGLYCOSIDES : In vitro studies have demonstrated that peni-cillins can have synergistic or additive activity against certain bac teria when used with aminoglycosides !TBACTERIOSTATIC ANTIBIOTICS (e. g., chloramphenicol, erythromycin, tetracyclines ): With penicillins are generally not recommend-ed, particularly in acute infections where the organism is pro-liferating rapidly as penicillins tend to perform better on actively gr owing bacteria !TPROBENECID : Competitively blocks the tubular secretion of most penicillins thereby increasing serum levels and serum half-lives, but may also lower urine levels Laboratory Considerations !TAs penicillins and other beta-lactams can inactivate aminoglyco-sides in vitro (and in vivo in patients in renal failure), serum con-centrations of aminoglycosides may be falsely decreased if the patie nt 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. The significance of this interaction when using oral carbenicillin in patients with normal renal function is in doubt. Doses !TDOGS: For susceptible infections in sites where therapeutic levels may be achieved (bladder/urine, and possibly prostate): a) For UTI: 22-33 mg/kg PO q8h for 7-10 da ys (Greene and Watson 1998) !TCATS: For susceptible infections in sites where therapeutic levels may be achieved (bladder/urine, and possibly prostate): a) For UTI: 22-33 mg/kg PO q8h for 7-10 da ys (Greene and Watson 1998) !TRABBITS/RODENTS/SMALL MAMMALS: a) Mice, Rats: 100 mg/kg PO q12h (Adamcak and Otten 2000) !TBIRDS: For susceptible infections in Psittacines: a) 100-200 mg/kg PO twice daily; N tab let added to 4 oz drink-ing water. Crush tablets and gavage or hide in mash or pal-atable soft food item. If adding to drinking water, disguise bitt er taste by adding Tang® or a Pina Colada mix to water. (Mc Donald 1989) b) 200 mg/kg, PO for 5-10 da ys. Crush tablets and apply to favorite food (e. g., cooked sweet potato works well) or mix in mash or hand-feeding formula. (Clubb 1986) 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.

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Client Information T ! Instruct clients to give carbenicillin to animal with an empty stomach, unless GI effects (anorexia, vomiting) occur T ! Compliance with the therapeutic regimen should be stressed Chemistry/Synonyms An alpha-carboxypenicillin, carbenicillin is now available only in an oral dosage form, the sodium salt of the indanyl ester of carbenicil-lin. It occurs as a bitter tasting, white to off-white powder that is soluble in wate r and alcohol. Carbenicillin may also be known as: carindacillin sodium, in-danylcarbenicillin sodium, BRL-2064, carbenicillinum natricum, alpha-carbo xybenzylpenicillin sodium, CP-15-639-2, GS-3159, NSC-111071, Carbapen®, Carbecin®, Geocillin®, Geopen®, Myciclid®, or Pyopen ®. Storage/Stability The oral indanyl sodium tablets should be stored in tight containers and protected from temperatures greater than 30°C. The sodium in-jection powder for reconstitution should be stored at temperatures less than 30°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Carbenicillin Indanyl Sodium Film-Coated Tablets: 382 mg (118 mg indanyl sodium ester); Geocillin® (Roerig); (Rx) CARBIMAZOLE (kar-bi-ma-zole) Neo-Carbimazole®, Carbazole® ANTI-THYROID Note : This drug is not available in the USA, but is routinely used in Europe and elsewhere in place of methimazole Prescriber Highlights TT Used outside of USA & Canada for medical treatment of feline hyperthyroidism TT Contraindications: Hypersensitive to carbimazole TT Caution: History of or concurrent hematologic abnor-malities, liver disease or autoimmune disease TT Adverse Effects: Most occur within first 3 months of treatment; vomiting, anorexia & depression most fre-quent. Eosinophilia, leukopenia, & lymphocytosis are usually transient. Rare, but serious: self-induced ex-coriations, bleeding , hepatopathy, thrombocytopenia, agranulocytosis, positive direct antiglobulin test, & acquired my asthenia gravis TT Place kittens on milk replacer if mother receiving carbimazole TT Unlike methimazole, has no bitter taste TT Potentially efficacious when used transdermally in cats Uses/Indications Carbimazole (a pro-drug of methimazole) or methimazole are considered by most clinicians to be the agents of choice when us-ing drugs to treat feline hyperthyroidism. Propylthiouracil has sig-nificantly higher incidences of adverse reactions when compared to methimazole. Me thimazole and therefore, carbimazole, may be useful for the prophy lactic prevention of cisplatin-induced nephrotoxicity in dogs. Pharmacology/Actions Carbimazole is converted almost entirely to methimazole in vivo. Methimazole interferes with iodine incorporation into tyrosyl resi-dues of thyroglobulin thereby inhibiting the synthesis of thyroid hormones. It also inhibits iodinated tyrosyl residues from coupling to form iodothyronine. Methimazole has no effect on the release or activity of thyroid hormones already formed or in the general cir-culation. Pharmacokinetics Carbimazole is rapidly absorbed from the GI tract and rapidly and nearly totally converted to methimazole. Because of differences in molar weight, to attain an equivalent serum level, carbimazole must be dosed approximately 2 times that of methimazole. In cats, the volume of distribution of methimazole is variable (0. 12-0. 84 L/kg). Methimazole ap parentl y concentrates in thy-roid tissue and biologic effects persist beyond measurable blood leve ls. After oral dosing, plasma elimination half-life ranges from 2. 3-10. 2 hours. There is usually a 1-3 we ek lag time between start-ing the drug and significant reductions in serum T 4. Car bimazole may be amenable for use transdermally in cats to control hyper-thyroidism. In dogs, methimazole has a serum half-life of 8-9 hours. Contraindications/Precautions/Warnings Carbamizole is contraindicated in patients who are hypersensitive to it or methimazole. It should be used very cautiously in patients with a history of or concurrent hematologic abnormalities, liver disease or autoimmune disease. Adverse Effects Adverse effects are reported less often with carbimazole than methi-mazole. Whether they indeed occur less frequently is debatable. Most adve rse effects associated with carbamizole or methimazole use in cats occur within the first three months of therapy with vomiting, anorexia and depression occurring most frequently. The GI effects may be related to the drug's bitter taste and are usually transient. Eosinophilia, leukopenia, and lymphocytosis may be noted in ap-proximately 15% of cats treated within the first 8 weeks of therapy. These hemat ologic effects usually are also transient and generally do not require drug withdrawal. Other more serious but rare adverse effects include: self-induced excoriations (2. 3%), bleeding (2. 3%), hepatopathy (1. 5%), thrombocytopenia (2. 7%), agranulocytosis (1. 5%), and positive direct antiglobulin test (1. 9%). These effects generally require withdrawal of the drug and adjunctive therapy. Up to 50% of cats receiving methimazole chronically (>6 months), will develop a positive ANA, which requires dosage reduction. Rarely, cats will develop an acquired myasthenia gravis that requires either withdrawal or concomitant glucocorticoid therapy. High levels of methimazole cross the placenta and may induce hypoth yroidism in kittens born of queens receiving the drug. Levels higher than those found in plasma are found in human breast milk. It is suggested that kittens be placed on a milk replacer after receiv-ing colostrum from mothers on methimazole. Reproductive/Nursing Safety Carbimazole, like methimazole (carbimazole is converted to me-thimazole), has been associated with teratogenic effects in humans (scalp def ects). It may also affect offspring thyroid development or function. In humans, the FDA categorizes methimazole as category D for use during pregnancy (There is evidence of human fetal risk, but

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Tthe potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) As methimazole can enter milk and have deleterious effects on offspr ing, switch to milk replacer if carbimazole or methimazole are required for nursing dams. Overdosage Acute toxicity that may be seen with overdosage include those that are listed above under Adverse Effects. Agranulocytosis, hepatopa-thy, and thrombocytopenias are perhaps the most serious effects that may b e seen. Treatment consists of following standard proto-cols in handling an oral ingestion (empty stomach if not contrain-dicated, administer charcoal, etc. ) and to treat symptomatically and suppo rtively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carbimazole and may be of significance in veterinary patients: ! !BUPROPION : Potential for increased risk for hepatotoxicity; in-creased monitoring (LFT's) necessary ! !DIGOXIN : Carbimazole may decrease digoxin efficacy ! !WARFARIN : Potential for decreased anticoagulant efficacy if carbi-mazole added Doses See also Methimazole. Usually, carbimazole dosages are twice that of methimazole. T ! CATS: For hyperthyroidism: a) 10-15 mg total dose daily per cat in divided doses for 1-3 weeks w ill produce a euthyroid state for most patients. Then adjust dosage for the patient to the lowest effective dose. Most cats will need dosing at least once daily. (Debuf 1991) b) Initially, give 5 mg (total dose) q8h for 2-3 weeks. Then ad-just. May need to increase dose in approximately 10% of cats (be sur e owner was compliant with previous dose). Most cats require 5 mg PO q12h to maintain euthyroidism. (Peterson 2000) Monitoring During first 3 months of therapy (baseline values and every 2-3 weeks): T ! CBC, platelet counts T ! Serum T 4 T ! If indicated by clinical signs: liver function tests, ANA After stabilized (at least 3 months of therapy): T ! 4 at 3-6 month intervals T ! Other diagnostic tests as dictated by adverse effects Client Information T ! It must be stressed to owners that this drug will decrease exces-sive thyroid hormones, but does not cure the condition T ! Adherence with the treatment regimen is necessary for success Chemistry/Synonyms A thioimidazole-derivative antithyroid drug, carbimazole occurs as a white to creamy white powder having a characteristic odor. It is slightly soluble in water and soluble in alcohol. Carbimazole may also be known as: carbimazolum, Basolest ®, Camazol®, Carbimazole®, Carbazole®, Carbistad®, Cazole®, Neo Tomizol®, Neo-Mercazole®, Neo-Thyreostat®, Thyrostat®, Tyrazol®, or Neo-morphazole®. Storage/Stability Unless otherwise labeled, carbimazole tablets should be stored at room temperature in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: There are no approved products in the USA; elsewhere it may be available as: Carbimazole Tablets: 5 mg & 20 mg. Trade names include Neo-Car-bimazo le®, Carbazo le®, Neo Mercazole®, etc. CARBOPLATIN (kar-boe-pla-tin) Paraplatin® ANTINEOPLASTIC Prescriber Highlights TT Platinum antineoplastic agent used for a variety of carci-nomas & sarcomas TT Unlike cisplatin, may be used in cats TT Contraindications: History of hypersensitivity to it or other platinum agents; severe bone marrow depression TT Caution: Hepatic/renal disease, hearing impairment, ac-tive infection TT Primary adverse effects: GI, Bone marrow depression. Nadir (neutrophils/platelets) in dogs about 14 days; in cats (neutrophils) about 17-21 days TT Fetotoxic TT Must be given IV TT May adversely affect vaccinations (safety/efficacy) Uses/Indications Like cisplatin, carboplatin may be useful in a variety of veterinary neoplastic diseases including squamous cell carcinomas, ovarian carcinomas, mediastinal carcinomas, pleural adenocarcinomas, nasal carcinomas and thyroid adenocarcinomas. Carboplatin's pri-mary use currently in small animal medicine is in the adjunctive treatme nt (post amputation) of osteogenic sarcomas. Its effective-ness in treating transitional cell carcinoma of the bladder has been disappoint ing; however, carboplatin may have more efficacy against melanomas than does cisplatin. Carboplatin, unlike cisplatin, appears to be relatively safe to use in cats. Carboplatin may be considered for intralesional use in condi-tions such as equine sarcoids or in treating adenocarcinoma in birds. Whe ther carboplatin is more efficacious than cisplatin for cer-tain cancers does not appear to be decided at this point, but the drug do es appear to have fewer adverse effects (less renal toxicity and reduced vomiting) in dogs. Pharmacology/Actions Carboplatin's exact mechanism of action is not fully understood. Both carboplat in's and cisplatin's properties are analogous to those of bifunctional alkylating agents producing in ter-and intrastrand cross-links in DNA, thereby inhibiting DNA replication, RNA transcrip-tion, and protein synthesis. Carboplatin is cell-cycle nonspecific.

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Pharmacokinetics After IV administration, carboplatin is well distributed through-out the body; highest concentrations are found in the liver, kidney, skin and tumor tissue. The metabolic fate and elimination of car-boplatin are complex and the discussion of this aspect of the drug's phar macokinetics is beyond the scope of this reference. Suffice it to say, the parent drug degrades into platinum and platinum-com-plexed compounds that are primarily eliminated by kidneys. In dogs, almost o ne half of the dose is excreted in the urine within 24 hours and approximately 70% of the platinum administered is secreted in the urine after 72 hours. Contraindications/Precautions/Warnings Carboplatin is contraindicated in patients hypersensitive to it or other platinum-containing compounds. It is also contraindicated in patients with severe bone marrow suppression. Patients with severe carboplatin-induced myelosuppression should be allowed to recover their counts before additional therapy. Caution is advised in patients with active infections, hearing im-pairment or preexisting renal or hepatic disease. Dosage may need adjustment in patients with reduced renal funct ion. One suggested dosage adjustment (Kitchell 2002) for cats, small dogs and those with real function follows: Cats usually dosed at 180-240 mg/m2 depending on the size and general health of the patient. Dogs usually dosed at 300 mg/m 2, but in dogs <10 lb. : 200 mg/m2; 10-20 lb. : 250 mg/m2; >20 lb. : 300 mg/m2. Dogs with se-rum creatinine levels of 2. 5-3 mg/dl are dosed at 200 mg/m2 and if creat inine is 2-2. 5 mg/dl: 250 mg/m2. Dogs with a creatinine greater than 3 mg/dl are not dosed with carboplatin. Do not give carboplatin IM or SC. Adverse Effects Established adverse effects in dogs include anorexia, vomiting (GI effects are uncommon) and dose-related bone marrow suppression that is exhibited primarily as thrombocytopenia and/or neutropenia. The nadir of platelet and neutrophil counts generally occur about 14 days post treatment in dogs. Recovery is generally seen by day 21. In cats, thrombocytopenia occurs infrequently, but the neutrophil nadir occurs about 21 days post treatment. Recovery usually occurs by day 28 in cats. Hepatotoxicity (increased serum bilirubin and liver enzymes) is se en in about 15% of human patients treated with carboplatin. Other potential adverse effects include: nephrotoxicity, neuropathies and ototoxicity. These effects occur with carboplatin therapy much less frequently than with cisplatin therapy. Anaphylactoid reactions have been reported rarely in humans that have received platinum-containing compounds (e. g., cisplatin). Hyperuricemia may occur after therapy in a small percentage of patients. Reproductive/Nursing Safety Carboplatin is fetotoxic and embryotoxic in rats and the risks of its use during pregnancy should be weighed with its potential benefits. In humans, the FDA categorizes this drug as category D for use dur-ing pregnancy (There is evidence of human fetal risk, but the potential be nefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is unknown whether carboplatin enters maternal milk. In hu-mans, it is recommended to discontinue nursing if the mother is re ceiving the drug. Overdosage/Acute Toxicity There is limited information available. An overdose of carboplatin would be expected to cause aggravated effects associated with the drug's bone marrow nephro-and liver toxicity. Monitor for neuro-toxicity, ototoxicity, hepatotoxicity and nephrotoxicity. Treatment is basically supportive; no specific antidote is avail-able. Plasmapheresis or hemodialysis could potentially be of benefit in re moving the drug. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carboplatin and may be of significance in veterinary patients: !TAMINOGLYCOSIDES : Potential for increased risk of nephrotoxicity or ototoxicity !TCISPLATIN : Human patients previously treated with cisplatin have an increased risk of developing neurotoxicity or ototoxicity after receiving carboplatin !TMYLEOSUPPRESSIVE D RUGS : The leukopenic or thrombocytopenic effects secondary to carboplatin may be enhanced by other my-elosuppressive medications !TRADIATION THERAPY : Potential for increased hematologic toxicity !TVACCINES : Live or killed virus vaccines administered after carbo-platin therapy may not be as effective as the immune response to these v accines may be modified by carboplatin therapy; carbopla-tin may also potentiate live virus vaccines replication and increase the ad verse effects associated with these vaccines Doses Note : Do not confuse cisplatin and carboplatin dosages; cisplatin dosages are much lower. For more information on cancer chemotherapy, refer to the pr otocols found in the appendix or other dosages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). !TDOGS: As adjunctive treatment of osteogenic sarcoma: a) 300 mg/m2 BSA IV every 21 days (Bergman, Mac Ewen et al. 1996) b) 300 mg/m2 BSA IV (admixed with D5W and given IV over 15 minu tes) usually within 7 days after amputation. Addition-al treatments given every 21 days for a total of 4 treatments (J ohnston 1997) As adjunctive treatment of osteogenic sarcoma, melanomas, or var ious carcinomas: a) Large Dogs: 350 mg/m2 BSA IV (diluted in dextrose) every 3 weeks Smal l Dogs: 300 mg/m2 BSA IV (diluted in dextrose) every 3 weeks (London and Frimberger 1997) !TCATS: As adjunctive treatment of osteogenic sarcoma, melanomas or various carcinomas: a) 210 mg/m2 BSA IV (diluted in dextrose) every 3 weeks (Lon-don and Frimberger 1997) b) 180-260 mg/m2 IV every 21 days (Kitchell and Dhaliwal 2000) Fo r Squamous cell carcinoma of the nasal planum (intra tumor administration): a) Give 100 mg/m2 BSA intratumorally (Kitchell and Dhaliwal 2000) b) 1. 5 mg (in a purified sesame oil)/cm3 of tissue (including gr oss tumor and a margin of normal tissue) injected intra-

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tumorally once a week for 4 weeks (Donecker, Sams et al. 1986) T ! BIRDS: For adenocarcinoma: a) 5 mg/kg IV over 3 minutes every 14-21 days (T ully 2006) Monitoring T ! CBC T ! Serum electrolytes, uric acid T ! Baseline renal and hepatic function tests Client Information T ! Clients should fully understand the potential toxicity of this agent and, ideally, should give informed consent for its use. T ! As carboplatin (and any platinum containing metabolites) is principally excreted in the urine over several days after treatment, clients should be warned to avoid direct contact with patient's urine. Chemistry/Synonyms Carboplatin, like cisplatin, is a platinum-containing antineoplastic agent. It occurs as white to off-white crystalline powder having a solubility of 14 mg/m L in water and is insoluble in alcohol. The commercially available powder for injection contains equal parts of mannitol and carboplatin. After reconstitution with sterile water for injection, a resulting solution of 10 mg/m L of carboplatin has a p H of 5-7 and an osmolality of 94 m Osm/kg. Carboplatin may also be known as: cis-Diammine-1,1-cyclob-utanedicarboxylato-platinum, carboplatinum; CBDCA; JM-8; or NSC-241240; many tr ade names are available. Storage/Stability/Compatibility/Preparation The powder for injection should kept stored at room temperature and protected from light. After reconstitution, solutions containing 10 mg/m L are stable for at least 8 hours. Some sources say that the solution is stable for up to 24 hours and can be refrigerated, but because there are no preservatives in the solution, the manufacturer recommends dis-carding unused portions after 8 hours. Previous recommendations to av oid the use of solutions to dilute carboplatin containing so-dium chloride are no longer warranted as only a minimal amount of carb oplatin is converted to cisplatin in these solutions. Because aluminum can displace platinum from carboplatin, the solut ion should not be prepared, stored or administered where aluminum-containing items can come into contact with the solu-tion. Should carboplatin come into contact with aluminum, a black precipitat e will form and the product should not be used. Directions for reconstitution for the 50 mg vial: Add 5 m L of ei-ther sterile water for injection, normal saline injection or D 5W that will provide a solution containing 10 mg/m L. May infuse directly (usually over 15 minutes) or further dilute. Visually inspect after reconstitution/dilution for discoloration or particulate matter. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Carboplatin Powder for reconstitution and IV Injection: 50 mg, 150 mg, and 450 mg vials (contains mannitol); Paraplatin®(Bristol-Myers Squibb Oncology); generic; (Rx) CARNITINE LEVOCARNITINE L-CARNITINE (kar-ni-teen) Carnitor® NUTRIENT Prescriber Highlights TT Nutrient required for normal fat utilization & energy metabolism TT May be useful in certain cardiomyopathies (including doxorubicin induced) in dogs TT Use only L (levo-) forms TT Preferably give with meals Uses/Indications Levocarnitine may be useful as adjunctive therapy of dilated cardio-myopathy in dogs. Up to 90% of dogs with dilated cardiomyopa-thy may have a carnitine deficiency. Levocarnitine may also protect against do xorubicin-induced cardiomyopathy and reduce risks of myocardial infarction. It may be beneficial in the adjunctive treat-ment of valproic acid toxicity. In cats, levocarnitine has been recommended as being useful as an adjunc tive therapy in feline hepatic lipidosis by facilitating he-patic lipid metabolism. Its use for this indication is controversial. Pharmacology/Actions Levocarnitine is required for normal fat utilization and energy me-tabolism in mammalian species. It serves to facilitate entry of long-chain fatty acids into cellular mitochondria where they can be used during oxidation and energy production. Severe chronic deficiency is generally a result of an inborn ge-netic defect where levocarnitine utilization is impaired and not the result o f dietary insufficiency. Effects seen in levocarnitine defi-ciency may include hypoglycemia, progressive myasthenia, hepato-megaly, CHF, cardiomegaly, hepatic coma, neurologic disturbances, encep halopathy, hypotonia and lethargy. Pharmacokinetics In humans, levocarnitine is absorbed via the GI with a bioavailabil-ity of about 15%, but is absorbed rapidly in the intestine via passive and act ive mechanisms. Highest levels of levocarnitine are found in skeletal muscle. Levocarnitine is distributed in milk. Exogenously administered levocarnitine is eliminated by both renal and fecal routes. Plasma levocarnitine levels may be increased in patients with renal failure. Contraindications/Precautions/Warnings Levocarnitine may also be known as Vitamin B T. Products labeled as such may have both D and L racemic forms. Use only Levo-(L-) forms as the D-form may competitively inhibit L-uptake with a resulting deficiency. Adverse Effects Adverse effect profile is minimal. Gastrointestinal upset is the most likely effect that may be noted and is usually associated with high dosages but is usually mild and limited to loose stools or possibly diarrhea; nausea and vomiting are possible. Human patients have reported increased body odor.

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TReproductive/Nursing Safety Studies done in rats and rabbits have demonstrated no teratogenic effects and it is generally believed that levocarnitine is safe to use in pregnancy though documented safety during pregnancy has not been established. 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 Levocarnitine is a relatively safe drug. Minor overdoses need only to be monitored; with massive overdoses consider gut emptying. Refer to a poison control center for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving levocarnitine and may be of significance in veterinary patients: T ! VALPROIC ACID: Patients receiving valproic acid may require higher dosages of levocarnitine Doses T ! DOGS: For myocardial carnitine deficiency associated with dilated car-diomyopathy: a) As a trial for treating canine dilated cardiomyopathy: For a large or giant breed dog: 2 grams (approximately 1 teaspoon-ful of pure powder) PO q8-12h For adjunctive (with traditional pharmacotherapy) therapy of dilate d cardiomyopathy in American Cocker spaniels: 1 gram (approximately H teaspoonful) PO q8-12h with tau-rine (Keene 2002) b) For boxers with severe myocardial failure: Give 2-3 grams carnitine PO q12h for 2-4 months to determine if they re-spond (Kittleson 2006a) c) For adjunctive treatment of American cocker spaniels with dilated car diomyopathy: Carnitine 1 g PO q12h with taurine 500 mg q12h PO (Kittleson 2006a) T ! CATS: a) As adjunctive dietary therapy in cats with severe hepatic lipi-dosis: 250 mg PO once daily (Use Carnitor®); also supplement with taurine (250 mg once to twice daily), Vitamin E (10 IU/ kg/day), water soluble vitamins and determine B12 status (treat while awaiting data at 1 mg/cat SC). See also Acetyl-cysteine. (Center 2006c) b) For supplementation in cats with liver disease: 250-500 mg/ day (Zor an 2006b) Monitoring T ! Efficacy T ! Periodic blood chemistries have been recommended for human patients, their value in veterinary medicine is undetermined. Client Information T ! Give with meals when possible to reduce likelihood of GI side ef-fects. T ! he majority of dogs responding to carnitine therapy for dilated cardiomyopathy will require other medication to control clinical signs. Chemistry/Synonyms Levocarnitine (the L-isomer of carnitine) is an amino acid deriva-tive, synthesized in viv o from methionine and lysine. It is required for energy metabolism and has a molecular weight of 161. Carnitine may also be known as: vitamin B(T), L-carnitine, or levocar nitinum; many trade names are available. Storage/Stability/Compatibility Levocarnitine capsules, tablets and powder should be stored in well-closed containers at room temperature. The oral solution should be kept in tight containers at room temperature. The injection should be stored at room temperature in the original carton; discard any unused portion after opening, as the injection contains no preser-vative. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Levocarnitine Tablets: 330 mg & 500 mg; Carnitor® (Sigma-Tau); L-Carnitine (Freeda Vitamins); Levocarnitine (Rising); (Rx & OTC) Levocarnitine or L-Carnitine Capsules: 250 mg; generic; (OTC—as a food s upplement) Levocarnitine Oral Solution: 100 mg/m L & 200 mg/m L (preserva-tive-free) in 118 m L vials & amps; Carnitor® (Sigma-Tau); generic; (Rx) Note : L-carnitine may also be available in bulk powder form from local health food stores CARPROFEN (kar-pro-fen) Rimadyl® NON-STEROIDAL ANTIINFLAMMATORY AGENT Prescriber Highlights TT NSAID used in dogs & other small animals TT Contraindicated in dogs with bleeding disorders (e. g., Von Willebrand's), history of serious reactions to it or other propionic-class NSAIDs TT Caution: Geriatric patients or those with preexisting chronic diseases (e. g., inflammatory bowel disease, renal or hepatic insufficiency) TT GI adverse effects are less likely than with older NSAIDs but can occur TT Rarely may cause hepatic failure; monitor liver enzymes Uses/Indications Carprofen is labeled (in the USA) for the relief of pain and inflam-mation in dogs. It may also prove to be of benefit in other species as well, but data is scant to support its safety beyond very short-term use at this time. In Europe, carprofen is reportedly registered for single dose use in cats, but there have been reported problems (e. g., vomiting) with cats receiving more than a single dose. Carprofen is being investigated for antineoplastic effects in dogs and may b e a useful adjunctive treatment for some types of tumors with COX-2 overexpression.

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Pharmacology/Actions Like other NSAIDs, carprofen exhibits analgesic, antiinflamma-tory, and antipyretic activity probably through its inhibition of cyc looxygenase, phospholipase A 2 and inhibition of prostaglandin synthesis. Carprofen is more sparing of COX-1 in vitro and in dogs appears to have fewer COX-1 effects (GI distress/ulceration, plate-let inhibition, renal damage) when compared to older non-COX-2 spe cific agents. COX-2 specificity appears to be species, dose, and tissue dependent. Carprofen in horses or cats does not seem to be as COX-2 specific as it is in dogs. Pharmacokinetics When administered orally to dogs, carprofen is approximately 90% bioavail able. Peak serum levels occur between 1-3 hours post dos-ing. The drug is highly bound to plasma proteins (99%) and has a low volume of distribution (0. 12-0. 22 L/kg). Carprofen is extensive-ly me tabolized in the liver primarily via glucuronidation and oxida-ti ve processes. About 70-80% o f a dose is eliminated in the feces; 10-20% eliminated in the urine. Some enterohepatic recycling of the drug occurs. Elimination half-life of carprofen in the dog is approxi-mately 13-18 hours with the S form having a longer half-life than the R f orm. In horses, the half-life of carprofen is reportedly 22 hours. Contraindications/Precautions/Warnings Carprofen is contraindicated in dogs with bleeding disorders (e. g., Von Willebrand's) or those that have had prior serious reactions to it or other propionic-class antiinflammatory agents. It should be used with caution in geriatric patients or those with preexisting chronic diseases (e. g., inflammatory bowel disease, renal or hepatic insufficiency). If discontinuing carprofen and switching to another NSAID, a one da y wash-out period has been recommended (Boothe 2005). Adverse Effects Although adverse effects appear to be uncommon with carprofen use in dogs, they can occur. Mild gastrointestinal effects are the most likely to appear, but serious effects (hepatocellular damage and/or renal disease; hematologic and serious gastrointestinal ef-fects) have been reported. Reported incidence of hepatopathy is app roximately 0. 05% of dogs treated. Geriatric dogs or dogs with chronic diseases (e. g., inflammatory bowel disease, renal or hepatic insufficiency) may be at greater risk for developing toxicity while receiving this drug. Although not proven statistically significant, Labrador Retrievers have been associated with G of the initially re-ported cases associated with the reported hepatic syndrome; but it is not believed that this breed has any greater chance of developing this adverse effect than others. Before initiating therapy, pre-treat-ment patient evaluation and discussion with the owner regarding the pot ential risks versus benefits of therapy are strongly advised. Reproductive/Nursing Safety The manufacturer states that the safe use of carprofen in dogs less than 6 weeks of age, pregnant dogs, dogs used for breeding pur-poses, or lactating bitches has not been established. Carprofen has be en given to pregnant rats at dosages of up to 20 mg/kg during day 7-15 of gestation. While no teratogenic effects were noted in pups, the drug did delay parturition with an increased number of dead pups at birth. Overdosage/Acute Toxicity In dog toxicologic studies, repeated doses of up to 10X resulted in little adversity. Some dogs exhibited hypoalbuminemia, melena or slight increases in ALT. However, post-marketing surveillance sug-gests that there may be significant interpatient variability in re-sponse to acute or chronic overdoses. There were 2296 exposures to carprofen reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 2066 were dogs with 90 showing clinical signs and the remaining 229 cases were cats with 11 show-ing clinical signs. Common findings in dogs recorded in decreasing fre quency included vomiting, anorexia, lethargy, bloody vomitus and diarrhea. Common findings in cats recorded in decreasing fre-quency included vomiting, anorexia, dehydration, abdominal pain and absent b owel movements. This medication is a NSAID. As with any NSAID, overdosage can lea d to gastrointestinal and renal effects. Decontamination with emetics and/or activated charcoal is appropriate. For doses where GI effects are expected, the use of gastrointestinal protectants is warranted. If renal effects are also expected, fluid diuresis is warranted. Drug Interactions Note : Although the manufacturer does not list any specific drug in-teractions in the package insert, it does caution to avoid or closely monit or carprofen's use with other ulcerogenic drugs (e. g., corticos-teroids or other NSAIDs ). The following drug interactions have either been reported or are theo retical in humans or animals receiving carprofen and may be of significance in veterinary patients: !TASPIRIN : When aspirin is used concurrently with carprofen, plas-ma levels of carprofen could decrease and an increased likelihood of GI adverse effects (blood loss) could occur. Concomitant ad-ministration of aspirin with carprofen cannot be recommended. !TCORTICOSTEROIDS : Concomitant administration with NSAIDs may significantly increase the risks for GI adverse effects !TDIGOXIN : Carprofen may increase serum levels of digoxin; use with caution in patients with severe cardiac failure !TFUROSEMIDE : Carprofen may reduce the saluretic and diuretic ef-fects of furosemide !THIGHLY PROTEIN BOUND D RUGS (e. g., phenytoin, valproic acid, oral anti-coagulants, other antiinflammatory agents, salicylates, sulfonamides, sulfonylurea antidiabetic agents ): Because carprofen is highly bound to plasma proteins (99%), it potentially could displace other highly bound drugs; increased serum levels and duration of actions may occur. Although these interactions are usually of little concern clinically, use together with caution. !TMETHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution !TPHENOBARBITAL, RIFAMPIN, or OTHER HEPATIC ENZYME INDUCING AGENTS : As carprofen hepatotoxicity may be mediated by its he-patic metabolites, these drugs should be avoided if carprofen is re quired !TPROBENECID : May cause a significant increase in serum levels and half-life of carprofen Laboratory Considerations !TIn dogs, carprofen may lower Total T 4 and TSH levels, but ap-parently does not affect free concentrations of T 4. Doses !TDOGS: As an antiinflammatory/analgesic: a) 4. 4 mg/kg PO; may be given once daily or divided and given as 2. 2. mg/kg twice daily; round dose to nearest half caplet increment. For postoperative pain, administer approximately 2 hours before the procedure. Injectable is dosed as the oral products, but administered SC. (Package Insert; Rimadyl®— Pfizer)

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b) Surgical pain: 4 mg/kg PO, IM, SC once. Pain/inflammation (non-s urgical): 2. 2 mg/kg PO q12-24h (Boothe 2005) !TCATS: As an antiinflammatory/analgesic: Extreme caution is advised, particularly with continued dosing. a) For surgical pain: 1-4 mg/kg SC pre-or post-operatively. Analg esia may last 12-18 hours. Use of 1-2 mg/kg SC gives similar efficacy as the higher doses, but is safer (Robertson and Lascelles 2003) b) 2 mg/kg PO q12h; limit to 2 days of therapy (Hardie 2000) c) Less than 1 mg/kg PO once daily (q24h) for 2-3 t reatments (Boothe 2005) d) For surgical pain: 2 mg/kg or less (lean weight) SC once at induc tion (Mathews 2005) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For chronic joint pain: 2. 2 mg/kg PO q12h (Ivey and Mo rrisey 2000) b) Rats: 5 mg/kg SC or 5-10 mg/kg PO. Chinchillas: 4 mg/kg SC onc e daily (Adamcak and Otten 2000) c) 1-4 mg/kg PO, SC q12-24h (Ba ys 2006) !THORSES: (Note : ARCI UCGFS Class 4 Drug) a) As an antiinflammatory/analgesic: 0. 7 mg/kg IV, one time (Clar k and Clark 1999), b) 0. 7 mg/kg IV, one time; may follow with 0. 7 mg/kg PO (gran-ules, mixed with a little feed) for up to 4-9 da ys according to clinical response (Label information; Rimadyl® Large Animal Solution, Rimadyl Granules®—Pfizer U. K. ) !TCATTLE: a) In young cattle (<12 months old) for adjunctive therapy of acu te inflammation associated with respiratory disease: 1. 4 mg/kg IV or SC once. Slaughter withdrawal = 21 days; not to be used in cows producing milk for human consumption. (Label information; Rimadyl® Large Animal Solution—Pfizer U. K. ) !TBIRDS: As an antiinflammatory/analgesic: a) 2 mg/kg PO q8-24 hours (C lyde and Paul-Murphy 2000) b) 1 mg/kg SC. Study demonstrated increased walking ability in lame chic kens. (Paul-Murphy 2003) c) 1-4 mg/kg IM, IV, PO (Bays 2006) !TREPTILES: As an antiinflammatory/analgesic: a) 1-4 mg/kg IV, IM, SC, PO q 24-72h (Ba ys 2006) Monitoring !TBaseline (especially in geriatric dogs, dogs with chronic diseases, or when prolonged treatment is likely): physical exam, CBC, Se-rum chemistry panel (including liver and renal function tests), and U A. It is recommended to reassess the liver enzymes at one, two and 4 weeks of therapy and then at 3-6 month intervals. Should elevation occur, recommend discontinuing the drug. !TClinical efficacy !TSigns of potential adverse reactions: inappetence, diarrhea, vomit-ing, melena, polyuria/polydipsia, anemia, jaundice, lethargy, be-havior changes, ataxia or seizures !TChronic therapy: Consider repeating CBC, UA and serum chem-istries on an ongoing basis Client Information !TAlthough rare, serious adverse effects have been reported with the use of this drug. Read and understand the client information sheet provided with this medication; contact the veterinarian with any questions or concerns. !TWatch for signs of potential adverse effects including: decreased appetite, vomiting, diarrhea, dark or tarry stools, increased water consumption, increased urination, pale gums due to anemia, yel-lowing of gums, skin or white of the eye due to jaundice, incoor-dination, seizures, or behavioral changes. Should these signs pres-ent, clients should stop the drug immediately and contact their ve terinarian. !TStore the flavored chewable tablets out of reach of dogs to avoid the potential for overdose. Chemistry/Synonyms A propionic acid derivative non-steroidal antiinflammatory agent, carprofen occurs as a white crystalline compound. It is practically insoluble in water and freely soluble in ethanol at room tempera-ture. Carprofen has both an S (+) enantiomer and R (-) enantiomer. The commercial product contains a racemic mixture of both. The S (+) enantiomer has greater antiinflammatory potency than the R (-) form. Carprofen may also be known as: C-5720; Ro-20-5720/000, Rimad yl®, Zinecarp®, Canidryl®, Novox ®, Carprodyl® or Norocarp®. Storage/Stability/Compatibility The commercially available caplets or chewable tablets should be stored at room temperature (15-30°C). The commercially available (in the USA) injection should be sto red in the refrigerator (2-8°C; 36-46°F). Once broached, the in-jection may be stored at temperatures of up to 25°C for 28 days. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Carprofen Scored Caplets: 25 mg, 75 mg & 100 mg; Rimadyl® Ca-plets (Pfizer), Nov ox® (Vedco); (Rx). Approved for use in dogs. Carprofen Chewable Tablets: 25 mg, 75 mg & 100 mg; Rimad yl® Chewable Tablets (Pfizer); (Rx). Approved for use in dogs. Carprofen Sterile Injectable Solution: 50 mg/m L in 20 m L vials; Rimad yl® (Pfizer); (Rx). Approved for use in dogs. In the U. K., Rimad yl® Injection is labeled for use in dogs, cats, horses, ponies and cattle (less than 12 months old; slaughter withdrawal = 21 days; not to be used in cattle producing milk for human con-sumption). Rimad yl® Granules are labeled for use in horses and po-nies. See Doses for more information. The ARCI (Racing Commissioners International) has designated this drug as a c lass 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None

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CARVEDILOL (kar-vah-da-lol) Coreg® BETA & ALPHA-1 ADRENERGIC BLOCKER Prescriber Highlights TT Non-selective Beta-adrenergic blocker with selective alpha1-adrenergic blocking activity that could be useful for treating heart failure in dogs; use is contro ver sial TT Very limited veterinary experience TT Negative inotrope that may prohibit its use in severely symptomatic patients; potentially could decompensate patient TT Additional adverse effects that may demonstrate intoler-ance include lassitude, inappetence, & hypotension TT Expense may be an issue Uses/Indications Carvedilol may be useful as adjunctive therapy in the treatment of heart failure (dilated cardiomyopathy) in dogs. There is a fair amount of controversy at present among veterinary cardiologists as to whether this drug will find a therapeutic niche. Pharmacology/Actions Carvedilol is a non-selective, beta-adrenergic blocker with selective alpha1-adrenergic blocking activity. Despite their negative inotro-pic effects, chronic dosing of beta blockers in human patients with dilated car diomyopathy can be useful in reducing both morbidity and mortality. Patients in heart failure, chronically activate their sympathetic nervous system, thereby leading to tachycardia, activa-tion of the renin-angiotensin-aldosterone system, down-regulation of be ta-receptors, induction of myocyte necrosis and myocyte en-ergy substrate and calcium ion handling. By giving beta-blockers, these negat ive effects may be reversed or diminished. As carvedilol also inhibits alpha1-adrenergic activity, it can cause vasodilation and red uce afterload. Carvedilol has free-radical scavenging and antidysrhythmic effects that could be beneficial in heart failure pa-tients. Pharmacokinetics In dogs, a pilot study (Arsenault, Boothe et al. 2003) showed carve-dilol's bioavailability after oral dosing averaged about 23% in the 4 dogs st udied, but in 3 of the 4, bioavailability ranged from 3-10%. Volume of distribution averaged about 1. 4 L/kg; elimination half-life was about 100 minutes. At least 15 different metabolites of carvedilol have been identified after dosing in dogs. Hydroxylation of the carbazolyl ring and glucuronidation of the parent compound are the most predominant processes of metabolism in dogs. In humans, carvedilol is rapidly and extensively absorbed but due to a high first-pass effect, bioavailability is about 30%. The drug is extensively bound to plasma proteins (98%). It is extensively metabolized and the R(+) enantiomer is metabolized 2-3 times greater than the S(-) form during the first pass. Both the R(+) and S(-) enantiomers have equal potency as non-specific beta-or al-pha-adrenergic blockers. CYP2D6 and CYP2C9 are the P450 isoen-zymes most responsible for hepatic metabolism. Some of these metabolites have pharmacologic activity. Metabolites are primarily excreted via the bile and feces. Elimination half-life of carvedilol in humans is about 8-9 hours. Contraindications/Precautions/Warnings In humans, carvedilol is contraindicated in class IV decompensated heart failure, bronchial asthma, 2nd or 3rd degree A V block, sick sinus syndrome (unless artificially paced), severe bradycardia, car-diogenic shock or hypersensitivity to the drug. Dogs with equiva-lent conditions should not receive the drug. Adverse Effects Veterinary experience is very limited and an accurate portrayal of adverse effects in dogs has yet to be elucidated. T oo rapid beta blockade can cause decompensation in patients with heart failure; cautious dosage titration is mandatory. Dogs that do not tolerate the medication may show signs of inappetence, lassitude, or hy-potension. Bronchospasm has been reported in humans. Because the drug is extensively metabolized in the liver, patients with hepat ic insufficiency should receive the drug with caution. In humans, carvedilol has on rare occasions, caused mild hepatocel-lular injury. Reproductive/Nursing Safety In humans, the FDA categorizes carvedilol 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). In rats and rabbits, carvedilol increased post-implantation loss. It is unknown if carvedilol enters maternal milk in dogs, but it does ent er milk in rats. Use with caution in nursing patients. Overdosage/Acute Toxicity The acute oral LD50 in healthy rats and mice is greater than 8 grams/ kg. Clinical signs associated with large overdoses include: severe hypotension, cardiac insufficiency, bradycardia, cardiogenic shock and death due to cardiac arrest. Gut emptying protocols should be considered if ingestion was recent. In humans, bradycardia is treated with atropine, and cardiovascular function supported with glucagon and sympathomimetics (e. g., dobutamine, epinephrine, etc. ). Contact an animal poison control center for specific informa-tion in the case of overdose. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carvedilol and may be of significance in veterinary patients: T ! BETA-BLOCKERS (other ): Use with carvedilol may cause additive effects T ! CALCIUM CHANNEL BLOCKERS (e. g., diltiazem, verapamil ): Carvedilol may rarely cause hemodynamic compromise in patients taking diltiazem or verapamil T ! CIMETIDINE : May decrease metabolism and increase AUC of carvedilol T ! CLONIDINE : Carvedilol may potentiate the cardiovascular effects of clonidine T ! CYCLOSPORINE : Carvedilol may increase cyclosporine levels T ! DIGOXIN : Carvedilol can increase (in humans) digoxin plasma concentrations by approximately 15% T ! FLUOX ETINE, PAROX ETINE, QUINIDINE : M a y i n c r e a s e R ( + )-c a r v e-dilol concentrations and increase alpha-1 blocking effects (vasodilatio n) T ! INSULIN; ORAL ANTIDIABETIC AGENTS : Carvedilol may enhance the blood glucose lowering effects of insulin or other antidiabetic agents T ! RIFAMPIN : Can decrease carvedilol plasma concentrations by as much as 70%

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T ! RESERPINE : Drugs such as reserpine can cause increased bradycar-dia and hypotension in patients taking carvedilol Laboratory Considerations No specific laboratory interactions or considerations noted Doses T ! DOGS: a) A reasonable target plasma carvedilol concentration is 50-100 ng/m L. Based upon prior studies and the small series of dogs studied in this study, doses of 0. 5 mg/kg PO twice daily should result in beta-blockade, but maximum beta-blockade may require doses of >0. 7-0. 9 mg/kg. Because of bioavailability variations, plasma monitoring, clinical trials and uptitration protocols may be beneficial. (Gordon, Boothe et al. 2004) Monitoring T ! Clinical efficacy T ! Adverse effects T ! Plasma drug levels (see Doses above) Client Information T ! Give this medication exactly as veterinarian prescribes. Do not stop the medication without the approval and guidance of veterinarian T ! Contact veterinarian if animal's condition worsens while receiv-ing this medication, or if it shows signs of reduced appetite, fa-tigue or listlessness, and dizziness or unsteadiness T ! Medication is best given with food T ! Veterinarians should inform clients of the relative “investigation-al” nature of this medication in veterinary patients Chemistry/Synonyms A non-selective beta-adrenergic blocker with selective alpha1-adrenergic blocking activity, carvedilol occurs as a white to off-white crystalline powder that is practically insoluble in water, dilute acids, and gastric or intestinal fluids. It is sparingly soluble in ethanol. The compound exhibits polymorphism and contains both R(+) and S(-) enantiomers. It is a basic, lipophilic compound. Carvedilol may also be known as: BM-14190, carvedilolum, Cardilol®, Cardiol®, Carloc®, Carvil®, Carvipress®, Coreg ®, Coritensil®, Coropres®, Dilatrend®, Dilbloc®, Dimitone®, Divelol ®, Eucardic®, Hybridil®, Kredex®, or Querto®. Storage/Stability Carvedilol tablets and extended release capsules should be stored below 30°C (86°F) and protected from moisture. They should be dispensed in tight, light-resistant containers. An oral suspension with documented 90 day stability may be compound ed to accurately dose dogs (Gordon, Boothe et al. 2006). Powder 25 mg tablets and add enough de-ionized water to make a paste, allowing the tablet coating to dissolve. Then suspend in a commercially available simple syrup to a concentration of either 2 mg/m L or 10 mg/m L. Store in amber bottles at temperatures not exceeding 25°C and protect from light for up to 90 days. Shake well before administering. 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: Carvedilol Oral Tablets: 3. 125 mg, 6. 25 mg, 12. 5 mg, and 25 mg; Coreg® (Glaxo Smith Kline); (Rx) Carvedilol Extended-Release Capsules: 10 mg, 20 mg, 40 mg & 80 mg; Coreg CR ® (Glaxo Smith Kline); (Rx) CASPOFUNGIN ACETATE (kas-poe-fun-jin) Cancidas® PARENTERAL ANTIFUNGAL Prescriber Highlights TT Parenteral antifungal that has potential for treating inva-sive aspergillosis or disseminated candidal infections in companion animals TT Very limited clinical experience in veterinary medicine TT Very Expensive Uses/Indications Caspofungin has potential for treating invasive aspergillosis or dis-seminated candidal infections in companion animals although little, if any, information on its use in dogs or cats is available. Pharmacology/Actions Caspofungin represents the echinocandins, a new class of antifungal agent. These drugs inhibit beta-glucan synthase, thereby blocking the synthesis of beta-(1,3)-D-glucan, a component found in cell walls of filamentous fungi. Caspofungin has activity against Aspergillus and Candida species and is effective in treating pneumonia caused by Pneumocystis carinii. Because it contains very little beta-glucan syn-thase, Cryptococcus neoformans infec tions are not effectively treated with caspofungin. Pharmacokinetics No information was located on the pharmacokinetics of caspo-fungin in dogs or cats. In humans, the drug is not appreciably absorbed from the gut and must b e administered IV. Protein binding (primarily to albu-min) is high (97%) and the drug is distributed to tissues over a 36-48 hour pe riod. Caspofungin is slowly metabolized via hydro-lysis and N-acetylation. It also spontaneously degrades chemically. Caspofung in exhibits polyphasic elimination, but little drug is ex-creted or biotransformed during the first 30 hours post-administra-tion. Elimination half-life for the primary phase is about 10 hours; the seco ndary phase between 40-50 hours. Excretion, consisting mostly as metabolites, is via the feces and urine. Only small amounts (1-2%) are excreted unchanged into the urine. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. Caspofungin is contraindicated in human patients hypersensitive to it. Dosage adjustment is recommended in humans with moderate hepatic impairment. No information is available for use in patients with significant hepatic impairment; avoid use. Reproductive/Nursing Safety In humans, the FDA categorizes caspofungin 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. ) Studies with caspofungin performed in pregnant rats and rabbits

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Tdemonstrated changes in fetal ossification. The drug should be avoided during the first trimester of pregnancy unless the benefits associated with treating outweigh the risks. Although no data is available, because the drug is not apprecia-bly absorbed from the gut, it would be expected that caspofungin would be safe t o administer during lactation. Adverse Effects An adverse effect profile for animals has not been determined. In humans, caspofungin is generally well tolerated. Histamine-mediated signs have occurred (rash, facial swelling, pruritus) and anaphylaxis has been reported. Intravenous site reactions (pain, redness, phlebitis) have occurred. Hepatic dysfunction has been re-ported but frequency is unknown. Overdosage/Acute Toxicity Limited information is available. Dosages of 210 mg (about 3x) in humans were well tolerated. Some monkeys receiving 5-8 mg/kg (approx. 4-6X) over 5 weeks developed sites of microscopic sub-capsular necrosis on their livers. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving caspofungin and may be of significance in veterinary patients: T ! CARBAMAZEPINE : Reduced caspofungin plasma levels T ! CYCLOSPORINE : Increased caspofungin plasma levels and increased risk of hepatic enzyme increases T ! DEXAMETHASONE : Reduced caspofungin plasma levels T ! PHENYTOIN : Reduced caspofungin plasma levels T ! RIFAMPIN : Reduced caspofungin plasma levels Laboratory Considerations No specific concerns noted; see Monitoring Doses T ! DOGS /CATS: No published doses for dogs or cats were located and the use of this medication in these patients must be considered highly investigational. Although not labeled for use in human pediat-ric patients, one study performed in immunocompromised hu-man pediatric patients administered doses of 0. 8-1. 6 mg/kg in patients weighing less than 50 kg and 50-75 mg (total dose) in those weighing more than 50 kg. The drug was well tolerated in both groups. Monitoring T ! Clinical efficacy T ! Periodic liver function tests, CBC, serum electrolytes Client Information T ! his medication is appropriate for inpatient use only T ! Clients should understand the investigational nature and the as-sociated expense of using this drug on veterinary patients Chemistry/Synonyms Caspofungin acetate is a semisynthetic echinocandin compound produced from a fermentation product of Glarea lozoyensis. It oc-curs as a white to off-white powder that is freely soluble in water and slightly sol uble in ethanol. The commercially available lyophilized powder for injection also contains acetic acid, sodium hydroxide, mannitol and sucrose. Caspofungin may also be known as: caspofungina, caspofungine, caspofungini, kaspofungiinia, kaspofungina, L-743873, MK-0991, or Cancidas®. Storage/Stability/Compatibility The commercially available product should be stored refrigerated (2-8°C). Refer to the package insert for very specific directions on preparing the solution for intravenous use. Do not use if the solution is cloudy or has precipitated. It is rec-ommended not to mix or infuse with any other medications and not to use with intr avenous solutions containing dextrose. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Caspofungin Acetate Powder for Injection: 50 mg, & 70 mg in sin-gle-use vials; Cancidas® (Merck); (Rx) CEFACLOR (sef-a-klor) Ceclor® ORAL 2nd GENERATION CEPHALOSPORIN Prescriber Highlights TT Oral 2nd generation cephalosporin that is more active against some gram-negative bacteria then first genera-tion (e. g., cephalexin) cephalosporins TT Potentially useful when an oral cephalosporin is desired to treat bacterial infections that are susceptible to cefa-clor, but resistant to first generation cephalosporins TT Limited clinical experience in veterinary medicine TT Adverse effects most likely seen in small animals would be GI-related Uses/Indications Cefaclor may potentially be useful when an oral cephalosporin is desired to treat infections that are susceptible to it but resistant to first generation cephalosporins such as cephalexin or cefadroxil. Little information is available with regard to its clinical use in small animals, however. Pharmacology/Actions Cefaclor, like other cephalosporins, is bactericidal and acts via in-hibiting cell wall synthesis. Its spectrum of activity is similar to that of ce phalexin, but it is more active against gram-negative bacteria including strains of E. coli, Klebsiella pneumoniae, and Proteus mira-bilis. For more information on cephalosporin pharmacology and spect rums of activity, refer to the Cephalosporin monograph. Pharmacokinetics Limited information is available on the pharmacokinetics of cefa-clor in dogs and none was located for cats. In dogs, about 75% of an oral dose is absorbed, but an apparent first-pass effect reduces bioavailability to about 60%. Cefaclor is distributed to many tis-sues, but levels are lower in interstitial fluid than those found in serum. V ery high levels are excreted into the urine unchanged. Bile levels are higher than those found in serum. Dogs appear to metab-olize a greater percentage of cefaclor than do rats, mice, or humans. Appr oximate elimination half-life is about 2 hours in dogs. In humans, cefaclor is well absorbed after oral administration; food delays, but does not appreciably alter the amount absorbed. The drug is widely distributed, crosses the placenta and enters breast milk. Up to 85% of a dose is excreted unchanged into the

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urine; elimination half-life is less than 1 hour in patients with nor-mal renal function. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. Cefaclor is contraindicated in human patients hypersensitive to it and must be cautiously used in patients with penicillin-allergy. Dosage adjust-ment is recommended in humans with severe renal impairment. Reproductive/Nursing Safety In humans, the FDA categorizes cefaclor 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. ) Studies performed in pregnant rats (doses up 12X human dose) and ferrets (doses up to 3X human dose) demonstrated no overt fetal harm. Cefaclor enters maternal milk in low concentrations. Although pr obably safe for nursing offspring the potential for adverse effects cannot be ruled out, particularly, alterations to gut flora with resul-tant diarrhea. Adverse Effects As usage of cefaclor in animals has been very limited, a comprehen-sive adverse effect profile has not been determined. In humans, cefa-clor is generally well tolerated but commonly can cause gastrointes-tinal effects (nausea, diarrhea). Hypersensitivity reactions including anaph ylaxis are possible; cefaclor appears to cause a higher incidence of serum-sickness-like reactions than other cephalosporins, particu-larly in children who have received multiple courses of treatment. Rar e adverse effects reported include erythema multiforme, rash, increases in liver function tests, and transient increases in BUN and serum creatinine. Overdosage/Acute Toxicity Cefaclor appears quite safe in dogs. Dogs given daily PO doses of 200 mg/kg/day for 30 days developed soft stools and occasional emesis. Two dogs in this study group developed transient moderate decreases in hemoglobin. One dog in another study group that was given 400 mg/kg/day for one year developed a reversible thrombocytopenia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefaclor and may be of significance in veterinary patients: !TANTACIDS (magnesium-or aluminum-containing ): Reduces extent of absorption of extended-release cefaclor tablets !!PROBENECID : Reduced renal excretion of cefaclor !!WARFARIN : Rare reports of increased anticoagulant effect Laboratory Considerations !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using the copper reduction method (Benedict's solution, Fehling's solution, Clinitest ®); tests utilizing glucose oxidase (Tes-Tape ®, Clinistix ®) are not affected by cephalosporins !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) given in high dos-ages may cause falsely elevated values !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine Doses !TDOGS /CATS: For susceptible infections: a) For skin or soft tissue infections: 7 mg/kg PO q8h for 21-30 days. Fo r systemic, lower respiratory tract infections: 10-13 mg/kg PO q8h for 14 days. Maximum daily dose is 1 gram. (Greene, Hartmannn et al. 2006) Monitoring !TClinical efficacy !TPatients with renal insufficiency should have renal function mon-itored Client Information !TPreferably should be administered to animal without food; how-ever, if patient vomits or develops a lack of appetite while receiv-ing medication it can be administered with food !TGive as directed by the veterinarian; even if animal appears well, continue treating for the full duration prescribed !TContact veterinarian if animal develops severe vomiting/diarrhea or rash/itching Chemistry/Synonyms Cefaclor occurs as a white to off-white powder that is slightly soluble in water. Cefaclor may also be known as: cefaclorum, cefaklor, cefkloras, ke fakloori or compound 99638. There are many internationally reg-istered trade names. Storage/Stability Capsules, tablets, and powder for suspension should be stored at room temperature (15-30°C). After reconstituting, the oral sus-pension should be stored in the refrigerator and discarded after 14 day s. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefaclor Capsules: 250 mg, & 500 mg; Ceclor® (Lilly), generic; (Rx) Cefaclor Chewable Tablets: 125 mg, 187 mg, 250 mg, & 375 mg; Ra-niclor® (Ranbaxy); (Rx) Cefaclor Extended-Release Tablets: 375 mg, & 500 mg; generic; (Rx) Cefaclor Powder for Oral Suspension: 125 mg/5 m L, 187 mg/5 m L, 250 mg/5 m L, & 375 mg/5 m L; generic; (Rx)

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CEFADROXIL (sef-a-drox-ill) Cefa-Drops®, Duricef® ORAL 1st-GENERATION CEPHALOSPORIN Prescriber Highlights TT Oral 1st generation cephalosporin TT May be administered with food (especially if GI upset occurs) TT Most likely adverse effects are GI in nature TT May need to reduce dose in renal failure TT May be expensive when compared to generic cephalexin Uses/Indications Cefadroxil is approved for oral therapy in treating susceptible infec-tions of the skin, soft tissue, and genitourinary tract in dogs and cats. The v eterinary oral tablets have been discontinued (in the USA), but human-labeled oral capsules and tablets are still available. Pharmacology/Actions A first generation cephalosporin, cefadroxil exhibits activity against the bacteria usually covered by this class. First generation cepha-losporins are usually bactericidal and act via inhibition of cell wall synthesis. While there may be differences in MIC's for individual first gen-eration cephalosporins, their spectrums of activity are quite similar. They g enerally possess excellent coverage against most gram-posi-tive pathogens; variable to poor coverage against most gram-neg-ative pathogens. These drugs are very active in vitr o against groups A beta-hemolytic and B Streptococci, non-enterococcal group D Streptococci (S. bovis), Staphylococcus intermedius and au-reas, Proteus mirabilis and some strains of E. coli, Klebsiella spp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most anaer-obes are very susceptible to the first generation agents. Most spe-cies of Corynebacteria are susceptible, but C. equi (Rho dococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally administered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the 1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-positi ve Proteus spp., Pseudomonas spp., Enterobacter spp., Serratia spp. and Citrobacter spp. Pharmacokinetics Cefadroxil is reportedly well absorbed after oral administration to dogs without regard to feeding state. After an oral dose of 22 mg/ kg, peak serum levels of approximately 18. 6 micrograms/m L occur within 1-2 hours of dosing. Only about 20% of the drug is bound to canine plasma proteins. The drug is excreted into the urine and has a half-life of about 2 hours. Over 50% of a dose can be recov-ered unchanged in the urine within 24 hours of dosing. In cats, the serum half-life has been reported as approximately 3 hours. Oral abso rption of cefadroxil in adult horses after oral suspen-sion was administered was characterized as poor and erratic. In a study d one in foals (Duffee, Christensen, and Craig 1989), oral bio-availability ranged from 36-99. 8% (mean=58. 2%); mean elimina-tion half-life was 3. 75 hours after oral dosing. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Oral systemic antibiotics should not be administered in patients with sep ticemia, shock or other grave illnesses as absorption of the medication from the GI tract may be significantly delayed or diminished. Parenteral routes (preferably IV) should be used for these cases. Adverse Effects Adverse effects with the cephalosporins 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 r ashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class an-tibiotics is controversial. In humans, it is estimated that up to 15% of patie nts hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary patients is unknown. When given orally, cephalosporins may cause GI effects (anorex-ia, vomiting, diarrhea). Administering the drug with a small meal may help alleviate these effects. Because the cephalosporins may al-ter gut flora, antibiotic-associated diarrhea can occur and allow the prolife ration of resistant bacteria in the colon (superinfections). While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with nor mal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use of cephalosporins have been associated with neurotoxicity, neutropenia, agranulocytosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as categ ory 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. ) Cephalosporins can be distributed into milk, but are unlikely to pose much r isk to nursing offspring; diarrhea is possible. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefadroxil and may be of significance in veterinary patients: T ! PROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives

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Laboratory Considerations T ! Except for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins T ! When using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values T ! In humans, particularly with azotemia, cephalosporins have caused a false-positive direct Combs' test T ! Cephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine Doses-T ! DOGS: For susceptible infections: a) 22 mg/kg PO twice daily. Treat skin and soft tissue infections for at least 3 days, and GU infections for at least 7 days. Treat for at least 48 hours after animal is afebrile and asymptomatic. Reevaluate therapy if no response after 3 days of treatment. Maximum therapy is 30 days. (Package Insert; Cefa-Tabs® — Fort-Dodge). b) For susceptible Staph infections: 30 mg/kg PO q12h (may not be ad equate dose for non-UTI's caused by E. coli) (Campbell and Rosin 1998) c) For UTI: 11-22 mg/kg PO q12h for 7-30 days Fo r skin, pyoderma: 22-35 mg/kg PO q12h for 3-30 days For systemic, orthopedic infections: 22 mg/kg PO q8-12h for 30 days (Greene and Watson 1998) d) 10 mg/kg q12h for susceptible Gram+ infections; 30 mg/kg q8h for susc eptible Gram-infections (Aucoin 2000) e) For canine pyoderma/infectious otitis: 22 mg/kg PO q12h (Kwoc hka 2003c); (Kwochka 2002) f) For UTI: 10-20 mg/kg PO q8h. For acute urethrocystitis, treatme nt may be 7-10 days; for chronic urethrocystitis, up to 4 weeks of treatment may be necessary; for pyelonephritis, 4-8 weeks may be adequate (Brovida 2003) g) For superficial and deep bacterial pyoderma: 22-33 mg/kg PO 2-3 times daily (Beale and M urphy 2006) T ! CATS: For susceptible infections: a) For UTI: 22 mg/kg PO once daily for 21 days or less For skin, p yoderma: 22-35 mg/kg PO q12h for 3-30 days For systemic, orthopedic infections: 22 mg/kg PO q8-12h for 30 days (Greene and Watson 1998) b) 10 mg/kg q12h for susceptible gram-positive infections; 30 mg/kg q8h fo r susceptible gram-negative infections (Aucoin 2000) c) 22 mg/kg PO q12h (Lappin 2002a) T ! FERRETS: For susceptible infections: a) 15-20 mg/kg PO twice daily (Williams 2000) Monitoring T ! Because cephalosporins usually have minimal toxicity associ-ated with their use, monitoring for efficacy is usually all that is requir ed. T ! Patients with diminished renal function may require intensified renal monitoring. Serum levels and therapeutic drug monitoring are not routinely performed with these agents. Chemistry/Synonyms A semisynthetic cephalosporin antibiotic, cefadroxil occurs as a white to yellowish-white, crystalline powder that is soluble in water and slightly soluble in alcohol. The commercially available product is available as the monohydrate. Cefadroxil may also be known as: BL-S578; cefadroxilum, ceph-adroxil, or MJF-11567-3; many trade names are available. Storage/Stability/Compatibility Cefadroxil tablets, capsules and powder for oral suspension should be stored at room temperature (15-30°C) in tight containers. After reconstitution, the oral suspension is stable for 14 days when kept refrigerated (2-8°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cefadroxil Powder for Oral Suspension: 50 mg/m L in 15 m L and 50 m L btls (orange-pineapple flavor); Cefa-Drops® (Fort-Dodge) (Rx). Approved for use in dogs and cats. HUMAN-LABELED PRODUCTS: Cefadroxil Oral Tablets: 1 gram; Duricef® (Bristol-Myers Squibb); generic; (Rx) Cefadroxil Oral Capsules: 500 mg; Duricef® (Bristol-Myers Squibb); gener ic; (Rx) Cefadroxil Powder for Oral Suspension: 125 mg/5 m L, 250 mg/5 m L, & 500 mg/5 m L in 50 m L, 75 m L and 100 m L; Duricef® (Bristol-Myers Squibb); (Rx) CEFAZOLIN SODIUM (sef-a-zoe-lin) Ancef®, Kefzol®, Zolicef® 1st GENERATION CEPHALOSPORIN Prescriber Highlights TT 1st generation parenteral cephalosporin TT Potentially could cause hypersensitivity reactions TT Can cause pain on IM injection; Give IV over 3-5 minutes (or more) TT May need to reduce dose in renal failure Uses/Indications In the United States, there are no cefazolin products approved for veterinary species but it has been used clinically in several species when an injectable, first generation cephalosporin is indicated. It is used for surgical prophylaxis, and for variety of systemic infections (including orthopedic, soft tissue, sepsis) caused by susceptible bac-teria. Most commonly given every 6-8 hours v ia parenteral routes, cefazolin constant rate intravenous infusion protocols are being developed as cefazolin is a time (above MIC)-dependent antibiotic, and serum/tissue concentrations can remain above MIC. Pharmacology/Actions A first generation cephalosporin, cefazolin exhibits activity against the bacteria usually covered by this class. First generation cepha-losporins are usually bactericidal and act via inhibition of cell wall synthesis.

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While there may be differences in MIC's for individual first generation cephalosporins, their spectrums of activity are quite similar. They possess generally excellent coverage against most gram-positive pathogens; variable to poor coverage against most gram-negative pathogens. These drugs are very active in vitro against groups A beta-hemolytic and B Streptococci, non-entero-coccal group D Streptococci (S. bovis), Staph ylococcus intermedius and aureas, Proteus mirabilis and some strains of E. coli, Klebsiella spp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most an-aerobes are very susceptible to the first generation agents. Most spe-cies of Corynebacteria are susceptible, but C. equi (R hodococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally administered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the 1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-p ositive Proteus spp., Pseudomonas spp., Enterobacter spp., Serratia spp. and Citrobacter spp. Pharmacokinetics Cefazolin is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum levels. Absorbed drug is excreted unchanged by the kidneys into the urine. Elimination half-lives may be significantly prolonged in patients with severely diminished renal function. In dogs, peak levels occur in about 30 minutes after IM admin-istration. The apparent volume of distribution at steady state is 700 m L/kg, total body clearance of 10. 4 m L/min/kg with a serum elimi-nation half-life of 48 minutes. Approximately 64% of the clearance can b e attributed to renal tubular secretion. The drug is approxi-mately 16-28% bound t o plasma proteins in dogs. In horses, the apparent volume of distribution at steady state is 190 m L/kg, total body clearance of 5. 51 m L/min/kg with a se-rum elimination half-life of 38 minutes when given IV and 84 min-utes after IM injection (gluteal muscles). Cefazolin is about 4-8% bound to equine plasma proteins. Because of the significant tubular secretion of the drug, it would be expected that probenecid admin-istration would alter the kinetics of cefazolin. One study performed in ho rses (Donecker, Sams, and Ashcroft 1986), did not show any effect, but the authors concluded that the dosage of probenecid may have been sub-therapeutic in this species. In calves, the volume of distribution is 165 m L/kg, and had a t erminal elimination half-life of 49-99 minutes after IM administration. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these age nts and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in pat ients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when adminis-tered intramuscularly, although this effect occurs less with cefazolin than w ith other agents. Sterile abscesses or other severe local tissue reactions are possible but are much less common. Thrombophlebitis is also possible after IV administration of these drugs. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocytosis, thrombocytopenia, hepa-titis, positive Comb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an imm unologic component. Cefazolin may be more likely than other cephalosporins to cause seizures at very high doses. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as cat egory 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. ) Cefazolin is distributed into milk and could potentially alter neo natal gut flora. Use with caution in nursing dams. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems, but other effects are possible (see Adverse Effects section). Very high doses given IV rapidly could potentially cause seizures. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefazolin and may be of significance in veterinary patients: !TNEPHROTOXIC D RUGS : The concurrent use of parenteral amino-glycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, ce-phalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu-mented with cephaloridine (no longer marketed). Nevertheless, use caut ion. !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. Laboratory Considerations !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine.

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Doses Note : If injecting IM, must be injected into a large muscle mass. IV injections should not be given faster than over 3-5 minutes. !TDOGS: For susceptible infections: a) For surgical prophylaxis: Orthopedic procedures: 20 mg/kg IV at induction followed by 20 mg/kg IV every 90 minutes until wound closure; Soft tissue surgery: 20 mg/kg IV at time of surgery followed by a second dose of 20 mg/kg SC 6 hours later (Trepanier 2003) b) Gram+ infections: 10 mg/kg IV, or IM q8h; 10-30 mg/kg IV q8h Gr am-infections: 30 mg/kg IM or SC; 10-30 mg/kg IV q8h (Aucoin 2000) c) For sepsis: 20-25 mg/kg IV q4-8h (Har die 2000) d) For surgical prophylaxis: 8 mg/kg IV just before and during surg ery 1 hour apart or 20-22 mg/kg IV just before and dur-ing surgery 2 hours apart. For systemic infections: 5-25 mg/kg IM or IV q6-8h as long as necessary. Fo r orthopedic infections: 22 mg/kg IV, IM or SC q6-8h for 7 days or less. For sepsis, bacteremia: 15-25 mg/kg IV, IM or SC q4-8h f or 7 days or less (Greene and Watson 1998) e) For infections in neonates: 10-30 mg/kg IV or IO (in-traosseous) q8h (Kampschmidt 2006) !TCATS: For susceptible infections: a) Gram+ infections: 10 mg/kg IV, or IM q8h; 10-30 mg/kg IV q8h Gr am-infections: 30 mg/kg IM or SC; 10-30 mg/kg IV q8h (Aucoin 2000) b) For surgical prophylaxis: Orthopedic procedures: 20 mg/kg IV at induction followed by 20 mg/kg IV every 90 minutes until wound closure; Soft tissue surgery: 20 mg/kg IV at time of surgery followed by a second dose of 20 mg/kg SC 6 hours later (Trepanier 2003) c) For sepsis: 20-25 mg/kg IV q4-8h (Har die 2000) d) For systemic infections: 33 mg/kg IV, or IM q8-12h as long as necessary (Greene and Watson 1998) e) 20-25 mg/kg q8h IM or IV (Lappin 2002a) f) For infections in neonates: 10-30 mg/kg IV or IO (in-traosseous) q8h (Kampschmidt 2006) !THORSES: For susceptible infections: a) 25 mg/kg IV, IM q6h (Bertone 2003b) b) 25 mg/kg IV, IM q6-8h (Papic h 2003a) c) Foals: 20 mg/kg IV q8-12h (C aprile and Short 1987); (Brum-baugh 1999) d) Neonatal foals: 15-20 mg/kg IV q8h (Magdesian 2003) !TREPTILES: For susceptible infections: a) Chelonians: 22 mg/kg IM q24h (Johnson 2002) Monitoring !TBecause cephalosporins usually have minimal toxicity associ-ated with their use, monitoring for efficacy is usually all that is required. !TPatients with diminished renal function may require intensified renal monitoring. Serum levels and therapeutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms An injectable, semi-synthetic cephalosporin antibiotic, cefazolin so-dium occurs as a practically odorless or having a faint odor, white to off-w hite, crystalline powder or lyophilized solid. It is freely soluble in water and very slightly soluble in alcohol. Each gram of the injec-tion contains 2 m Eq of sodium. After reconstitution, the solution for injec tion has a p H of 4. 5-6 and has a light-yellow to yellow color. Cefazolin sodium may also be known as: 46083, cefazolinum na-tricum, cephazolin sodium, or SKF-41558; many trade names are av ailable. Storage/Stability/Compatibility Cefazolin sodium powder for injection and solutions for injection should be protected from light. The powder for injection should be stored at room temperature (15-30°C); avoid temperatures above 40°C. The frozen solution for injection should be stored at tempera-tures no higher than-20°C. After reconstitution, the solution is stable for 24 hours when kept at r oom temperature; 96 hours if refrigerated. If after reconstitu-tion, the solution is immediately frozen in the original container, the pr eparation is stable for at least 12 weeks when stored at-20°C. The following drugs or solutions are reportedly compatible with cephapirin: Amino acids 4. 25%/dextrose 25%, D 5W in Ringer's, D5W in Lactated Ringer's, D 5W in sodium chloride 0. 2%-0. 9%, D5W, D10W, Ringer's Injection, Lactated Ringer's Injection, normal saline, me tronidazole, verapamil HCl and vitamin B-complex. The following drugs or solutions are reportedly incompatible or only compatible in specific situations with cefazolin: amikacin sul-fate, amobarbital sodium, ascorbic acid injection, bleomycin sul-fate, calcium chloride/gluconate, cimetidine HCl, erythromycin gl uceptate, kanamycin sulfate, lidocaine HCl, oxytetracycline HCl, pentobarbital sodium, polymyxin B sulfate, tetracycline HCl and vi-tamin B-complex with C injection. Compatibility is dependent upon factors such as p H, concentra-tion, temperature and diluent used; consult specialized references or a hospital phar macist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefazolin Sodium Powder for Injection: 500 mg, 1g, 5g, 10g, and 20g; generic (Apothecon); (Rx) Cefazolin Sodium for Injection (IV infusion): 500 mg, 1 g; in 50 m L plastic c ontainers, or duplex bags, Ancef® (SKB); generic; (Rx)

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CEFEPIME HCL (sef-eh-pim) Maxipime® 4th GENERATION CEPHALOSPORIN Prescriber Highlights TT Injectable 4th generation cephalosporin that is more active against some gram-negative & gram-positive bac-teria than 3rd generation cephalosporins TT Potentially useful for treating neonatal foals & dogs with serious infections TT Limited clinical experience in veterinary medicine TT Adverse effects most likely seen in small animals or foals would be GI-related (diarrhea) TT Treatment may be very expensive Uses/Indications Cefepime is a semi-synthetic 4th generation cephalosporin with enhanced activity against many gram-negative and gram-positive pathogens. It potentially may be useful in treating serious infections in dogs or foals particularly when aminoglycosides, fluoroquinolo-nes or other more commonly used beta-lactam drugs are ineffective or cont raindicated. Pharmacology/Actions Cefepime, like other cephalosporins, is usually bactericidal and acts by inhibiting cell wall synthesis. It is classified as a 4th-generation cephalosporin, implying increased gram-negative activity (particu-larly against Pseudomonas ) and better activity against many gram-positive bacteria than would be seen with the 3rd generation agents. It rapidly penetrates into gram-negative bacteria and targets pen-icillin-binding proteins (PBPs). Cefepime does not readily induce beta-lactamases and is highly resistant to hydrolysis by them. Cefepime has activity against many gram-positive aerobes in-cluding many species and strains of Staphylococci and Streptococci. It is not clinically effective in treating infections caused by entero-cocci, L. monocytog enes, or methicillin-resistant staphylococci. Cefepime has good activity against many gram-negative bacte-ria and has better activity than other cephalosporins against many Entero bacteriaceae including Enterobacter spp., E. coli, Proteus spp. and Klebsiella. Its activity against Pseudomonas is similar to, or slightly less than, that of ceftazidime. Cefepime also has activity against certain atypicals like Myco bacterium avium-intracellulare complex. Some anaerobes are sensitive to cefepime, but Clostridia and Bac teroides are not. For more information on cephalosporin pharmacology and spect rums of activity, refer to the Cephalosporin monograph. Pharmacokinetics Cefepime is not absorbed from the GI tract and must be admin-istered parenterally. In dogs, cefepime's volume of distribution at steady state is approximately 0. 14 L/kg, elimination half-life about 1. 1 hours and clearance 0. 13 L/kg/hr. In neonatal foals, cefepime's volume of distribution at steady state is ap proximately 0. 18 L/kg, elimination half-life about 1. 65 hours and clearance 0. 08 L/kg/hr. In humans, volume of distribution is about 18 L in adults; 20% of the dr ug is bound to plasma proteins. Elimination half-life is about 2 hours. Approximately 85% of a dose is excreted unchanged into the urine, less than 1% is me tabolized. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. Cefepime is contraindicated in human patients hypersensitive to it or other cephalosporins. Dosage adjustment is recommended in humans with severe renal impairment. Adverse Effects As usage of cefepime in animals has been very limited, a compre-hensive adverse effect profile has not been determined. There are some reports of dogs or foals developing loose stools or diarr hea after receiving cefepime. IM injections may be painful (alleviated by using 1% lidocaine as diluent). Human patients generally tolerate cefepime well. Injection site inflammation and rashes occur in approximately 1% of treated patients. Gastrointestinal effects (dyspepsia, diarrhea) occur in less than 1% treated patients. Hypersensitivity reactions including ana-phylaxis are possible. Rarely, patients with renal dysfunction who have r eceived cefepime without any dosage adjustment will develop neurologic effects (see Overdosage). Reproductive/Nursing Safety Studies performed in pregnant mice, rats, and rabbits demonstrat-ed no overt fetal harm. In humans, the FDA categorizes cefepime as categ ory 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. ) Cefepime enters maternal milk in very low concentrations. Although p robably safe for nursing offspring, the potential for ad-verse effects cannot be ruled out, particularly alterations to gut flora with resultant diar rhea. Overdosage/Acute Toxicity No specific information was located for acute toxicity in veterinary patients. Humans with impaired renal function receiving inadvertent over doses have developed encephalopathy, seizures and neuromus-cular excitability. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefepime and may be of significance in veterinary patients: T ! AMINOGLYCOSIDES : Potential for increased risk of nephrotoxicity— monitor renal function Laboratory Considerations T ! Cefepime may cause false-positive urine glucose determinations when using the copper reduction method (Benedict's solution, Fehling's solution, Clinitest ®); tests utilizing glucose oxidase (Tes-Tape ®, Clinistix ®) are not affected by cephalosporins T ! In humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test Doses T ! DOGS: For susceptible infections: a) 40 mg/kg IV q6h (Gardner and Papich 2001)

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T ! HORSES: Uses/Indications Uses for cefixime are limited in veterinary medicine. Its use should For susceptible infections in foals: be reserved for those times when infections (systemic or urinary Papich 2001) a) 11 mg/kg IV q8h; for gram-negative infections (Gardner and tract) are caused by susceptible gram-negative organisms where oral t reatment is indicated or when approved fluoroquinolones or b) 11 mg/kg IV q8h; use has been limited primarily to neonates other 3rd generation cephalosporins (e. g., cefpodoxime) are either with poor aminoglycoside kinetics or documented multi-re-contraindicated or ineffective. sistant infections (Mc Kenzie 2005) Pharmacology/Actions Monitoring Like other cephalosporins, cefixime inhibits bacteria cell wall syn-T ! Clinical efficacy thesis. It is considered bactericidal and relatively resistant to bacte-T ! Monitor renal function in patients with renal insufficiency rial beta-lactamases. Client Information Cefixime's main spectrum of activity is against gram-negative T ! Veterinary professionals only should administer this medication bacteria in the family Enterobacteriaceae (excluding Pseudomonas) including Escherichia, Proteus, and Klebsiella. It is efficacious against T ! Because of the dosing intervals required, this drug is best admin-Streptococcus, Rhodococcus, and apparently, Borrelia. Efficacy for istered to inpatients only E. coli is rapidly decreasing as significant resistance has developed Chemistry/Synonyms in recent years. Cefepime HCl occurs as a white to off-white, non-hygroscopic pow-Cefixime is not efficacious against Pseudomonas aeruginosa, der that is freely soluble in water. Enter o coccus, Staphylococcus, Bordetella, Listeria, Enterobacter, Cefepime may also be known as: BMY-28142, cefepimi, or Bact eroides, Actinomyces or Clostridium. For other than Streptococ-cefepima; internationally registered trade names include: Axepime®, cus spp., it has limited efficacy against many gram-positive organ-Biopime®, Cefepen ®, Ceficad®, Cemax®, Cepim®, Cepimix®, Forpar®, isms or anaerobes. Maxcef®, Maxipime® or Maxil®. Because sensitivity of various bacteria to the 3rd generation ce-phalosporin antibiotics is unique to a given agent, cefixime specific Storage/Stability/Compatibility disks or dilutions must be used to determine susceptibility. The powder for injection should be stored between (2-25°C) and prot ected from light. Cefepime can be reconstituted and adminis-Pharmacokinetics tered with a variety of diluents including normal saline and D5W. Cefixime is relatively rapidly absorbed after oral administration. Generally, the solution is stable for up 24 hours at room tempera-Bioavailability in the dog is about 50%. Food may impede the rate, ture; up to 7 days if kept refrigerated. but not the extent, of absorption. The suspension may have a higher Drugs that may be admixed with cefepime include: amikacin (but bioav ailability than tablets. The drug is fairly highly bound to plas-not gentamicin or tobramycin), ampicillin, vancomycin, metronida-ma prot eins in the dog (about 90%). It is unknown if the drug pen-zole and clindamycin. These admixtures have varying times that they etrat es into the CSF. remain stable. For more information on dosage preparation, stabil-Elimination of cefixime is by both renal and non-renal means, ity and compatibility, refer to the package insert for Maxipime®. but serum half-lives are prolonged in patients with decreased renal function. In dogs, elimination half-life is about 7 hours. Dosage Forms/Regulatory Status Contraindications/Precautions/Warnings VETERINARY-LABELED PRODUCTS: None Cefixime is contraindicated in patients hypersensitive to it or other HUMAN-LABELED PRODUCTS: cephalosporins. Because cefixime is excreted by the kidneys dosages Cefepime Powder for Injection: 500 mg, 1 gram, & 2 gram; Maxip-and/or dosage frequency may need to be adjusted in patients with ime® (Elan); (Rx) significantly diminished renal function. Use with caution in patients with seizur e diso rders and patients allergic to penicillins. Adverse Effects CEFIXIME Adverse effects in the dog may include GI distress (vomiting, etc. ) and hypersensitivity reactions (urticaria and pruritus, possibly (sef-ix-eem) Suprax® fever). 3rd GENERATION CEPHALOSPORIN Reproductive/Nursing Safety Cefixime has not been shown to be teratogenic, but should only Prescriber Highlights be used during pregnancy when clearly indicated. In humans, the TT Oral 3rd generation cephalosporin that may be useful in FDA categorizes this drug as category B for use during pregnancy dogs; only available commercially (in the USA) as a pedi-(Animal studies have not yet demonstrated risk to the fetus, but there atric oral suspension are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have TT Contraindications: Hypersensitivity to it or other cepha-not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) losporins TT May need to adjust dose if patient has renal disease TT Adverse Effects: Primarily GI, but hypersensitivity possible Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems, but other effects are possible (see Adverse Effects section).

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Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefixime and may be of significance in veterinary patients: T ! PROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives T ! SALICYLATES : May displace cefixime from plasma protein binding sites; clinical significance is unclear Laboratory Considerations T ! Cefixime may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix® ) are not affected by cephalosporins. T ! If using the nitroprusside test for determining urinary ketones, ce-fixime may cause false-positive results. Doses T ! DOGS: For susceptible infections: a) For infectious endocarditis when documented resistance against or other contraindications for fluoroquinolones and aminoglycosides: 10 mg/kg PO q12h (De Francesco 2000) b) For UTI: 5 mg/kg PO once to twice daily for 7-14 days Fo r respiratory, systemic infections: 12. 5 mg/kg PO q12h for 7-14 days (Gr eene and Watson 1998) c) 5 mg/kg PO once to twice a day (Boothe 1999) T ! CATS: For susceptible infections: a) 5-12. 5 mg/kg PO q12h (Lappin 2002a) Monitoring T ! Efficacy T ! Adverse effects Client Information T ! Can be given without regard to meals T ! Give as directed for as long as veterinarian recommends, even if patient appears well Chemistry/Synonyms An oral 3rd generation semisynthetic cephalosporin antibiotic, ce-fixime is available commercially as the trihydrate. Cefixime occurs as a whit e to slightly yellowish white crystalline powder with a char-acteristic odor and a p Ka of 3. 73. Solubility in water is p H depen-dent. At a p H of 3. 2, 0. 5 mg/m L is soluble and 18 mg/m L at p H 4. 2. The or al suspension is strawberry flavored and after reconstitution has p H of 2. 5-4. 2. Cefixime may also be known as: cefiximum, CL-284635, FK-027, FR-17027 and Sup rax®; many internationally registered trade names are available. Storage/Stability Cefixime powder for suspension should be stored at room tempera-ture in tight containers. After reconstitution of the oral suspension, refrig eration is not required, but it should be discarded after 14 days whether refrigerated or not. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Powder for Oral Suspension: 100 mg/5 m L in 50 m L, & 75 m L; Su-prax® (Lupin Pharma); (Rx) CEFOPERAZONE SODIUM (sef-oh-per-a-zone) Cefobid® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT 3rd generation parenteral cephalosporin; has reasonably good activity against Pseudomonas aeruginosa TT Potentially could cause hypersensitivity reactions, throm-bocytopenia, Vitamin K deficiency/bleeding, or diarrhea TT Causes pain on IM injection; give IV over 15-30 minutes (or more) TT May need to reduce dose in hepatic failure or consider other drugs Uses/Indications Cefoperazone is used to treat serious infections, particularly sus-ceptible Enterobacteriaceae not susceptible to other less expensive agents o r when aminoglycosides are not indicated (due to their po-tential toxicity). Pharmacology/Actions Cefoperazone is a third generation injectable cephalosporin agent and, like other cephalosporins, it inhibits bacteria cell wall synthe-sis. Cefoperazone is considered bactericidal and relatively resistant to bac terial beta-lactamases. The third generation cephalosporins retain much of the gram-positive activity of the first and second-generation agents, but in comparison, have much expanded gram-negative activity. As with the 2nd generation agents, enough vari-ability exists with individual bacterial sensitivities that susceptibility testing is necessary for most bacteria. Usually only ceftazidime and cefoperazone are active against most strains of Pseudomonas aeruginosa. Pharmacokinetics Cefoperazone is not absorbed after oral administration and must be given parenterally. It is widely distributed throughout the body; CSF levels are low if meninges are not inflamed. Cefoperazone crosses the placenta and enters maternal milk in low concentra-tions; no documented adverse effects to offspring have been noted. Unlike most cephalosporins, cefoperazone is principally excreted in the bile; elimination half-lives are approximately 2 hours in hu-mans. Dosage adjustments generally are not required for patients with renal ins ufficiency. In dogs, cefoperazone has a volume of distribution of 0. 233 L/kg and a clear ance of 2 m L/kg/minute. IM bioavailability is only about 40%. Elimination half-life is approximately 2. 1 hours in the dog. Contraindications/Precautions/Warnings Only prior allergic reaction to cephalosporins contraindicates ce-foperazone's use. In humans documented hypersensitive to peni-cillin, up to 16% may also be allergic to cephalosporins; the veteri-nary significance of this is unclear. Because cefoperazone is excreted in the bile, patients with significant hepatic disease or biliary ob-

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struction may have their serum half-lives increase 2-4 times above normal; dosage adjustment may be necessary. Cefoperazone should be used with caution in patients with preexisting bleeding disorders. It contains a thiomethyltetrazole side-chain that has been associated with causing coagulation abnormalities. Adverse Effects Cefoperazone is a relatively safe agent. Rarely, hypersensitivity reac-tions could occur in animals. Because of its thiomethyltetrazole side-c hain, it may rarely cause hypoprothrombinemia. Diarrhea, secondary to changes in gut flora, has been reported. Some human patients demonstrate mild, transient increases in liver enzymes, se-rum creatinine and BUN. Clinical significance of these effects is in doub t. If administered via the IM route, pain at the injection site has also been noted. Reproductive/Nursing Safety No teratogenic effects were demonstrated in studies in pregnant mice, rats, and monkeys given up to 10X labeled doses of cefopera-zone. In humans, the FDA categorizes cefoperazone as category B fo r 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. ) Although cefoperazone may enter milk, it is unlikely to pose muc h risk to nursing offspring. Overdosage/Acute Toxicity No specific antidotes are available. Overdoses should be monitored and treated symptomatically and supportively, if required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefoperazone and may be of significance in veterinary patients: !TALCOHOL : A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who have ingested alcohol within 48-72 hours of receiving beta-lactam antibiotics with a thiom-ethyltetrazole side-chain (e. g., cefoperazone) !TORAL ANTICOAGULANTS (warfarin ): Because these antibiotics have been associated with bleeding, they should be used cautiously in patients receiving oral anticoagulants Laboratory Considerations !TWhen using Kirby-Bauer disk diffusion procedures for testing sus-ceptibility, a specific 75 microgram cefoperazone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for cefoperazone susceptibility. An inhibition zone of 21 mm or more indicates susceptibility; 16-20 mm, inter-mediate; and 15 mm or less, resistant. !TWhen using a dilution susceptibility procedure, an organism with a MIC of 16 micrograms/m L or less is considered susceptible and 64 micrograms/m L or greater is considered resistant. With either method, infections caused by organisms with intermediate susceptibility may be effectively treated if the infection is limited to tissues where the drug is concentrated (e. g., urine, bile) or if a higher than normal dose is used. !TIn some human patients receiving cefoperazone, a positive direct antiglobulin ( Coombs' ) test has been reported. !TCefoperazone, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e. g., Clinitest®). Doses !TDOGS: For susceptible infections: a) Soft tissue infections: 22 mg/kg IV or IM q12h for 7-14 day s For bacteremia, sepsis: 22 mg/kg IV or IM q6-8h as long as necessary. Note : Doses are extrapolated from human litera-ture. (Greene and Watson 1998) !THORSES: For susceptible infections: a) 30-50 mg/kg q8-12h IV or IM ( Note : This is a human dose and should be used as a general guideline only) (Walker 1992) b) 20-30 mg/kg IV or IM q8-12h (Br umbaugh 1999) Monitoring !TEfficacy !TIf bleeding occurs: PT's/INR, CBC Client Information !TBecause cefoperazone use is generally associated with inpatient therapy, client monitoring is not required. If administered as an outpatient, be alert to either bleeding problems or signs associated with hypersensitivity. Chemistry/Synonyms A third generation cephalosporin, cefoperazone sodium contains a piperazine side chain giving it antipseudomonal activity. It occurs as a white, crystalline powder and is freely soluble in water and poorly soluble in alcohol. At room temperature, cefoperazone sodium has a maximum solubility in compatible IV solutions of 475 mg/m L (at concentrations >333 mg/m L vigorous and prolonged shaking may be required). Reconstituted solutions of the drug have a p H from 4. 5-6. 5. One gram contains 1. 5 m Eq of sodium. Cefoperazone sodium may also be known as: cefoperazonum na-tricum, CP-52640-2, CP-52640, CP-52640-3, T-1551 and Ce fobid®; there are many internationally registered trade names available. Storage/Stability/Compatibility The sterile powder for injection should be stored at temperatures less than 25°C and protected from light. Once reconstituted, solu-tions do not need to be protected from light. After reconstitution, cefoperazone sodium is generally stable for 24 hour s at room temperature and 5 days when refrigerated in a va-riety of IV solutions (e. g., sterile or bacteriostatic water for injection, de xtrose in water/saline/LRS solutions, lactated Ringer's injection, Normasol R, and saline IV solutions). When frozen at-2 to-10°C in dextrose, sodium chloride or sterile water for injection, cefop-erazone sodium is stable for 3 weeks (dextrose solutions) to 5 weeks (wate r or saline solutions). Cefoperazone sodium is reportedly compatible with cimetidine HCl, clindamycin phosphate, furosemide and heparin sodium, acyclovir sodium, cyclophosphamide, esmolol HCl, famotidine, hydromorphone HCl, magnesium sulfate, and morphine sulfate. It is reportedly incompatible with some TPN mixtures, doxapram HCl, gentamicin sulfate, hetastarch, labetolol HCl, meperidine HCl, odansetron HCl, perphenazine, promethazine, and sargostim. Compatibility is dependent upon factors such as p H, concentra-tion, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information. Do not mix cefoperazone in same syringe or IV bag with aminoglycosides as in-activation may occur.

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Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefoperazone Sodium Powder for Injection: 1 g & 2 g in vials and piggyback units; Cefobid® (Roerig); (Rx) Cefoperazone Sodium Injection: 1 g and 2 g premixed, frozen in 50 m L container s, and 10 g in bulk package; Cefobid ® (Roerig); (Rx) CEFOTAXIME SODIUM (sef-oh-taks-eem) Claforan® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT 3rd generation parenteral cephalosporin TT Potentially could cause hypersensitivity reactions, granu-locytopenia, or diarrhea TT Causes pain on IM injection; give IV over 3-5 minutes (or more) TT May need to reduce dose in renal failure Uses/Indications In the United States, there are no cefotaxime products approved for veterinary species but it has been used clinically in several species when an injectable 3rd generation cephalosporin may be indicated. Pharmacology/Actions Cefotaxime is a third generation injectable cephalosporin agent and, like other cephalosporins, inhibits bacteria cell wall synthe-sis. It is usually bactericidal and it is a time-dependent antibiot-ic. Cefotaxime has a relatively wide spectrum of activity against both gr am-positive and gram-negative bacteria. While less ac-tive against Staphyloc occus spp. than the first generation agents, it still has significant activity against those and other gram-positive cocci. Cefotaxime, like the other 3rd generation agents, has ex-tended coverage of gram-negative aerobes particularly in the fam-ily Enterobacteriaceae, including Klebsie lla spp., E. coli, Salmonella, Serratia marcescens, Proteus spp., and Enterobacter spp. Cefotaxime's in vitro activity against Pseudomonas aeruginosa is variable and results are usually disappointing when the drug is used clinically against this organism. Many anaerobes are also susceptible to ce-fotaxime including strains of Bacte roides fragilis, Clostridium spp., Fusobacterium spp., Peptococcus spp., and Peptostreptococcus spp. Because 3rd generation cephalosporins exhibit specific activi-ties against bacteria, a 30 microgram cefotaxime disk should be used whe n performing Kirby-Bauer disk susceptibility tests for this antibiotic. Pharmacokinetics Cefotaxime is not appreciably absorbed after oral administration and must be given parenterally to attain therapeutic serum levels. After administration, the drug is widely distributed in body tissues including bone, prostatic fluid (human), aqueous humor, bile, as-citic and pleural fluids. Cefotaxime crosses the placenta and activity in amniotic fluid either equals or exceeds that in maternal serum. Cefotaxime distributes into milk in low concentrations. In humans, approximately 13-40% of the drug is bound to plasma proteins. Unlike the first generation cephalosporins (and most 2nd gen-eration agents), cefotaxime will enter the CSF in therapeutic levels (at high dosages) w hen the patient's meninges are inflamed. Cefotaxime is partially metabolized by the liver to de-sacetylcefotaxime which exhibits some antibacterial activity. Desace tylcefotaxime is partially degraded to inactive metabolites by the liver. Cefotaxime and its metabolites are primarily excreted in the urine. Because tubular secretion is involved in the renal ex-cretion of the drug, in several species probenecid has been demon-strated to prolong the serum half-life of cefotaxime. Pharmacokinetic parameters in certain veterinary species fol-low: In dogs, the apparent volume of distribution at steady state is 480 m L/kg, and a total body clearance of 10. 5 m L/min/kg after intravenous injection. Serum elimination half-lives of 45 minutes when given IV, 50 minutes after IM injection, and 103 minutes after SC injection have been noted. Bioavailability is about 87% after IM injection and approximately 100% after SC injection. In cats, total body clearance is approximately 3 m L/min/kg after intrav enous injection and the serum elimination half-life is about 1 hour. Bioavailability is about 93-98% after IM injection. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins 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 r ashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile abscesses or other severe local tis-sue reactions are also possible but are much less common. Throm-bophlebitis is also possible after IV administration of these drugs. Because the cephalosporins may also alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resis-tant bacteria in the colon (superinfections). While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with nor mal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocytosis, thrombocytopenia, hepa-titis, positive Comb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic c omponent. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them 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 cefotaxime as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate

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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. ) Most of these agents (cephalosporins) are excreted in milk in small quantities. Modification/alteration of bowel flora with resul-tant diarrhea is theoretically possible. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems, but other effects are possible (see Adverse effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefotaxime and may be of significance in veterinary patients: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of par-enteral aminoglycosides or other nephrotoxic drugs (e. g., ampho-tericin B) with cephalosporins is somewhat controversial. Poten-tially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have syner-gistic or additive activity against certain bacteria when used with aminog lycosides, but they should not be mixed together (admin-ister separately). !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins, thereby increasing serum levels and serum half-lives Laboratory Considerations !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may cause falsely elevated 17-ketosteroid values in urine. !TCefotaxime like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e. g., Clinitest®), Benedict's solution or Fehling's solution. Doses !TDOGS: For susceptible infections: a) For soft tissue infections: 22 mg/kg IV, IM or SC q8h for 7 days or less or 50 mg/kg IV or IM q12h for 7 days or less. Fo r orthopedic infections: 20-40 mg/kg IV, IM or SC q6-8h for 7 days or less. For severe bacteremia: 20-80 mg/kg IV q6h or 10-50 mg/kg IV q4-6h for as long as necessary (Greene and Watson 1998) b) 25-50 mg/kg IV, IM or SC q8h (Riviere 1989); (Vaden and Papic h 1995) c) For sepsis: 20-80 mg/kg IV, IM q8h (T ello 2003a) d) For CNS infections (spinal cord): 25 mg-50 mg/kg IV, IM q8h (Dic kinson 2003) !TCATS: For susceptible infections: a) For severe bacteremia: 20-80 mg/kg IV or IM q6h as long as nec essary (Greene and Watson 1998) b) 25-50 mg/kg IV, IM or SC q8h (Vaden and Papich 1995), (Lappin 2002a) c) F or sepsis: 20-80 mg/kg IV, IM q8h (T ello 2003b) For CNS infections (spinal cord): 25 mg-50 mg/kg IV, IM q8h (Dic kinson 2003) !THORSES: For susceptible infections: a) Foals: 40 mg/kg IV q6h (Giguere 2003a) b) For meningitis in foals: 40 mg/kg IV 3-4 t imes a day (Furr 1999) c) Foals: 15-30 mg/kg IV or IM q6-12h (Br umbaugh 1999) !TBIRDS: For susceptible infections: a) For most birds: 50-100 mg/kg IM three times a day; may be used with aminoglycosides, but nephrotoxicity may occur. Reconstituted vial good for 13 weeks if frozen. (Clubb 1986) b) 75-100 mg/kg IM or IV q6-8h (Ho effer 1995) c) Ratites (young birds): 25 mg/kg IM 3 times daily (Jenson 1998) d) 75-100 mg/kg IM or IV q4-8h (Hess 2002a) e) 75 mg/kg IM q8h (Tully 2002) !TREPTILES: For susceptible infections: a) 20-40 mg/kg IM once daily for 7-14 day s (Gauvin 1993) b) Chelonians: 20-40 mg/kg IM q24h (Johnson 2002) c) Nebulized antibiotic therapy: 100 mg twice daily (Raiti 2003) Monitoring !TBecause cephalosporins usually have minimal toxicity associ-ated with their use, monitoring for efficacy is usually all that is required. !TPatients with diminished renal function may require intensified renal monitoring. Chemistry/Synonyms A semisynthetic, 3rd generation, aminothiazolyl cephalosporin, ce-fotaxime sodium occurs as an odorless, white to off-white crystalline po wder with a p K a of 3. 4. It is sparingly soluble in water and slightly soluble in alcohol. Potency of cefotaxime sodium is expressed in terms of cefotaxime. One gram of cefotaxime (sodium) contains 2. 2 m Eq of sodium. Cefotaxime sodium may also be known as: cefotaximum natri-cum, CTX, HR-756, RU-24756 and Clafor an®; many other trade names are available internationally. Storage/Stability/Compatibility Cefotaxime sodium sterile powder for injection should be stored at temperatures of less than 30°C; protected from light. The com-mercially available frozen injection should be stored at temperatures no g reater than-20°C. Depending on storage conditions, the pow-der or solutions may darken which may indicate a loss in potency. Ce fotaxime is not stable in solutions with p H >7. 5 (sodium bicar-bonate). All commonly used IV fluids and the following drugs are report-edly compatible with cefotaxime: clindamycin, metronidazole and verapamil. 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.

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Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefotaxime Sodium Powder for Injection: 500 mg, 1 g (as cefotaxi-me), 2 g, and 10 g in vials, infusion bottles & ADD-Vantage syst em vials; Claforan® (Hoechst Marion Roussel); generic; (Rx) Cefotaxime Sodium for Injection: 1 g and 2 g in premixed, frozen 50 m L & infusion bottles; Clafor an® (Hoechst Marion Roussel); (Rx) CEFOTET AN DISODIUM (sef-oh-tee-tan) Cefotan® 2nd GENERATION CEPHALOSPORIN (CEPHAMYCIN) Prescriber Highlights TT 2nd to 3rd generation parenteral cephalosporin (ce-phamycin) similar to cefoxitin TT Pharmacokinetic profile better and may be more effec-tive against E. coli in dog s than cefoxitin TT Contraindications: Hypersensitivity to it or cephalosporins TT Adverse Effects: Unlikely; potentially could cause bleeding TT If severe renal dysfunction, may need to increase time between doses Uses/Indications Cefotetan may be a reasonable choice for treating serious infec-tions caused by susceptible bacteria, including E. co li or anaerobes. It appears to be well tolerated in small animals and may be given less frequently than cefoxitin. Pharmacology/Actions Often categorized as a 2nd or 3rd generation cephalosporin, cefo-tetan is usually bactericidal and acts by inhibiting mucopeptide synt hesis in the bacterial cell wall. Cefotetan's in vi tro activity against aerobes include E. coli, Proteus, Klebsiella, Salmonella, Staphylococcus and most Streptococcus. It has efficacy against most strains of the fol-lowing anaerobes: Actinomyces, Clostridium, Peptococcus, Pept ostreptococcus and Propionibacterium. Many strains of Bacteroides are still sensitive to cefotetan. Cefotetan is generally ineffective against Pseu domonas aerugi-nosa and Enterococci. Because 2nd generation cephalosporins exhibit specific ac-tivities against bacteria, a 30-microgram cefoxitin disk should be used when performing Kirby-Bauer disk susceptibility tests for this antibi otic. Pharmacokinetics Cefotetan is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum lev-els. The drug is well distributed into most tissues, but only has limi ted penetration into the CSF. Cefotetan is primarily excreted unchanged by the kidneys into the urine via both glomerular fil-tration (primarily) and tubular secretion. Elimination half-lives may b e significantly prolonged in patients with severely dimin-ished renal function. Contraindications/Precautions/Warnings Cephamycins are contraindicated in patients who have a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented to be hypersensitive to other beta-lactam antibiotics (e. g., penicil-lins, cephalosporins, carbapenems). Adverse Effects There is little information on the adverse effect profile of this medication in veterinary species, but it appears to be well toler-ated. In humans, less than 5% of patients report adverse effects. Because c efotetan contains an N-methylthiotetrazole side chain (like cefoperazone), it may have a greater tendency to cause hema-tologic effects (e. g. hypoprothrombinemia) or disulfiram-like reac-tions (vomiting, etc) than other parenteral cephalosporins. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as r ashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile abscesses or other severe local tissue reactio ns are also possible but are less common. Thrombophlebitis is also possible after IV administration of these drugs. Even when administered parenterally, cephalosporins may alter gut flor a and antibiotic-associated diarrhea or the proliferation of resistant bacteria in the colon (superinfections) can occur. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with nor mal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neurotoxicity, neutropenia, agranulocytosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Safe use during pregnancy has not been established; use only when justified. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrat-ed risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but ad-equate studies in pregnant women have not demonstrated a risk to the fet us in the first trimester of pregnancy, and there is no evidence of risk in later trimesters) Cefotetan enters maternal milk in small quantities. Alteration of bowe l flora with resultant diarrhea is theoretically possible. Overdosage/Acute Toxicity Unlikely to cause adverse effects, unless massive or chronically over-dosed; seizures possible. Treat symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefotetan and may be of significance in veterinary patients: T ! ALCOHOL: A disulfiram reaction is possible T ! AMINOGLYCOSIDES/NEPHROTOXIC DRUGS: The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been

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well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have CEFOXITIN SODIUM synergistic or additive activity against certain bacteria when used (se-fox-i-tin) Mefoxin® with aminoglycosides, but they should not be mixed together (ad-minister separately). 2nd GENERATION CEPHALOSPORIN (CEPHAMYCIN) Laboratory Considerations T ! Except for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution Prescriber Highlights (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase TT 2nd generation parenteral cephalosporin; effective (Tes-Tape®, Clinistix®) are not affected by cephalosporins. against anaerobes, including Bacteroides T ! When using the Jaffe reaction to measure serum or urine creati-TT Potentially could cause hypersensitivity reactions, throm-nine, cephalosporins (not ceftazidime or cefotaxime) in high dos-bocytopenia, & diarrhea ages may falsely cause elevated values. TT Causes pain on IM injection; Give IV over 3-5 minutes T ! In humans, particularly with azotemia, cephalosporins have (or more)caused a false-positive direct Coombs' test. TT May need to reduce dose in renal failure T ! Cephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine. Doses Uses/Indications T ! DOGS: In the United States, there are no cefoxitin products approved for vet-erinary species, but it has been used clinically in several species when For susceptible infections: an injectab le se cond generation cephalosporin may be indicated. a) 30 mg/kg SC q12h; 30 mg/kg IV q8h (Petersen and Rosin 1993), (Tr epanier 1999) Pharmacology/Actions b) For sepsis: 30 mg/kg q5-8h IV (Hardie 2000) Although not a true cephalosporin, cefoxitin is usually classified as c) For soft tissue infections: 30 mg/kg SC q12h for 7 days or a 2nd ge neration agent. Cefoxitin has activity against gram-posi-less; tive cocci, but less so on a per weight basis than the 1st generation For ba cteremia, sepsis: 30 mg/kg IV, SC q8h for as long as re-agents. Unlike the first generation agents, it has good activity against quired. (Greene, Hartmannn et al. 2006) many strains of E. coli, Klebsiella and Proteus that may be resistant T ! CATS: to the first generation agents. In human medicine, cefoxitin's activ-ity against many strains of Bacte roides fragilis has placed it in a sig-For susceptible infections: nificant therapeutic role. While Bacte roides fragilis has been isolated a) For sepsis: 30 mg/kg q5-8h IV (Hardie 2000) from anaerobic infections in veterinary patients, it may not be as Monitoring significant a pathogen in veterinary species as in humans. T ! Because cephalosporins usually have minimal toxicity associ-Because 2nd generation cephalosporins exhibit specific activities ated with their use, monitoring for efficacy is usually all that is against ba c teria, a 30-microgram cefoxitin disk should be used when required. performing Kirby-Bauer disk susceptibility tests for this antibiotic. T ! Patients with diminished renal function may require intensified Pharmacokinetics renal monitoring. Serum levels and therapeutic drug monitoring Cefoxitin is not appreciably absorbed after oral administration and are not routinely done with these agents. must be given parenterally to achieve therapeutic serum levels. The absorb e d drug is primarily ex creted unchanged by the kidneys into Chemistry/Synonyms the urine via both tubular secretion and glomerular filtration. In hu-A semisynthetic cephamycin similar to cefoxitin, cefotetan disodium mans, app r oximately 2% of a dose is metabolized to descarbamylce-occurs as a white to pale yellow, lyophilized powder. It is very soluble foxi tin, which is inactive. Elimination half-lives may be significantly in water and alcohol. The injection contains approximately 3. 5 m Eq prolon ged in patients with severely diminished renal function. of sodium per gram of cefotetan and after reconstitution has a p H In hor ses, the apparent volume of distribution at steady state is of 4-6. 5. 110 m L/kg, t otal body clearance of 4. 32 m L/min/kg with a serum Cefotetan Disodium may also be known as: ICI-156834, elimination half-lif e of 49 minutes. YM-09330, Apace f®, Apatef®, Cefotan®, Ceftenon®, Cepan®, Darvilen®, In calves, the volume of distribution is 318 m L/kg, and it has a or Yamatetan®. terminal elimination half-life of 67 minutes after IV dosing, and 81 Storage/Stability minutes after IM administration. Cefoxitin is approximately 50% The sterile powder for injection should be stored below 22°C and bound to calf plasma proteins. Probenecid (40 mg/kg) has been prote cted from light. A darkening of the powder with time does not demonstrated to significantly prolong elimination half-lives. indicate lessene d potency. After reconstituting with sterile water for Contraindications/Precautions/Warnings injection, the resultant solution is stable for 24 hours if stored at Cephalosporins are contraindicated in patients with a history of room temperature, 96 hours if refrigerated, and at least one week if hype rsensitivity to them. Because there may be cross-reactivity, use frozen at-20C. cephalosp orins cautiously in patients who are documented hyper-Dosage Forms/Regulatory Status sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). VETERINARY-LABELED PRODUCTS: None Patients in renal failure may need dosage adjustments. HUMAN-LABELED PRODUCTS: Cefotetan Disodium Powder for Injection: 1 g, 2 g, and 10 g in vials and 100 m L vials; generic (Abraxis, Braun); (Rx)

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Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these age nts and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in pat ients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile abscesses or other severe local tissue reac tions are also possible but are less common. Thrombophlebitis is also possible after IV administration of these drugs. Even when administered parenterally, cephalosporins may alter gut flora and antibiotic-associated diarrhea or the proliferation of resistant bacteria in the colon (superinfections) can occur. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neurotoxicity, neutropenia, agranulocytosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and t ubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs; however, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as cat egory 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. ) Cefoxitin can be distributed into milk in low concentrations. It is unlike ly to pose significant risk to nursing offspring. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefoxitin and may be of significance in veterinary patients: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In v itro studies have demonstrated that cephalosporins can have syne rgistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. Laboratory Considerations !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine. Doses !TDOGS: For susceptible infections: a) For mixed infections (e. g., aspiration pneumonia, bowel per-foration): 30 mg/kg SC q8h; 30 mg/kg IV q4-6h ( Trepanier 1999) b) For sepsis: 30 mg/kg IV q5h (Hardie 2000) c) For soft tissue infections: 30 mg/kg SC q8h or 30 mg/kg IV q5h Fo r bacteremia: 15-30 mg/kg IV, IM SC q6-8h For orthopedic infections: 22 mg/kg IV, IM q6-8h Use for all indications above as long as necessary to control initial infection, then switch to oral drugs for longer therapy. (Greene and Watson 1998) d) For Gram+ infections: 10 mg/kg q8h IV, IM or SC For Gram-infections: 20 mg/kg q8h IV, IM or SC (Aucoin 2000) e) For septic shock: 20 mg/kg IV q8h (T ello 2003a) !TCATS: For susceptible infections: a) For systemic infections: 25-30 mg/kg IV or IM q8h; use for as lo ng as necessary to control initial infection, then switch to oral drugs for longer therapy (Greene and Watson 1998) b) For sepsis: 30 mg/kg IV q5h (Hardie 2000) c) 30 mg/kg IV q8h (Vaden and Papich 1995) d) For Gram+ infections: 10 mg/kg q8h IV, IM or SC For Gram-infections: 20 mg/kg q8h IV, IM or SC (Aucoin 2000) e) For septic shock: 20 mg/kg IV q8h (T ello 2003a) !THORSES: For susceptible infections: a) Foals: 20 mg/kg IV q4-6h (C aprile and Short 1987); (Brum-baugh 1999) Monitoring !TBecause cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is re-quired. !TPatients with diminished renal function may require intensified renal monitoring. Chemistry/Synonyms Actually a cephamycin, cefoxitin sodium is a semisynthetic an-tibiotic that is derived from cephamycin C that is produced by St reptomyces lactamdurans. It occurs as a white to off-white, some-what hygroscopic powder or granules with a faint but characteristic od or. It is very soluble in water and only slightly soluble in alcohol. Each gram of cefoxitin sodium contains 2. 3 m Eq of sodium.

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Cefoxitin may also be known as: MK-306, L-620-388, cefoxiti-num, cefoxitina, cefoxitine, Mefo xin®, Mefoxitin®, Cefociclin®, or Cefoxin®. Storage/Stability/Compatibility Cefoxitin sodium powder for injection should be stored at tem-peratures less than 30°C and should not be exposed to temperatures greate r than 50°C. The frozen solution for injection should be stored at temperatures no higher than-20°C. After reconstitution, the solution is stable for 24 hours when kept at roo m temperature and from 48 hours to 1 week if refrigerated. If after reconstitution the solution is immediately frozen in the origi-nal container, the preparation is stable up to 30 weeks when stored at-20°C. Stabilit y is dependent on the diluent used and the reader should refer to the package insert or other specialized references for more information. The powder or reconstituted solution may dark-en but this apparently does not affect the potency of the product. All commonly used IV fluids and the following drugs are report-edly compatible with cefoxitin: amikacin sulfate, cimetidine HCl, gentamicin sulfate, kanamycin sulfate, mannitol, metronidazole, multivitamin infusion concentrate, sodium bicarbonate, tobramy-cin sulfate and vitamin B-complex with C. Compatibility is depen-dent upon factors such as p H, concentration, temperature and di-luent used; consult specialized references or a hospital pharmacist for mor e specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefoxitin Sodium Powder for Injection: 1 g (of cefoxitin), 2 g, & 10 g in vials, infusion bottles, bulk bottles, or duplex bags; Mefoxin® (Merck); generic; (Rx) Cefoxitin Sodium Injection: 1 g & 2 g premixed, frozen in 50 m L; Mefo xin® (Merck); (Rx) CEFPODOXIME PROXETIL (sef-poe-docks-eem) Simplicef®, Vantin® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT Oral 3rd generation cephalosporin that may be useful in dogs or cats TT Contraindications: Hypersensitivity to it or other cepha-losporins TT May need to adjust dose if patient has renal disease TT Adverse Effects: Primarily GI, but hypersensitivity possible Uses/Indications In dogs, cefpodoxime is indicated for the treatment of skin infec-tions caused by Staphyloc occus intermedius, Staphylococcus aureus, Streptococcus canis, E. coli, Proteus mirabilis, and Pasteurella multo-cida. Although not currently approved for cats, it may also be useful as well. Pharmacology/Actions Like other cephalosporins, cefpodoxime inhibits bacterial cell wall synthesis. It is considered bactericidal and relatively resistant to bac-terial beta-lactamases. Cefpodoxime's main spectrum of activity is against gram-negative bacte ria in the family Enterobacteriaceae (excluding Pseudomonas) including Escherichia, Proteus, and Klebsiella, and gram-positive streptococci (not enterococcus) and Staphylococci. Cefpodoxime is not efficacious against Pseudomonas aeruginosa, Enterococcus, anaerobes, and methicillin-resistant Staphylococcus strains. Because sensitivity of various bacteria to the 3rd generation ce-phalosporin antibiotics is unique to a given agent, cefpodoxime spe-cific disks or dilutions must be used to determine susceptibility. Pharmacokinetics Cefpodoxime proxetil is not active as an antibiotic. Cefpodoxime is active after the proxetil ester is cleaved in vivo. After single oral doses (10 mg/kg) to fasted dogs, bioavailability is approximately 63%; vol-ume of distribution 150 m L/kg; peak concentrations about 16 mg/ m L; time t o peak was 2. 2 hours; and terminal elimination half-life of approximately 5-6 hours. In humans, cefpodoxime proxetil is about 40-50% absorb ed from the GI tract. Food can alter the rate, but not the extent, of ab-sorption. Cefpodoxime penetrates most tissues well; it is unknown if it pe netrates into the CSF. The drug is eliminated in both the urine and feces. Serum half-life may be prolonged in patients with im-paired renal function. In foals after an oral dose (suspension) of 10 mg/kg, peak lev-els occur in about 100 minutes and peak at about 0. 8 mcg/m L. Elimination half-lif e is about 7 hours in foals. Levels in synovial and peritoneal fluids were similar to those found in the serum, but no drug was detected in the CSF. Contraindications/Precautions/Warnings Cefpodoxime is contraindicated in patients hypersensitive to it or other cephalosporins. Because cefpodoxime is excreted by the kid-neys, dosages and/or dosage frequency may need to be adjusted in patients w ith significantly diminished renal function. Use with cau-tion in patients with seizure disorders. Adverse Effects Although usage of this drug in veterinary patients remains limited to date, it appears to be tolerated very well. The most likely adverse effects seen with this medication have been inappetence, diarrhea, and vomiting. Hypersensitivity reactions are a possibility. Cefpodoxime may occasionally induce a positive direct Coombs' test. Rar ely, blood dyscrasias may be seen following high doses of cephalosporins. Reproductive/Nursing Safety Cefpodoxime has not shown to be teratogenic but should only be used during pregnancy when clearly indicated. The veterinary prod-uct is labeled: “The safety of cefpodoxime proxetil in dogs used for bree ding, pregnant dogs, or lactating bitches has not been demon-strated. ” In humans, the FDA categorizes this drug as category B for use d uring 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. ) The drug enters maternal milk in low concentrations. Modificatio n/alteration of bowel flora with resultant diarrhea is theoretically possible. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems but other effects are possible (see Adverse effects section).

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Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefpodoxime and may be of significance in veterinary patients: T ! AMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). T ! ANTACIDS : Drugs that can increase stomach p H may decrease the absorption of the drug T ! H-2 ANTAGONISTS (ranitidine, famotidine, etc. ): Drugs that can in-crease stomach p H may decrease the absorption of the drug T ! PROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives T ! PROTON P UMP I NHIBITORS (e. g., omeprazole ): Drugs that can in-crease stomach p H may decrease the absorption of the drug Laboratory Considerations T ! Cefpodoxime may cause false-positive urine glucose determina-tions when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. T ! If using the nitroprusside test for determining urinary ketones, cefpodoxime may cause false-positive results. Doses T ! DOGS: a) For susceptible skin infections: 5-10 mg/kg PO once daily. Should be a dministered for 5-7 days or 2-3 days beyond cessation of clinical signs, up to a maximum of 28 days. Treatment of acute infections should not be continued for more than 3-4 days if no response to therapy is seen. May be given with or without food. (Label information; Simplicef®— Pfizer) b) For staphylococcal skin infections: 5-10 mg/kg PO q12h (Campbe ll 1999); (Mac Donald 2002b) c) For susceptible infections: 5-10 mg/kg PO tw ice daily (Boothe 1999) T ! CATS: a) For susceptible skin and soft tissue infections: 5 mg/kg PO q12h or 10 mg/kg PO once daily ( Note : Extrapolated from human dosage) (Greene and Watson 1998) Monitoring T ! Clinical efficacy Client Information T ! Can be given without regard to meals (in humans presence of food enhances absorption). T ! Give as directed for as long as veterinarian recommends, even if patient appears well. Chemistry/Synonyms An orally administered semisynthetic 3rd generation cephalosporin, cefpodoxime proxetil is a prodrug that is hydrolyzed in vivo to cef-podoxime. The esterified form (proxetil) enhances lipid solubility and oral absor ption. Cefpodoxime proxetil may also be known as: CS-807; R-3763, U-76252, U-76253, Banan®, Biocef®, Cefodox ®, Cepodem®, Garia®, Instana®, Kelbium®, Orelox®, Otreon®, Podomexef®, Simplicef®, or Vantin®. Storage/Stability/Compatibility Tablets and unreconstituted powder should be stored at 20-25°C in well-closed containers. After reconstitution, the oral suspension should be stored in the refrigerator and discarded after 14 days. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cefpodoxime Proxetil Tablets: 100 mg & 200 mg; Simplicef® (Pfiz-er); (Rx). Approved for use in dogs. HUMAN-LABELED PRODUCTS: Cefpodoxime Proxetil Tablets: 100 mg & 200 mg; Vantin®(Pharma-cia & Upjohn), generic (Putney); (Rx) Cefpodoxime Proxetil Granules for Suspension: 50 mg/5 m L & 100 mg/5 m L in 50 m L, 75 m L & 100 m L bottles; Vantin®(Pharmacia & Upjohn), generic (Putney); (Rx) CEFTAZIDIME (sef-taz-i-deem) Ceptaz®, Fortaz®, Tazicef® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT 3rd generation cephalosporin used parenterally for gram-negative infections TT Particularly useful in reptiles TT Could cause hypersensitivity reactions, granulocytopenia/ thrombocytopenia, diarrhea, mild azotemia TT May cause pain on IM injection; SC injection probably less painful TT May need to reduce dose in renal failure; use with caution TT Check drug-lab interactions Uses/Indications Ceftazidime is potentially useful in treating serious gram-negative bacterial infections particularly against susceptible Enterobacteriaceae including Pseudomonas aeruginosa, that are not susceptible to other, less-expensive agents, or when aminogly-cosides are not indicated (due to their potential toxicity). It is of particular int erest for treating gram-negative infections in reptiles due to a very long half-life. Pharmacology/Actions Ceftazidime is a third generation injectable cephalosporin agent. It is bactericidal and acts via its inhibition of enzymes responsible for bacterial cell wall synthesis. The third generation cephalosporins re-tain much of the gram-positive activity of the first and second gen-eration agents, but, have much expanded gram-negative activity. As with the 2nd generation agents, enough variability exists with indi-vidual bacterial sensitivities that susceptibility testing is necessary for most bacteria. Ceftazidime is considered an anti-pseudomonal

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cephalosporin, but resistance development is an issue. A European study (Seol, Naglic et al. 2002) looking at antibiotic susceptibility of Pseudomonas aeruginosa isolates obtained from dogs, demonstrated that 77% of strains tested were sensitive to ceftazidime. Pharmacokinetics Ceftazidime is not appreciably absorbed after oral administration. In dogs after SC injection, the terminal half-life of ceftazidime was 0. 8 hours; a 30 mg/kg dose was above the MIC for Ps eudomonas aeruginosa for 4. 3 hours. When administered as a 4. 1/mg/kg/hr con-stant rate infusion (after a loading dose of 4. 4. mg/kg), mean serum co ncentration was above 165 mcg/m L. The authors concluded that either dosage regimen would be appropriate treatment for infec-tions in dogs caused by Ps eudomonas aeruginosa (Moore, Trepanier et al. 2000). Ceftazidime is widely distributed throughout the body, including into bone and CSF and is primarily excreted unchanged by the kidneys via glomerular filtration. As renal tubular excretion does not play a major role in the drug's excretion probenecid does not affect elimination kinetics. Contraindications/Precautions/Warnings Only prior allergic reaction to cephalosporins contraindicates cef-tazidime's use. In humans documented hypersensitive to penicillin, up t o 16% may also be allergic to cephalosporins; veterinary signifi-cance is unclear. Because the drug is primarily excreted via the kidneys, accumu-lation may result in patients with significantly impaired renal func-tion; use with caution and adjust dose as required. Adverse Effects Because veterinary usage of ceftazidime has been very limited, a full adverse effect profile has not been determined for veterinary patients. Gastrointestinal effects have been reported in dogs that have received the drug subcutaneously. When given IM, pain may be noted at the injection site; pain on injection could also occur after SC administration in animals. Hypersensitivity reactions and gastrointestinal signs have been re ported in humans and may or may not apply to veterinary pa-tients. Pseudomembranous colitis (C. difficile) may occur with this antib iotic. Increased serum concentrations of liver enzymes have been described in 1-8% of human patients given ceftazidime. 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 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. ) No teratogenic effects were demonstrated in studies in pregnant mice and rats given up to 40X labeled doses of ceftazidime. Because of the drug's low absorbability, it is unlikely to be harm-ful to nursing offspring, but alterations to GI flora of nursing ani-mals could occur. Overdosage/Acute Toxicity An acute overdose in patients with normal renal function is unlikely to be of great concern; but in humans with renal failure, overdosage of ceftazidime has caused seizures, encephalopathy, coma, neuro-muscular excitability, asterixis, and myoclonia. Treatment of signs associat ed with overdose is primarily symptomatic and supportive. Hemodialysis could be used to enhance elimination. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ceftazidime and may be of significance in veterinary patients: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of par-enteral aminoglycosides or other nephrotoxic drugs (e. g., ampho-tericin B) with cephalosporins is somewhat controversial. Poten-tially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have syner-gistic or additive activity against certain bacteria when used with aminog lycosides, but they should not be mixed together (admin-ister separately). !TCHLORAMPHENICOL : May be antagonistic to the ceftazidime's effects on gram-negative bacilli; concurrent use Is not recommended Laboratory Considerations !TCeftazidime, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e. g., Clinitest®). !TIn humans, ceftazidime rarely causes positive direct antiglobulin ( Coombs' ) tests and increased prothrombin times. !TWhen using Kirby-Bauer disk diffusion procedures for testing susceptibility, a specific 30 microgram ceftazidime disk should be used. An inhibition zone of 18 mm or more indicates suscep-tibility; 15-17 mm, intermediate; and 14 mm or less, resistant. When using a dilution susceptibility procedure, an organism with a MIC of 8 mcg/m L or less is considered susceptible; 16 mcg/m L intermediate; and 32 mcg/m L or greater is resistant. With either method, infections caused by organisms with intermediate sus-ceptibility may be effectively treated if the infection is limited to tiss ues where the drug concentrates, or when a higher than nor-mal dose is used. Doses !TDOGS: a) For initial antibiotic therapy of gram-negative infections: 25 mg/kg IM or SC q8-12h (K ruth 1998) b) For initial treatment of orthopedic infections: 25 mg/kg IV, IM q8-12h; Fo r initial treatment of soft tissue infections: 30-50 mg/kg IV, IM q8-12h; For initial treatment of sepsis, bacteremia: 15-30 mg/kg IV, IM q6-8h. (G reene and Watson 1998) !TCATS: a) For initial treatment of systemic infections: 25-30 mg/kg IV, IM or int raosseous q8-12h (Greene and Watson 1998) !TREPTILES: a) For susceptible infections: 20 mg/kg IM or SC q72hours (ev-ery 3 days). (Lewbart 2001) b) For bacterial infections in snakes, particularly when Enter-obacteriaceae or Pseudomonas aeruginosa are confronted: 20 mg/kg IM q72h at 30°C. (K lingenberg 1996) c) For chelonians: 50 mg/kg IM q24h (Johnson 2002) Monitoring !TEfficacy !TBaseline renal function

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Client Information T ! Clients may be instructed to administer this drug SC for outpa-tient therapy. Be certain they understand the storage and stability issues before dispensing. Chemistry/Synonyms A semi-synthetic, third-generation cephalosporin antibiotic, cef-tazidime occurs as a white to cream-colored crystalline powder that is slightl y soluble in water (5 mg/m L) and insoluble in alcohol, chloroform and ether. The p H of a 0. 5% solution in water is be-tween 3 and 4. Ceftazidime may also be known as ceftazidimum, GR-20263, or LY-139381, Fortaz®, Ceptaz®, Tazicef®, and Tazidime®; there are many international trade names. Storage/Stability/Compatibility Commercially available powders for injection should be stored at 15-30°C (59-86°F) and protected from light. The commercially available frozen ceftazidime for injection should be stored at tem-peratures no higher than-20°C (-4°F). The commercial products containing the sodium carbonate (Fortaz ®, Tazicef®, Tazidime®) all release carbon dioxide (effer-vesce) when reconstituted and are supplied in vials under negative pressur e; do not allow pressure to normalize before adding diluent. The product containing arginine (Ceptaz®), does not effervesce. Once reconstituted, the solution retains potency for 24 hours (18 hours f or arginine formulation) at room temperature and 7 days when refrigerated. Solutions frozen in the original glass vial after reconstitution with sterile water are stable for 3 months when stored at-20°C (-4°F). While no stability data was located, veteri-narians have anecdotally reported efficacy when individual dosages are fro zen in plastic syringes. Once thawed, they should not be re-frozen. Thawed solutions are stable for 8 hours at room tempera-ture and 4 days when refrigerated. Ceftazidime is compatible with the following diluents when being prepared for IM (or SC) injection: sterile or bacteriostatic water for injection, 0. 5% or 1% lidocaine. Once reconstituted it is compatible with the more commonly used IV fluids, including: D5W, normal saline or half-normal saline, Ringer's, or lactated Ringer's. Do not use sodium bicarbonate solution for a diluent; it is not rec ommended to mix with aminoglycosides, vancomycin or metronidazole. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ceftazidime Powder for Injection: (with sodium carbonate) 500 mg, 1 g, 2 g, and 6 g in 20 m L & 100 m L vials, infusion packs, ADD-Vantage vials & piggyback vials; Fortaz® & Ceptaz® (Glaxo Smith-Kline); Tazicef® (Smith Kline Beecham/Bristol-Myers); Tazidime® (Lilly); (Rx) Ceftazidime Injection: 1 g & 2 g premixed, frozen in 50 m L & Gal-axy co ntainers; Fortaz ® (Glaxo Wellcome); Tazicef® (Smith Kline Beecham/Bristol-Myers Squibb); (Rx) CEFTIOFUR CRYSTALLINE FREE ACID (sef-tee-oh-fur) Excede® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT Veterinary-only 3rd generation cephalosporin labeled for use in cattle & swine TT Potentially could cause hypersensitivity reactions, granu-locytopenia, thrombocytopenia, or diarrhea TT Administered SC at the posterior aspect of ear in cattle; administered IM in swine TT Shake well prior to use Monograph by Elaine Lust, Pharm D Uses/Indications In beef, lactating and non-lactating cattle, ceftiofur crystalline free acid (CCFA) is labeled for the treatment of bovine respiratory dis-ease (BRD, shipping fever, pneumonia) associated with Mannheimia haemo lytica, Pasteurella multocida, and Histophilus somni and for the control of respiratory disease in cattle at high risk of developing BRD associated with M. haemolytica, P. multocida, and H. somni. In swine, Ceftiofur CFA is labeled for the treatme nt of swine respiratory disease (SRD) associated with Actinobacillus pleuro-pneumoniae, Pasteurella multocida, Haemophilus parasuis, and Stre ptococcus suis. Pharmacology/Actions Ceftiofur is a 3rd generation cephalosporin antibiotic active against a variety of gram-positive and gram-negative bacteria and like oth-er cephalosporins, inhibits bacteria cell wall synthesis; it is usually bacte ricidal and is a time-dependent antibiotic. After administration, the parent compound (ceftiofur) is rapidly cleaved into furoic acid and desfuroylceftiofur (active). Desfuroylceftiofur inhibits cell wall synthesis (at stage three) of susceptible multiplying bacteria and exhibits a spectrum of activ-ity similar to that of cefotaxime. Parent ceftiofur and the primary metabolite are equally potent and assays to measure microbial sen-sitivity (plasma and tissue levels) are based on ceftiofur equivalents refe rred to as CE. The protein binding activity of ceftiofur creates a “reservoir effect” to maintain active levels at the site of infection. In cattle, ceftiofur has a broad range of in vitr o activity against a variety of pathogens including many species of Pasturella, Streptococcus, Staphylococcus, Salmonella, and E. coli. In Swine, ceftiofur CFA at a single IM dosage of 2. 27 mg/lb (5 mg/kg) BW provides concentrations of ceftiofur and desfuroylceft-iofur-related metabolites in plasma that are multiples above the MIC90 fo r an extended period of time for the swine respiratory disease (SRD) label pathogens Actinobacillus pleuropneumoniae, Pasteurella multocida, Haemophilus parasuis and Streptococcus suis. Pharmacokinetics In cattle, subcutaneous administration of ceftiofur CFA, in the middle third of the posterior aspect of the ear (middle third of the ear) of beef and non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the head (base of the ear) of beef, non-lactating dairy, and lactating dairy cattle, provides therapeutic concentrations of ceftiofur and desfuroylceftiofur-related metabo-

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lites in plasma above the MIC90 for the bovine respiratory disease (BRD) label pathogens, Pasteurella multocida, Mannheimia haemo-lytica and Hist ophilus somni for generally not less than 150 hours after single administration. Pharmacokinetic studies indicate that base of ear administra-tions (BOE) in dairy cattle are consistent with middle of ear (MOE) administ ration in beef cattle with blood levels at therapeutic thresh-old within 2 hours of administration at labeled doses. The systemic safety of ceftiofur concentrations resulting from pr oduct administration at the base of the ear was established via a pharmacokinetic comparison of the two routes of administration (base of the ear versus middle third of the ear). Based upon the re-sults of this relative bioavailability study, the two routes of adminis-tration are therapeutically equivalent. In swine, ther apeutic plasma levels for the parent compound and primary metabolite, desfuroylceftiofur, are reached within 1 hour of treatment. Plasma levels remained above the MIC for nearly 100% of target swine respiratory disease (SRD) pathogens for an average of 8 days. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Hypersensitivity reactions unrelated to dose can occur with these age nts and can manifest as rashes, fever, eosinophilia, lymphade-nopathy, or full-blown anaphylaxis. The use of cephalosporins in patie nts documented to be hypersensitive to penicillin-class antibi-otics is controversial. In humans, it is estimated 1-15% of patients hy persensitive to penicillins will also be hypersensitive to cepha-losporins. The incidence of cross-reactivity in veterinary patients is unknow n. Avoid direct contact of the product with the skin, eyes, mouth and c lothing. Sensitization of the skin may be avoided by wearing latex gloves. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. Administration of ceftiofur free acid into the ear arteries is likely to r esult in sudden death in cattle. Following label use as a single treatment in cattle, slaughter with-drawal time = 13 days and zero day (no) milk discard time. Extra-labe l drug use may result in violative residues. A withdrawal period has not been established for this product in pre-ruminating calves; do not use in calves to be processed for veal. In swine, slaughter withdrawal is 14 days. A maximum of 2 m L of formulation should be injected at each injection site. Injection volumes in excess of 2 m L may result in violative residues. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence, but cephalosporins can cause allergic reactions in sensitized individuals. T opical expo-sures to such antimicrobials, including ceftiofur, may elicit mild to sev ere allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. In cattle, administration of ceftiofur free acid into the ear arter-ies is likely to result in sudden death. Following SC injection in the middle third of the posterior aspect of the ear, thickening and swell-ing (characterized by aseptic cellular infiltrate) of the ear may occur. As with other parenteral injections, localized post-injection bacte-rial infections may result in abscess formation; attention to hygienic pr ocedures can minimize occurrence. Following SC injections at the posterior aspect of the ear where it attaches to the head (base of the ear), areas of discoloration and signs of inflammation may persist at least 13 days post administration resulting in trim loss of edible tiss ue at slaughter. Injection of volumes greater than 20 m L in the middle third of the ear, may result in open draining lesions in a small percentage of cattle. Reproductive/Nursing Safety The manufacturer states that the effects of ceftiofur on bovine re-productive performance, pregnancy, and lactation have not been de termined and the safety of ceftiofur has not been demonstrated for pregnant swine or swine intended for breeding. However, cepha-losporins as a class are relatively safe to use during pregnancy, and te ratogenic or embryotoxic effects would not be anticipated. Target animal safety studies report administration of a single dose of ce ftiofur free acid at the base of the ear to high-producing dairy cat-tle did not adversely affect milk production compared to untreated co ntrols. Ceftiofur in maternal milk would unlikely pose significant risk to offspring. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Use of dosages in excess of 6. 6 mg ceftiofur equiva-lents (CE)/kg or administration by unapproved routes in cattle (sub cutaneous injection in the neck or intramuscular injection) may cause violative residues. Dosages in excess of 5 mg ceftiofur equivalents (CE)/kg or administration by an unapproved route in swine may result in illegal residues in edible tissues. Contact FARAD (see appendix) for assistance in determining appropriate withdrawal times in circumstances where the drug has been used at higher than labeled dosages. Drug Interactions Although the manufacturer does not list any drug interactions on the label for ceftiofur, the following drug interactions have either been reported or are theoretical in humans or animals receiving in-jectable 3rd generation cephalosporins and may be of significance in ve terinary patients receiving ceftiofur: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of par-enteral aminoglycosides or other nephrotoxic drugs (e. g., ampho-tericin B) with cephalosporins is somewhat controversial. Poten-tially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have syner-gistic or additive activity against certain bacteria when used with aminog lycosides, but they should not be mixed together (admin-ister separately). !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins, thereby increasing serum levels and serum half-lives Laboratory Considerations !TNote : Ceftiofur is structurally similar to cefotaxime and it is not known if these interactions occur with ceftiofur. !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test.

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T ! Cephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine. Doses T ! CATTLE: Beef and lactating cattle treatment dose: Administer as a single SC injection in the posterior aspect of the ear where it attaches to the head at the base o f the ear to cattle at 3 mg per lb (6. 6 mg ceftiofur equivalents/kg) body weight (1. 5 m L sterile suspension per 100 lb body weight). The approved site of injection in lactat-ing dairy cattle is at the base of the ear (BOE). (Excede ® Ster ile Suspension; Package Insert—Pfizer) Beef and non-lactating dairy cattle treatment dose: Administer as a single SC injection in the middle third o f the posterior aspect of the ear at a dosage of 6. 6 mg ceftiofur equivalents/kg body weight (1. 5 m L sterile suspension per 100 lb body weight). Most animals will respond to treatment within 3-5 days. If no improvement is observed, the diagnosis should be reevaluated. Administration of ceftiofur free acid into the ear arteries is likely to result in sudden death in cattle. Beef and non-lactating dairy cattle control dose: Administer as a SC injection either in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) to beef and non-lactating dairy cattle at a dosage of 6. 6 mg ceftiofur equivalents (CE)/kg body weight (1. 5 m L sterile suspension per 100 lb body weight). See package in-sert for graphics depicting locations of injection and anatomical landmarks to avoid. (Excede® Sterile Suspension; Package Insert—Pfizer) T ! SWINE: Administer by IM injection in the post-auricular region of the neck as a single dosage of 2. 27 mg ceftiofur equivalents (CE)/lb (5 mg CE/kg) body weight (BW). This is equivalent to 1 m L ster-ile suspension per 44 lb (20 kg) BW. No more than 2 m L should be inject ed in a single injection site Injection volumes in excess of 2 m L may result in violative resi-dues. Pigs heavier than 88 lb (40 kg) will require more than one injectio n. Most animals will respond to treatment within 3-5 days. If no improvement is observed, the diagnosis should be reevaluated. (Excede® For Swine; Package Insert—Pfizer) Monitoring Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Some clinicians recommend weekly CBC monitoring of small ani-mals receiving ceftiofur. Patients with diminished renal function may re quire intensified renal monitoring. Serum levels and thera-peutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms Ceftiofur CFA has a molecular weight of 523. 58. Ceftiofur may also be known as CM-31916, ceftiofuri, or Excede®. Storage/Stability Ceftiofur CFA cattle and swine products should be stored at con-trolled room temperature 20-25 °C (68-77°F). Shak e well before using. Contents should be used within 12 weeks after the first dose is removed. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Ceftiofur Crystalline Free Acid equivalent to 200 mg/m L ceftiofur (in a Miglyol ® cottonseed oil based suspension) in 100 m L vials; Ex-cede® (Pfizer). Approved for use in beef, lactating and non-lactating cattle. If use d in an extra-label manner, contact FARAD (see ap-pendix) for guidance in determining withdrawal times for milk or meat. Ceftiofur Crystalline Free Acid equivalent to 100 mg/m L ceftiofur (in a Migl yol® cottonseed oil based suspension) in 100 m L vials; Ex-cede® for Swine (Pfizer); HUMAN-LABELED PRODUCTS: None CEFTIOFUR HCL (sef-tee-oh-fur) Excenel®, Spectramast® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT A veterinary-only 3rd generation cephalosporin TT Potentially could cause hypersensitivity reactions, granu-locytopenia, thrombocytopenia, or diarrhea TT Causes pain on IM injection to small animals TT May need to reduce dose in renal failure Monograph by Elaine Lust, Pharm D Uses/Indications In swine, ceftiofur HCl injection is labeled for the treatment and control of swine bacterial respiratory disease (swine bacterial pneumonia) associated with Actinobacillus (Haemophilus) pleu-ropneumoniae, Pasteur ella multocida, Salmonella choleraesuis and Streptococcus suis. In cattle, ceftiofur HCl is labeled for the treatment of the fol-lowing bacterial diseases: Bovine respiratory disease (BRD, ship-ping fever, pneumonia) associated with Mannheimia hae molytica, Pasteurella multocida, and Histophilus somni; Acute bovine inter-digital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus; and acute metritis (0-14 days post-partum) associated with bacterial organisms susceptible to ceftiofur. The intramammary syringe for dry dairy cattle (Spectramast DC®) is labe led for the treatment of subclinical mastitis in dairy cattle at the time of dry off associated with Staphylococcus aureus, Streptococcus dysgalactiae, and Streptococcus uberis. The intramam-mary syringe for lactating dairy cattle (Spectramast LC®) is labeled for the treatment of clinical mastitis in lactating dairy cattle associ-ated with coagulase-negative staphylococci, Stre ptococcus dysgalac-tiae, and Escherichia coli. Pharmacology Ceftiofur is a 3rd generation cephalosporin antibiotic active against a variety of gram-positive and gram-negative bacteria and like oth-er cephalosporins inhibits bacteria cell wall synthesis; it is usually bacte ricidal and is a time-dependent antibiotic. After administration, the parent compound (ceftiofur) is rapidly cleaved into furoic acid and desfuroylceftiofur (active). Desfuroylceftiofur inhibits cell wall synthesis (at stage three) of susceptible multiplying bacteria and exhibits a spectrum of activ-ity similar to that of cefotaxime. Parent ceftiofur and the primary metabolite are equally potent and assays to measure microbial sen-sitivity (plasma and tissue levels) are based on ceftiofur equivalents

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referred to as CE. The protein binding activity of ceftiofur creates a “reservoir effect” to maintain active levels at the site of infection. In cattle, ceftiofur has a broad range of in vitro activity against a vari-ety of pathogens,including many species of Pasturella, Str eptococcus, Staphylococcus, Salmonella, and E. coli. In swine, ceftiofur HCl has activity against the pathogens Ac tinobacillus pleuropneumoniae,Pasteurella multocida,Haemophilus parasuis and Streptococcus suis for an extended period of time. Pharmacokinetics In cattle and swine, ceftiofur is rapidly metabolized to desfuroyl-ceftiofur, the primary metabolite. In cattle, ceftiofur sodium and HCl have practically equivalent pharmacokinetic parameters. The following pharmacokinetic values for cattle are for the active me-tabolite desfuroylceftiofur. The volume of distribution in cattle is abou t 0. 3 L/kg. Peak levels are about 7 mcg/m L after IM injection of ceftiofur sodium (Naxcel®), but areas under the curve are practically equal as well as elimination half-lives (approx. 8-12 hours). The elimination kinetics of ceftiofur HCl in milk when used in an ext ralabel manner to treat coliform mastitis has been studied. Milk samples were tested after two, 300 mg doses (6 m L), administered 12 hours apart into the affected mammary quarters. The samples tested at less than the tolerance level for this drug set by FDA by 7 hours after the last intramammary administration. However, the au-thors noted considerable variability in the time required for samples fro m individual cows and mammary gland quarters to consistently have drug residues less than the tolerance level and reported that elimination rates of the drug may be related to milk production. Therefore, cows producing smaller volumes of milk many have pro-longed withdrawal times. (Smith, Gehring et al. 2004) In lactating dairy cattle, active ceftiofur concentrations were measur ed after the administration of 1 mg/kg SC in healthy dairy cattle within 24 hours of calving. Drug concentrations were found to exceed MIC in uterine tissues and lochial fluid for common patho-gens (Okker, J. et al. 2002). In swine, a study measuring tissue distribution following IM injec tion of varying doses revealed the highest concentration were detected in the kidneys, followed by lungs, liver and muscle tissue (Beconi-Barker, Hornish et al. 1996). In swine, the intramuscular bioavailability of the ceftiofur sodium salt and the hydrochloride salt at doses of 3mg/kg or 5mg/kg were compared. The study report-ed similar therapeutic efficacy for both salt forms (Brown, Hanson et al. 1999). Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). In swine, areas of discoloration associated with the injection site at t ime periods of 11 days or less may result in trim-out of edible tissues at slaughter. In cattle, after intramuscular or subcutaneous administration in the ne ck, areas of discoloration at the site may persist beyond 11 days resulting in trim loss of edible tissues at slaughter. Following intramuscular administration in the rear leg, areas of discoloration at the injection site may persist beyond 28 days resulting in trim loss of edible tissues at slaughter. Swine treated with ceftiofur HCl (Excenel ® RTU ) must not be slaughtered for 4 days following the last treatment. Cattle treated with ceftiofur HCl (Excenel® RTU ) must not be slaughtered for 3 days following the last treatment. There is no re-quired milk discard time. Cattle treated with Spectramast DC®, must not be slaughtered for 16 days following the last treatment. Milk taken from cows com-pleting a 30 day dry cow period may be used with no milk discard. Fol lowing label use, no slaughter withdrawal period is required for neonatal calves born from treated cows regardless of colostrum con-sumption. Cattle treated with Sp ectramast LC®, must not be slaughtered for 2 days following the last treatment. Milk taken from cows dur-ing treatment and for 72 hours after the last treatment must be discard ed. Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these age nts and can manifest as rashes, fever, eosinophilia, lymphade-nopathy, or full-blown anaphylaxis. The use of cephalosporins in patie nts documented to be hypersensitive to penicillin-class antibi-otics is controversial. In humans, it is estimated 1-15% of patients hy persensitive to penicillins will also be hypersensitive to cepha-losporins. The incidence of cross-reactivity in veterinary patients is unknow n. Swine safety data: results from a five-day tolerance study in nor-mal feeder pigs indicated that ceftiofur sodium was well tolerated whe n administered at 125 mg ceftiofur equivalents/kg BW (more than 25 times the highest recommended daily dosage) for five con-secutive days. Ceftiofur administered intramuscularly to pigs pro-duced no overt adverse signs of toxicity. Cattle safety data: results from a five-day tolerance study in feed-er calves indicated that ceftiofur sodium was well tolerated at 55 mg ce ftiofur equivalents/kg BW (25 times the highest recommended dose) for five consecutive days. Ceftiofur administered intramuscu-larly had no adverse systemic effects. Reproductive/Nursing Safety The effects of ceftiofur on cattle and swine reproductive perfor-mance,pregnancy,and lactation have not been determined. However, ce phalosporins as a class are relatively safe to use during pregnancy, and teratogenic or embryotoxic effects would not be anticipated. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Cephalosporin overdoses are unlikely to cause significant prob-lems other than GI distress, but other effects are possible (see Ad verse Effects section). Use of dosages in excess of those labeled or by unapproved routes of administration may cause violative resi-dues. Contact FARAD (see appendix) for assistance in determining app ropriate withdrawal times in circumstances where the drug has been used at higher than labeled dosages. Drug Interactions Although the manufacturer does not list any drug interactions on the label for ceftiofur, the following drug interactions have either been reported or are theoretical in humans or animals receiving in-jectable 3rd generation cephalosporins and may be of significance in ve terinary patients receiving injectable ceftiofur: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of par-enteral aminoglycosides or other nephrotoxic drugs (e. g., ampho-tericin B) with cephalosporins is somewhat controversial. Poten-tially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have syner-

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gistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (admin-ister separately). !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives Laboratory Considerations !TNote : Ceftiofur is structurally similar to cefotaxime and it is not known if these interactions occur with ceftiofur. !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine. Doses !TSWINE: a) Administer IM at 3 to 5 mg/kg body weight (1 m L of sterile susp ension per 22 to 37 lb body weight). Treatment should be repeated at 24-hour intervals for a total of three consecu-tive days. (Excenel® RTU; Package Insert—Pfizer) !TCATTLE: For bovine respiratory disease and acute bovine interdigital necrobacillosis: a) Administer IM or SC at 1. 1 to 2. 2 mg/kg (1 to 2 m L sterile susp ension per 100 lb) daily for a total of three consecutive days. Additional treatments may be administered on Days 4 and 5 for animals which do not show a satisfactory response. For or BRD only, administer IM or SC 2. 2 mg/kg every other day on Days 1 and 3 (48h interval). Do not inject more than 15 m L per injection site. (Excenel ® RTU; Package Insert— Pfizer) For acute post-partum metritis: a) Administer by IM or SC 2. 2 mg/kg (2 m L sterile suspension pe r 100 lb ) daily for five consecutive days. Do not inject more than 15 m L per injection site. (Excenel ® RTU; Package Insert—Pfizer) For neonatal salmonellosis: a) Ceftiofur HCl 5 mg/kg IM once daily for 5 days (Fecteau, House et al. 2002) Fo r the treatment of subclinical mastitis in dairy cattle at time of dry off associated with Staphylococcal aureus, Streptococcus dys-galactiae or Streptococcus uberis: a) Infuse one syringe of Sp ectramast® D C into each affected quarter at the time of dry off. (Spectramast® DC; Package Insert—Pfizer) For the treatment of clinical mastitis in lactating dairy cattle associat ed with coagulase-negative staphylococci Streptococcus dysgalactiae or E. coli: a) Infuse one syringe of Sp ectromast® L C into each affected quarter. Repeat this treatment in 24 hours. For extended duration therapy, once daily treatment may be repeated for up to 8 consecutive days. (Spectramast® LC Package Insert— Pfizer) Monitoring Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Some clinicians recommend weekly CBC monitoring of small ani-mals receiving ceftiofur. Patients with diminished renal function may require intensified renal monitoring. Serum levels and ther-apeutic drug monitoring are not routinely performed with these age nts. Chemistry/Synonyms Ceftiofur HCl is a semisynthetic 3rd generation cephalosporin. Ceftiofur HCl is a weak acid and is acid stable and water-soluble with a molecular weight of 560. The injectable sterile suspension in a ready to use formulation that contains ceftiofur hydrochloride equivalent to 50 mg ceftiofur, 0. 50 mg phospholipon, 1. 5 mg sorbi-tan monooleate, 2. 25 mg sterile water for injection, and cottonseed oil. Both Spectramast® products are sterile, oil based suspensions of ceftiofur HCl. Ceftiofur HCl may also be known as U-64279A, ceftiofuri hy-drochloridium or Excenel RTU®. Storage/Stability The ready-to-use injectable product should be stored at controlled room temperature 20 to 25 °C (68 to 77 °F). Shake well before us-ing; protect from freezing. The intramammary syringes should be stored at controlled ro om temperature 20 to 25 °C (68 to 77 °F). Protect from light. Store plastets in carton until used. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Ceftiofur HCL Sterile Suspension for injection, 50 mg/m L in 100 m L vials; Excenel RTU® (Pharmacia/Upjohn); (Rx). Approved for use in cattle and swine. Slaughter withdrawal = 3 days in cattle, and 4 days in swine. There is no required milk discard time. Ceftiofur HCl Sterile Suspension for Intramammary Infusion in Dry Cows 500 mg ceftiofur equivalents (as the HCl) per 10 m L syringe (plastets) in packages of 12 syringes with 70% isopropyl alcohol pads; Spectramast® DC (Pfizer); (Rx) Slaughter withdrawal for cattle = 16 days (no slaughter withdrawal required for neonatal calves born from treated cows) Ceftiofur HCl Sterile Suspension for Intramammary Infusion in Lac tating Cows 125 mg ceftiofur equivalents (as the HCl) per 10 m L syringe (plastets) in packages of 12 syringes with 70% isopropyl alcohol pads; Spectramast® LC (Pfizer); (Rx) Cattle slaughter with-drawal = 2 days; milk discard = 72 hours HUMAN-LABELED PRODUCTS: None

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CEFTIOFUR SODIUM (sef-tee-oh-fur) Naxcel® 3rd GENERATIO N C EPHAL OSPORIN Prescriber Highlights TT A veterinary-only 3rd generation cephalosporin TT Potentially could cause hypersensitivity reactions, granu-locytopenia, thrombocytopenia, or diarrhea TT Causes pain on IM injection to small animals TT May need to reduce dose in patients with renal failure Monograph by Elaine Lust, Pharm D Uses/Indications Labeled indications for ceftiofur sodium: In cattle for treatment of bovine respiratory disease (ship-ping fever, pneumonia) associated with Mannheimia hae molytica, Pasteurella multocida and Histophilus somni. It is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. In swine for treatment/control of swine bacterial respiratory disease (swine ba cterial pneumonia) associated with Actinobacillus (Haemophilus) pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis and Streptococcus suis. In sheep/goats for treatment of sheep/caprine respiratory disease (sheep/go at pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. In horses for treatment of respiratory infections in horses associ-ated with Streptococcus zooepidemicus. In dogs for the treatment of canine urinary tract infections as-sociated with E. coli and Proteus mirabilis. In day old chicks/poults for the control of early mortality, associ-ated with E. coli organisms susceptible to ceftiofur. Ceftiofur sodium has also been used in an extra-label manner in a var iety of veterinary species (see Doses) to treat infections that likely to be susceptible to a 3rd generation cephalosporin. Pharmacology/Actions Ceftiofur is a 3rd generation cephalosporin antibiotic active against a variety of gram-positive and gram-negative bacteria and like other cephalosporins inhibits bacteria cell wall synthesis, is usually bacte-ricidal and is a time-dependent antibiotic. Ceftiofur is rapidly cleaved into furoic acid and desfuroyl-ceftiofur, which is active. Desfuroylceftiofur inhibits cell wall syn-thesis (at stage three) of suscepti ble mu ltiplying bacteria and ex-hibits a spectrum of activity similar to that of cefotaxime. It has a broad range of in vitro activity against a variety of pathogens, in-cluding many species of Pasturella, Strep tococcus, Staphylococcus, Salmonella, and E. coli. Pharmacokinetics In cattle, ceftiofur sodium and HCl have practically equivalent phar-macokinetic parameters. The following pharmacokinetic values for cattle are f or the active metabolite desfuroylceftiofur. The volume of distribution in cattle is about 0. 3 L/kg. Peak levels are about 7mcg/ m L after IM injection of Naxcel®, but areas under the curve are prac-tically equal as well as elimination half-lives (approx. 8-12 hours). Peak levels occur 30-45 minutes after IM dosing. Pharmacokinetic parameters of ceftiofur sodium are very similar for either SC or IM injectio n in cattle. In dairy goats, dosing at 1. 1 mg/kg or 2. 2 mg/kg, administered IV or IM, d emonstrated 100% bioavailability via the IM route. After 5 daily IM doses of the drug, serum concentrations were found to be dose-proportional (Courtin, Craigmill et al. 1997). In horses, 2 grams of ceftiofur were administered via regional IV perfusio n or systemic IV to determine radiocarpal joint synovial flu-id and plasma concentrations. Mean synovial fluid concentrations were higher for the regional IV perfusion than systemic IV adminis-tration. The study concluded regional IV perfusion induced signifi-cantly higher intraarticular antibiotic concentrations in the radio-carpal joint compared to systemic IV administration. Additionally, synovial fluid drug concentrations remained above the MIC for common pathogens for more than 24 hours (Pille, De Baere et al. 2005). Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hy-persensitivity to the drug. Because there may be cross-reactivity, use cephalosp orins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymphade-nopathy, or full-blown anaphylaxis. The use of cephalosporins in patients d ocumented to be hypersensitive to penicillin-class antibi-otics is controversial. In humans, it is estimated 1-15% of patients hype rsensitive to penicillins will also be hypersensitive to cepha-losporins. The incidence of cross-reactivity in veterinary patients is unknown. Withdr awal times: Cattle: 4-day slaughter withdrawal time is re-quired. No milk discard time is required. Swine: A 4-day slaughter withdrawal time is required. Sheep/Goats: No slaughter withdrawal time or milk discard time is required. Not to be used in horses in-tended for human consumption. Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. The use of ceftiofur may result in some signs of immediate and transient local pain to the animal. Following subcutaneous administration of ceftiofur so-dium in the neck, small areas of discoloration at the site may persist beyo nd five days, potentially resulting in trim loss of edible tissues at slaughter. Localized post-injection bacterial infections may result in abscess formation in cattle. Attention to hygienic procedures can minimize their occurrence. The administration of antimicrobials to horses under conditions of str ess may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this antimicrobial and initiate appropriate therapy. One report however, found that ceft-iofur administered to horses (4 mg/kg IM) had minimal effects on fecal flor a (Clark and Dowling 2005). Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymphade-nopathy, or full-blown anaphylaxis. The use of cephalosporins in patients d ocumented to be hypersensitive to penicillin-class antibi-otics is controversial. In humans, it is estimated 1-15% of patients hype rsensitive to penicillins will also be hypersensitive to cepha-losporins. The incidence of cross-reactivity in veterinary patients is unknown.

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Reproductive/Nursing Safety The effects of ceftiofur on the reproductive performance, pregnan-cy, and lactation of cattle, dogs, horses, swine, sheep, and goats have not be en determined. Cephalosporins have been shown to cross the placenta and safe use o f them during pregnancy have 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. Most of these agents (cephalosporins) are excreted in milk in small quantities. Modification/alteration of bowel flora with resul-tant diarrhea is theoretically possible. When dosed as labeled, there are no milk withdrawal times necessary for ceftiofur products in dairy cattle. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). However, overdoses in food animals may result in significantly extended withdrawal times, contact FARAD (see ap-pendix) for assistance. Drug Interactions Although the manufacturer does not list any drug interactions on the label for ceftiofur, the following drug interactions have either been reported or are theoretical in humans or animals receiving in-jectable 3rd generation cephalosporins and may be of significance in ve terinary patients receiving ceftiofur: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. Laboratory Considerations !TNote : Ceftiofur is structurally similar to cefotaxime and it is not known if these interactions occur with ceftiofur. !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins.. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. !TCephalosporins may also cause falsely elevated 17-ketosteroid val-ues in urine. Doses !TCATTLE: a) Administer to cattle by IM or SC injection at 1. 1 to 2. 2 mg/ kg o f body weight (1-2 m L reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24-hour intervals for a total of three consecutive days. Ad-ditional treatments may be given on days four and five for animals which do not show a satisfactory response (not re-covered) after the initial three treatments. (Package Insert; Nax cel®—Pfizer) !TSWINE: a) Administer to swine by IM injection at 3 to 5 mg/kg of body we ight (1m L of reconstituted sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at 24-hour in-tervals for a total of three consecutive days. (Package Insert; Nax cel®—Pfizer) !TSHEEP / GOATS: a) Administer to sheep/goats by IM injection at 1. 1 to 2. 2 mg/ kg o f body weight (1-2 m L reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24 hour intervals for a total of three consecutive days. Addition-al treatments may be given on days four and five for animals whic h do not show a satisfactory response (not recovered) after the initial three treatments. When used in lactating does, the high end of the dosage is recommended. (Package Insert; Naxcel®—Pfizer) !THORSES: a) Administer to horses by IM injection at the dosage of 1 to 2 mg c eftiofur per pound (2. 2 to 4. 4 mg/kg) of body weight (2-4 m L reconstituted sterile solution per 100 lbs body weight). A maximum of 10 m L may be administered per in-jection site. Repeat treatment at 24-hour intervals, continued fo r 48 hours after symptoms have disappeared. Do not ex-ceed 10 days of treatment. (Package Insert; Nax cel®—Pfizer) b) 1-2 mg/kg IV or IM q12-24h (Be rtone 2003b) c) For Lyme disease: 2. 2-4. 4 mg/kg IV q12 hours via a long-term catheter (Divers 1999) d) Foals: 2. 2-4. 4 mg/kg IV or IM q12-24h (B rumbaugh 1999) e) For strangles: Early in infection when only fever and depres-sion are present: ceftiofur sodium 2. 2 mg/kg IM q12-24h. I f lymphadenopathy noted in otherwise healthy and alert horse do not treat. If lymphadenopathy present and horse is de-pressed, febrile, anorexic and especially if dyspneic, treat as abo ve. (Foreman 1999) f) For intrauterine infusion: 1 gram. Little science is available fo r 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) g) Foals: 2. 2-5 mg/kg IM q12h (Giguere 2003a) !TDOGS: a) For susceptible UTI's: 2. 2 mg/kg SC once daily for 5-14 da ys Administer to dogs by subcutaneous injection at the dos-age of 1 mg ceftiofur per pound (2. 2 mg/kg) of body weight (0. 1 m L reconstituted sterile solution per 5 lbs body weight). Tr eatment should be repeated at 24-hour intervals for 5-14 days. (Package Insert; Naxcel®—Pfizer) b) 10 mg/kg once to twice daily (q12-24h) SC (Auc oin 2000) c) For UTI: 2. 2 mg/kg SC once daily for 5-14 day s For systemic, soft tissue infections: 2. 2 mg/kg q12h or 4. 4 mg/kg q24h SC fo r 5-14 days For sepsis, bacteremia: 4. 4 mg/kg q12h SC for 2-5 days (Greene and Watson 1998) d) For neonatal septicemia: 2. 5 mg/kg SC q12h for no longer than 5 day s (Davidson 2004a)

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T ! CATS: a) For UTI: 2. 2 mg/kg SC once daily for 5-14 days Fo r systemic, soft tissue infections: 2. 2 mg/kg q12h or 4. 4 mg/ kg q24h SC for 5-14 day s For sepsis, bacteremia: 4. 4 mg/kg q12h SC for 2-5 days (Greene and Watson 1998) T ! BIRDS: a) Day-Old Turkey Poults: Administer by SC injection in the neck r egion of day-old turkey poults at the dosage of 0. 17 to 0. 5 mg ceftiofur/poult. One m L of the 50 mg/m L recon-stituted solution will treat approximately 100 to 294 day-old poults. Day O ld Chicks: Administer by SC injection in the neck re-gion of day-old chicks at the dosage of 0. 08 to 0. 20 mg ceft-iofur/chick. One m L of the 50 mg/m L reconstituted solution will t reat approximately 250 to 625 day-old chicks. A sterile 26 gauge needle and syringe or properly cleaned automatic injection machine should be used. (Package Insert; Naxcel®— Pfizer) b) Ratites: 10-20 mg/kg IM twice daily (Jenson 1998) T ! REPTILES: a) For chelonians: 4 mg/kg IM once daily for 2 weeks. Common-ly used in respiratory infections. (Gauvin 1993) b) Green iguanas: for microbes susceptible at > 2 µg/m L, 5 mg/ kg, IM or SC, every 24 hours (Bensen, Lee et al. 2003) c) For bacterial pneumonia: 2. 2 mg/kg IM q24-48h; kee p patient at upper end of ideal temperature range (Johnson 2004b) T ! EXOTICS /WILDLIFE: a) Captive Female Asian Elephants: 1. 1 mg/kg IM given two to three t imes a day or, alternatively 1. 1 mg/kg IV once daily, depending upon the MIC of the pathogen (Dumonceax, Isaza et al. 2005) Treatment Monitoring Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Some clinicians recommend weekly CBC monitoring of small ani-mals receiving ceftiofur. Patients with diminished renal function may re quire intensified renal monitoring. Serum levels and thera-peutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms Ceftiofur sodium is a semisynthetic 3rd generation cephalosporin. Ceftiofur sodium is a weak acid and is acid stable and water-soluble. Ceftiofur sodium may also be known as CM 31-916, U 64279E, ceftio fen sodium, Excenel ® (not Excenel ® RTU), Naxcel®, or Accent®. Storage/Stability Unreconstituted ceftiofur sodium powder for reconstitution should be stored at room temperature. Protect from light. Color of the cake may vary from off-white to tan, but this does not affect potency. After reconstitution with bacteriostatic water for injection or sterile water for injection, the solution is stable up to 7 days when refrigerated and for 12 hours at room temperature (15-30°C). According to the manufacturer, if a precipitate should form while being stored refrigerated during this time, the product may be used if it goes back into solution after warming. If not, contact the man-ufacturer. Frozen reconstituted solutions are stable up to 8 weeks. Thawing may be done at room temperature or by swirling the vial under running warm or hot water. One-time salvage procedure for reconstituted product: At the end of the 7-day refrigeration or 12-hour room temperature stor-age period following reconstitution, any remaining reconstituted prod uct may be frozen up to 8 weeks without loss in potency or other chemical properties. This is a one-time only salvage procedure for the remaining product. T o use this salvaged product at any time during the 8-week storage period, hold the vial under warm running water, gently swirling the container to accelerate thawing, or allow the frozen material to thaw at room temperature. Rapid freezing or thawing may result in vial breakage. Any product not used immedi-ately upon thawing should be discarded. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Ceftiofur Sodium Powder for Injection 50 mg ceftiofur/m L when reconstituted in 1 g and 4 g vials; Naxcel®(Pfizer); (Rx). Withdrawal times: Cattle: 4-day slaughter withdrawal time is required. No milk discard time is required. Swine: A 4-day slaughter withdrawal time is required. Sheep/Goats: No slaughter withdrawal time or milk dis-card time is required. Not to be used in horses intended for human consump tion. HUMAN-LABELED PRODUCTS: None CEFTRIAXONE SODIUM (sef-try-ax-ohn) Rocephin® 3rd GENERATION CEPHALOSPORIN Prescriber Highlights TT 3rd generation cephalosporin; achieves high levels in CNS; long half life TT Potentially could cause hypersensitivity reactions, granu-locytopenia/thrombocytopenia, diarrhea, mild azotemia, biliary “sludging” TT Causes pain on IM injection; Give IV over 30 minutes (or more) TT May need to reduce dose in renal failure; avoid with icterus Uses/Indications Ceftriaxone is used to treat serious infections, particularly against susceptible Enterobacteriaceae that are not susceptible to other less expensive agents or when aminoglycosides are not indicated (due to their potential toxicity). Its long half life, good CNS penetration, and activity against Borrelia burgdorferi also has made it a potential choice for treating Lyme's disease. Pharmacology/Actions Ceftriaxone is a third generation injectable cephalosporin agent. The third generation cephalosporins retain the gram-positive activity of the first and second-generation agents, but, have much expanded gram-negative activity. As with the 2nd generation agents, enough variability exists with individual bacterial sensitivities that suscepti-bility testing is necessary for most bacteria. Because of the excel-lent gram-negative coverage of these agents and when compared to the aminogl ycosides and their significantly less toxic potential, they have been used on an increasing basis in veterinary medicine.

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Pharmacokinetics Ceftriaxone is not absorbed after oral administration and must be given parenterally. It is widely distributed throughout the body; CSF levels are higher when meninges are inflamed. Ceftriaxone crosses the placenta and enters maternal milk in low concentra-tions; no documented adverse effects to offspring have been noted. Ce ftriaxone is excreted by both renal and non-renal mechanisms; in humans, elimination half-lives are approximately 6-11 hours. In dogs, ceftriaxone bioavailability after IM or SC administra-tion equal that of IV, but peak levels occur much faster after IM (app roximately 30 minutes) than SC (80 minutes). Peak levels are higher with IM administration than SC, but total area under the curve is similar for both routes. Elimination half-life is longer af-ter SC administration (1. 73 hrs) than either IM (1. 17 hrs) or IV administ ration (0. 88 hrs). The authors of the study (Rebuelto, Albarellos et al. 2002) concluded that once or twice daily IM or SC injections of 50 mg/kg should be adequate to treat most susceptible infections in dogs. Contraindications/Precautions/Warnings Only prior allergic reaction to cephalosporins contraindicates cef-triaxone's use. In humans documented hypersensitive to penicillin, up t o 16% may also be allergic to cephalosporins. The veterinary significance of this is unclear. Although bleeding times have only been reported rarely in hu-mans, ceftriaxone should be used with caution in patients with vi-tamin K utilization or synthesis abnormalities (e. g., severe hepatic disease). Patients in renal failure may need dosage adjustments; but are not g enerally required unless severely uremic, or with concomitant hepatic impairment. Adverse Effects Because veterinary usage of ceftriaxone is very limited, an ac-curate adverse effect profile has not been determined. The fol-lowing adverse effects have been reported in humans and may or may not apply to veterinary patients: hematologic effects, includ-ing eosinophilia (6%), thrombocytosis (5%), leukopenia (2%) and, mo re rarely, anemia, neutropenia, lymphopenia and throm-bocytopenia. Approximately 2-4% o f humans get diarrhea. Very high dosages (100 mg/kg/day) in dogs have caused a “sludge” in bile. Hypersensitivity reactions (usually a rash) have been noted. Increased serum concentrations of liver enzymes, BUN, creatinine, and urine casts have been described in about 1-3% of patients. When given IM, pain may be noted at the injection site. Reproductive/Nursing Safety No teratogenic effects were demonstrated in studies in pregnant mice and rats given up to 20X labeled doses of ceftriaxone. In hu-mans, the FDA categorizes this drug as category B fo r use during 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. ) Ceftriaxone is distributed into milk in low concentrations and is unlike ly to pose much risk to nursing offspring. Overdosage/Acute Toxicity Limited information available; overdoses should be monitored and treated symptomatically and supportively if required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ceftriaxone and may be of significance in veterinary patients: !TAMINOGLYCOSIDES/NEPHROTOXIC DRUGS : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides. !TCALCIUM : Concomitant use with calcium containing solutions have caused fatal calcium-ceftriaxone precipitates in lungs and kidneys of neonatal humans. Do not mix with calcium or admin-ister calcium-containing solutions or products within 48 hours of ceftriaxone administration. Laboratory Considerations !TWhen using Kirby-Bauer disk diffusion procedures for testing susceptibility, a specific 30 micrograms ceftriaxone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for ceftriaxone susceptibility. An inhibition zone of 18 mm or more indicates susceptibility; 14-17 mm, in-termediate; and 13 mm or less, resistant. !TWhen using a dilution susceptibility procedure, an organism with a MIC of 16 micrograms/m L or less is considered susceptible and 64 micrograms/m L or greater is considered resistant. With either method, infections caused by organisms with intermediate sus-ceptibility may be effectively treated if the infection is limited to tiss ues where the drug is concentrated or if a higher than normal dose is used. !TCeftriaxone, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e. g., Clinitest®). !TCeftriaxone in very high concentrations (50 micrograms/m L or greater) may cause falsely elevated serum creatinine levels when manual methods of testing are used. Automated methods do not appear to be affected. Doses !TDOGS: a) For meningitis/borreliosis: 15-50 mg/kg (maximum single dose in humans is 1 gram) IV or IM q12h for 4-14 day s For preoperative/intraoperative use: 25 mg/kg (maximum single dose in humans is 1 gram) IM or IV one time For skin, genitourinary infections: 25 mg/kg IM once daily (q24h) fo r 7-14 days (Greene and Watson 1998) b) For infectious endocarditis and documented resistance against or other contraindications for fluoroquinolones and aminoglycosides in dogs: 20 mg/kg IV q12h (De Francesco 2000) c) 15-50 mg/kg (route not specified) once daily (Trepanier 1999) !TCATS: For systemic infections: a) 25-50 mg/kg IV, IM or Intraosseous q12h as long as neces-sary (Greene and Watson 1998) !THORSES: For susceptible infections: a) 25-50 mg/kg q12h IV or IM ( Note : This is a human dose and should be used as a general guideline only) (Walker 1992) b) 20 mg/kg IV q12h (B rumbaugh 1999)

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Monitoring T ! Efficacy CEFUROXIME AXETIL T ! If long-term therapy, occasional CBC, renal function (BUN, Se-CEFUROXIME SODIUM rum Creatinine, urinalysis) and liver enzymes (AST, ALT) may be considered. (sef-yoor-oks-eem) Ceftin®, Zinacef® Chemistry/Synonyms 2nd GENERATION CEPHALOSPORIN A third generation cephalosporin, ceftriaxone sodium occurs as a white to yellowish-orange crystalline powder. It is soluble in water Prescriber Highlights (400 mg/m L at 25°C). Potencies of commercial products are ex-pressed in terms of ceftriaxone. One gram of ceftriaxone sodium TT Oral & parenterally administered 2nd generation cepha-losporin that is more active against some gram-negative contains 3. 6 m Eq of sodium. bacteria than first generation (e. g., cephalexin, cefazolin) Ceftriaxone Sodium may also be known as: ceftriaxonum na-cephalosporins tricum, Ro-13-9904, or Ro-13-9904/000; many trade names are available. TT Potentially useful in small animals when a cephalosporin is desired to treat bacterial infections susceptible to ce-Storage/Stability/Compatibility furoxime, but resistant to first generation cephalosporins, The sterile powder for reconstitution should be stored at or below when enhanced gram-negative coverage is desired 25°C and protected from light. for surgery prophylaxis, or when high CNS levels are After reconstituting with either 0. 9% sodium chloride or D 5W, necessary ceftriaxone solutions (at concentrations of approximately 100 mg/ m L) are stable for 3 days at room temperature and for 10 days when TT Limited clinical experience in veterinary medicine refrigerated. Solutions of concentrations of 250 mg/m L are stable TT Adverse effects most likely seen in small animals would for 24 hours at room temperature and 3 days when refrigerated. At be GI-related concentrations of 10-40 mg/m L solutions frozen at-20°C are stable for 26 weeks. The manufacturer does not recommend admixing any other anti-infective drugs with ceftriaxone sodium, but amikacin Uses/Indications and metronidazole are reported compatible. Cefuroxime is a semi-synthetic 2nd generation cephalosporin with Do not mix with calcium or calcium-containing solutions, or ad-enhanced activity against some gram-negative pathogens when minister calcium-containing solutions or products within 48 hours compared to the first generation agents. Cefuroxime is available in of ceftriaxone administration (see Drug Interactions). both oral and parenteral dosage forms. It potentially may be useful in small animals when a cephalosporin is desired to treat bacterial Dosage Forms/Regulatory Status infections susceptible to cefuroxime, but resistant to first generation VETERINARY-LABELED PRODUCTS: None cephalosporins, when enhanced gram-negative coverage is desired HUMAN-LABELED PRODUCTS: for surgery prophylaxis, or when high CNS levels are necessary. Ceftriaxone Powder for Injection: 250 mg, 500 mg, 1 g, & 2g (as Little information is available with regard to its clinical use in small base) in vials, piggyback vials, ADD-Vantage vials, duplex bags and animals, however. in bulk; Rocephin® (Roche); generic; (Rx) Pharmacology/Actions Ceftriaxone Injection: in 5% dextrose in Water 1 g and 2 g in frozen, Cefuroxime, like other cephalosporins, is bactericidal and acts by premix ed 50 m L containers; Rocephin® (Roche); generic; (Rx) inhibiting cell wall synthesis. Its spectrum of activity is similar to that of c ephalexin, but it is more active against gram-negative bac-teria including strains of E. coli, Klebsiella pneumoniae, Salmonella and Enterobacter. It is not effective against methicillin-resistant Staphylococcus, Pseudomonas, Serratia or Enterococcus. For more information on cephalosporin pharmacology and spectrums of ac-tivity, refer to the Cephalosporin monograph. Pharmacokinetics No information was located for the pharmacokinetics of cefuroxime in dogs, cats or horses. In humans, cefuroxime axetil is well absorbed after oral admin-istration and is rapidly hydrolyzed in the intestinal mucosa and cir-culation to the parent compound. Bioavailability ranges on average from 37% (fasted) to 52% (with food). Peak serum levels occur in about 2-3 hours after oral dosing. When the sodium salt is adminis-tered IM, peak levels occur within 15 minutes to 1 hour. Cefuroxime is wide ly distributed after absorption, including to bone, aqueous humor and joint fluid. Therapeutic levels can be attained in the CSF if meninges are inflamed. Binding to human plasma proteins ranges from 35-50%. Cefuroxime is primarily excreted unchanged in the urine; elimination half-life in patients with normal renal function is between 1-2 hours.

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Contraindications/Precautions/Warnings No specific information is available for veterinary patients. In hu-mans, cefuroxime is contraindicated in patients hypersensitive to it o r other cephalosporins. Dosage adjustment is recommended in humans with severe renal impairment. Adverse Effects As usage of cefuroxime in animals has been limited, a comprehen-sive adverse effect profile has not been determined. A six-month to xicity study of oral cefuroxime axetil given at dosages ranging from 100 mg/kg/day to 1600 mg/kg day in Beagles demonstrated little adversity associated with cefuroxime. At the highest dosing levels (approximately 80X), some vomiting and slight suppression of body weight gain were noted. Minor reductions in neutrophils and red cells, with increases in prothrombin times were also seen. When used clinically in dogs, gastrointestinal effects (inap-petance, vomiting, diarrhea) would be the most likely expected ad-verse effects, but incidence rates are not known. Cefuroxime is generally well tolerated in human patients. Inje ction site inflammation can occur when cefuroxime is used in-travenously. Gastrointestinal effects (nausea, diarrhea) may occur, bu t are not frequently reported. Eosinophilia and hypersensitivity reactions (including anaphylaxis) are possible. Neurologic effects (hearing loss, seizures), pseudomembranous colitis, serious derma-tologic reactions (TEN, Stevens-Johnson syndrome, etc. ), hema-tologic effects (pancytopenia, thrombocytopenia), and interstitial nep hritis have all been reported rarely in humans. Reproductive/Nursing Safety Studies performed in pregnant mice at dosages of up to 6400 mg/kg and rabbits at 400 mg/kg demonstrated no adverse fetal effects. In humans, the FDA categorizes cefuroxime 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. ) Cefuroxime enters maternal milk in low concentrations. Althoug h probably safe for nursing offspring the potential for ad-verse effects cannot be ruled out, particularly alterations to gut flora with r esultant diarrhea. Overdosage/Acute Toxicity Beagles receiving daily dosages of up to 1600 mg/kg/day orally tol-erated cefuroxime well (see Adverse Effects). Cerebral irritation with seizures has been reported with large ov erdoses in humans. Plasma levels of cefuroxime can be reduced with hemodialysis or peritoneal dialysis. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefuroxime and may be of significance in veterinary patients: !TAMINOGLYCOSIDES : Potential for increased risk of nephrotoxicity— monitor renal function; however, aminoglycosides and cepha-losporins may have synergistic or additive actions against some gram-negative bacteria (Enterobacteriaceae) !TFUROSEM IDE, TORSEM IDE: Possible increased risk of nephrotoxicity !TPROBENECID : Reduced renal excretion of cefaclor Laboratory Considerations !TCefuroxime may cause false-positive urine glucose determinations when using the copper reduction method (Benedict's solution, Fehling's solution, Clinitest ®); tests utilizing glucose oxidase (Tes-Tape ®, Clinistix ®) are not affected by cephalosporins !! In humans, particularly with azotemia, cephalosporins have cause d a false-positive direct Coombs' test Doses !TDOGS: For susceptible infections: a) For soft tissue infections: 10 mg/kg PO q12h for 10 days. For syst emic infections: 15 mg/kg IV q8h. For meningitis: 30 mg/ kg IV q8h. Note : All dosages extrapolated from human dos-ages. (Greene, Hartmannn et al. 2006) For surgery prophylaxis: a) 20 mg/kg IV 30 minutes prior to surgery and every 2 hours dur ing surgery. (Greene, Hartmannn et al. 2006) Monitoring !TClinical efficacy !TMonitor renal function in patients with renal insufficiency Client Information !TGive the oral tablets with food as it may enhance the absorption of the drug !TAvoid crushing tablets; a strong, bitter taste results even if mixed into food; if tablets must be crushed, give with dairy products such as milk or chocolate milk to improve absorption and palatability !TGive as directed by the veterinarian; even if animal appears well, continue treating for the full duration prescribed !TContact veterinarian if animal develops severe vomiting/diarrhea or rash/itching Chemistry/Synonyms Cefuroxime axetil occurs as a white or almost white, powder that is insoluble in water and slightly soluble in dehydrated alcohol. Cefuroxime sodium occurs as a white or almost white, hygro-scopic powder that is freely soluble in water. Cefuroxime may also be known as: CCI-15641, cefuroxim, cefu-roxima, cefuroximum, cefuroksiimi, or cefuroksimas; many inter-nationally registered trade names are available. Storage/Stability/Compatibility Cefuroxime axetil tablets should be stored in tight containers at room temperature (15-30°C); protect from excessive moisture. The powder for suspension should be stored at 2-30°C. Onc e reconstituted, it should be kept refrigerated (2-8°C) and any un-used suspension discarded after 10 days. The powder for injection of infusion should be stored at room te mperature (15-30°C). The powder may darken, but this does not indicate any loss of potency. When reconstituted with sterile water to a concentration of 90 mg/m L, the resulting solution is stable for 24 hours at room temperature; 48 hours if refrigerated. If further diluted into a compatible IV solution such as D5W, normal saline or Ringer's, the resulting solution is stable for 24 hours at room tem-perature; up to 7 days if refrigerated. Drugs that are reportedly compatible when mixed with cefu-roxime for IV use include, clindamycin, furosemide and metron-idazole. Drugs that may be given at a Y-site with a cefuroxime in-fusion running include, morphine, hydromorphone, and propofol. Amino glycosides, ciprofloxacin, or ranitidine should not be ad-mixed with cefuroxime. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cefuroxime Axetil Tablets (film coated): 125 mg, 250 mg, & 500 mg; Ceftin® (Glaxo Wellcome), generic; (Rx)

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Cefuroxime Axetil Powder for Oral Suspension: 25 mg/m L & 50 mg/ m L in 50 and 100 m L bottles; Ceftin® (Glaxo Wellcome); (Rx) Cefuroxime Sodium Powder for Injection: 750 mg, 1. 5 g, and 7. 5 g (bulk packag e); Zinacef® (Glaxo Wellcome); generic; (Rx) Also available in premixed 750 mg and 1. 5 g per 50 m L frozen bags. CEPHALEXIN (sef-a-lex-in) Keflex® 1st GENERATION CEPHALOSPORIN Prescriber Highlights TT 1st generation oral cephalosporin (available for injection in other countries) TT May be administered with food (especially if GI upset occurs) TT Most likely adverse effects are GI in nature; hypersensi-tivity reactions possible TT May need to reduce dose in patients with renal failure Uses/Indications There are no approved cephalexin products for veterinary use in the USA. However, it has been used clinically in dogs, cats, horses, rab-bits, ferrets, and birds, particularly for susceptible Staphylococcal infect ions. Pharmacology/Actions A first generation cephalosporin, cephalexin exhibits activity against the bacteria usually covered by this class. Cephalosporins are bacte-ricidal against susceptible bacteria and act by inhibiting mucopep-tide synthesis in the cell wall resulting in a defective barrier and an osmotically unstable spheroplast. The exact mechanism for this ef-fect has not been definitively determined, but beta-lactam antibiot-ics have been shown to bind to several enzymes (carboxypeptidases, transpe ptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that various beta-lactam antibiotics have for these enzymes (also known as penicillin-binding proteins; PBPs) help explain the differences in spectrums of activity of these drugs that are not ex-plained by the influence of beta-lactamases. Like other beta-lactam antibiotics, cephalosporins are generally considered to be more ef-fective against actively growing bacteria. While there may be differences in MIC's for individual first gen-eration cephalosporins, their spectrums of activity are quite similar. They p ossess generally excellent coverage against most gram-pos-itive pathogens and variable to poor coverage against most gram-negati ve pathogens. These drugs are very active in vitro against groups A beta-hemolytic and B Streptococci, non-enterococcal group D Streptococci (S. bovis), Staphylococcus intermedius and aureas, Proteus mirabilis and some strains of E. coli, Klebsiella spp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most anaer-obes are very susceptible to the first generation agents. Most spe-cies of Corynebacteria are susceptible, but C. equi (Rhod ococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally administered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the 1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-positi ve Proteus spp., Pseudomonas sp., Enterobacter spp., Serratia spp. and Citrobacter spp. Pharmacokinetics After oral administration, cephalexin is rapidly and completely ab-sorbed in humans. Cephalexin (base) must be converted to the HCl befo re absorption can occur and, therefore, absorption can be de-layed. There is a form of cephalexin HCl commercially available for oral use that apparently is absorbed more rapidly, but the clinical significance of this is in question. Food apparently has little impact on absorption. In a study done in dogs and cats (Silley et al. 1988), peak serum levels reached 18. 6 micrograms/m L about 1. 8 hours after a mean oral dose of 12. 7 mg/kg in dogs, and 18. 7 micrograms/m L, 2. 6 hours after an oral dose of 22. 9 mg/kg in cats. Elimination half-lives ranged from 1-2 hours in both species. Bioavailability was about 75% in both species after oral administration. In horses, oral cephalexin has low bioavailability (approx. 5%) and a shor t plasma half-life (about 2 hours), but at doses of 30 mg/ kg PO q8h sufficient plasma and interstitial levels were achieved to treat gram-positive bacteria (MIC ≤5 mcg/m L) (Davis, Salmon et al. 2005). In the U. K., an oily suspension of the sodium salt (Ceporex ® Inject ion—Glaxovet) is apparently available for IM or SC injection in animals. In calves, the sodium salt had a 74% bioavailability after IM injection and a serum half-life of about 90 minutes. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Oral systemic antibiotics should not be administered in patients with sep ticemia, shock or other grave illnesses as absorption of the medication from the GI tract may be significantly delayed or di-minished. Parenteral routes (preferably IV) should be used for these cases. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. In addition to the adverse effects listed below, cephalexin has repor tedly caused salivation, tachypnea and excitability in dogs, and emesis and fever in cats. Nephrotoxicity occurs rarely during ther-apy with cephalexin, but patients with renal dysfunction, receiving other nep hrotoxic drugs or that are geriatric may be more suscep-tible. Interstitial nephritis, a hypersensitivity reaction, has been re-ported with many of the cephalosporins including cephalexin. The incidence o f these effects is not known. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymphade-nopathy, or full-blown anaphylaxis. The use of cephalosporins in patients d ocumented to be hypersensitive to penicillin-class antibi-otics is controversial. In humans, it is estimated 1-15% of patients hype rsensitive to penicillins will also be hypersensitive to cepha-losporins. The incidence of cross-reactivity in veterinary patients is unknown. Whe n given orally, cephalosporins may cause GI effects (anorexia, vomiting, diarrhea). Administering the drug with a small meal may help alleviate these effects. Because the cephalosporins may also alter gut flora, antibiotic-associated diarrhea or proliferation of resistant bacteria in the colon can occur.

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Rarely, cephalexin has been implicated in causing toxic epider-mal necrolysis in cats. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocytosis, thrombocytopenia, hepa-titis, positive Coomb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an immunolo gic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes cephalexin as cat egory 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. ) Small amounts of cephalexin may be distributed into maternal milk; it c ould potentially affect gut flora in neonates. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cephalexin and may be of significance in veterinary patients: !TPROBENECID : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives Laboratory Considerations !TExcept for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. !TWhen using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values. !TIn humans, particularly with azotemia, cephalosporins have caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated 17-ketosteroid values in urine. Doses !TDOGS: For susceptible infections: a) For susceptible Staph infections: 30 mg/kg PO q12h (may not be adequate dose for non-UTI's caused by E. coli) (Campbell and Rosin 1998) b) For pyoderma: 22-35 mg/kg PO q12h or 22 mg/kg PO q8h For respiratory infections: 20-40 mg/kg PO q8h; For soft tis-sue infections: 30-50 mg/kg PO q12h Fo r systemic infections: 25-60 mg/kg PO q8h For orthopedic infections: 22-30 mg/kg PO q6-8h for 28 days For above doses, guideline for duration of therapy is treat for 5-7 da ys beyond resolution of clinical disease or preferably negative culture (Greene and Watson 1998) c) For Gram-positive infections: 22 mg/kg PO twice daily For Gram-negative infections: 30 mg/kg PO three times daily (Auc oin 2000) d) For treating infectious otitis: 22 mg/kg PO q12h (Kwochka 2002) e) For pyometra/metritis: 10-30 mg/kg PO q8-12h (F resh-man 2002a) f) For UTI: 30-40 mg/kg PO q8h. For acute urethrocystitis, tr eatment may be 7-10 days for chronic urethrocystitis, up to 4 weeks of treatment may be necessary; for pyelonephritis, 4-8 weeks may be adequate (Brovida 2003) g) For neonates: 10-30 mg/kg PO (weak neonates should be gi ven via stomach tube) twice daily-three times daily (Fresh-man 2002b) h) For juvenile cellulitis in 3-16 w eek old puppies: 20 mg/kg PO three times daily (Macintire 2004) i) For recurrent pyoderma: 22 mg/kg PO q12h (use at q8h for de ep pyoderma) (Hillier 2006b) j) For superficial and deep pyoderma: 22-33 mg/kg PO two to thre e times daily (Beale and Murphy 2006) !TCATS: For susceptible infections: a) For soft tissue infections: 30-50 mg/kg PO q12h Fo r systemic infections: 35 mg/kg PO q6-8h. For above doses, guideline for duration of therapy is treat for 5-7 days beyond resolution of clinical disease or preferably ne gative culture (Greene and Watson 1998) b) 22 mg/kg PO q8h; administer with food if GI upset occurs (V aden and Papich 1995) c) For Gram+ infections: 22 mg/kg PO twice daily d) For Gram-infections: 30 mg/kg PO three times daily (Au-coin 2000) e) 20-40 mg/kg PO q8h (Lappin 2002a) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 11-22 mg/kg PO q8h (Ivey and Morrisey 2000) b) Guinea pigs: 50 mg/kg IM q24h (Adamcak and Otten 2000) !TFERRETS: For susceptible infections: a) 15-25 mg/kg PO 2-3 times dail y (Williams 2000) !THORSES: For susceptible infections: a) 30 mg/kg PO q8h (Davis, Salmon et al. 2005) b) 22-33 mg/kg PO q6h (Brumbaugh 1987) !TBIRDS: For susceptible infections: a) 35-50 mg/kg PO four times daily (using suspension); most pr eps are well accepted (Clubb 1986) b) 40-100 mg/kg q6h PO (Hoeffer 1995) c) Ratites: 15-22 mg/kg PO three times daily; For megabacte-riosis: 50 mg/kg PO 4 times daily for 5 days (Jenson 1998)

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Monitoring T ! Because cephalosporins usually have minimal toxicity associ-ated with their use, monitoring for efficacy is usually all that is requ ired T ! Patients with diminished renal function may require intensified renal monitoring. Serum levels and therapeutic drug monitoring are not routinely done with these agents Chemistry/Synonyms A semi-synthetic oral cephalosporin, cephalexin (as the monohy-drate) occurs as a white to off-white crystalline powder. It is slightly soluble in wate r and practically insoluble in alcohol. Cephalexin may also be known as: cefalexin, 66873, or cefalexi-num; many trade names are available. Storage/Stability Cephalexin tablets, capsules, and powder for oral suspension should be stored at room temperature (15-30°C) in tight containers. After reconstitution, the oral suspension is stable for 2 weeks. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cephalexin Capsules: 250 mg, 333 mg, 500 mg & 750 mg; Tablets: 250 mg & 500 mg; Keflex® (Advancis); generic; (Rx) Cephalexin Powder for Oral Suspension: 125 mg/5m L and 250 mg/5 m L (after reconstitution) in 100 m L and 200 m L; Keflex®(Advancis); generic; (Rx) CEPHAPIRIN SODIUM CEPHAPIRIN BENZATHINE (sef-a-pye-rin) Cefa-Lak®, Cefa-Dri® 1st GENERATION CEPHALOSPORIN Prescriber Highlights TT 1st generation intramammary cephalosporin TT Potentially could cause hypersensitivity reactions TT Watch withdrawal times Uses/Indications In the USA, there are no longer parenterally administered cephapi-rin products available. An intramammary cephapirin sodium product (Cefa-Lak®, To DAY ®—Fort Dodge) is approved for use in the treatment of mas-titis in lactating dairy cows and cephapirin benzathine (Cefa-Dri®, To MORROW ®—Fort Dodge) is approved in dry cows. Pharmacology/Actions A first generation cephalosporin, cephapirin exhibits activity against the bacteria usually covered by this class. A cephalothin disk is usu-ally used to determine bacterial susceptibility to this antibiotic when using the Kir by-Bauer method. Cephalosporins are usually bacteri-cidal against susceptible bacteria and act by inhibiting mucopeptide synthesis in the c ell wall resulting in a defective barrier and an os-motically unstable spheroplast. The exact mechanism for this effect has not be en definitively determined, but beta-lactam antibiotics have been shown to bind to several enzymes (carboxypeptidases, transpeptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that v arious beta-lactam antibiotics have for these enzymes (also known as penicillin-binding proteins; PBPs) help explain the differences in these drugs' spectrums of activity that are not ex-plained by the influence of beta-lactamases. Like other beta-lactam antibiotics, cephalosporins are generally considered more effective against actively growing bacteria. Pharmacokinetics In cattle when used systemically, the apparent volume of distribu-tion has been reported as 0. 335-0. 399 L/kg; total body clearance is 12. 66 m L/min/kg and serum elimination half-life is about 64-70 minutes in cattle. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in patients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam antibiotics (e. g., penicillins, cefamy-cins, carbapenems). Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Potentially, hypersensitivity reactions could occur with intra-mammary infusion. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eo-sinophilia, lymphadenopathy, or full-blown anaphylaxis. The use of ce phalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is esti-mated 1-15% of pat ients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary patients is unknown. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but neither have there been any documented teratogenic problems associated with these drugs. See label information for more information. Overdosage/Acute Toxicity No clinical effects would be expected but if used at doses or rates higher than labeled, withdrawal times may be prolonged. Drug Interactions No significant concerns when used via the intramammary route Laboratory Considerations No significant concerns when used via the intramammary route Doses T ! CATTLE: For mastitis: a) Lactating cow (Cefa-Lak®): After milking out udder, clean and dry t eat area. Swab teat tip with alcohol wipe and allow to dry. Insert tip of syringe into teat canal; push plunger to instill entire contents. Massage quarter and do not milk out for 12 hours. May repeat dose q12h. (Label directions; Cefa-Lak®—Fort Dodge) b) Dry Cow (Cefa-Dri®): Same basic directions as above, but should be d one at the time of drying off and not later than 30 days prior to calving. (Label directions; Cefa-Dri®—Fort Dodge)

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Monitoring T ! Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is re-quired. T ! Patients with diminished renal function may require intensified renal monitoring. Serum levels and therapeutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms An intramammary semi-synthetic cephalosporin antibiotic, cep-hapirin sodium occurs as a white to off-white, crystalline powder having a faint odor. It is very soluble in water and slightly soluble in alcohol. Each gram of the injection contains 2. 36 m Eq of so-dium. After reconstitution, the solution for injection has a p H of 6. 5-8. 5. Cephapirin sodium may also be known as: BL-P-1322, cefapirin, cefapirin um natricum, Brisfirina®, Cefa-Dri®, Cefa-Lak®, Cefaloject®, Cefatrex®, Lopitrex®, or Piricef®, To DAY®or To MORROW®. Storage/Stability Cephapirin intramammary syringes should be stored at controlled room temperature (15-30°C); avoid excessive heat. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cephapirin Sodium Mastitis Tube; 200 mg cephapirin per 10 m L tube; To DAY® (Fort Dodge), Cefa-Lak® (Fort Dodge); (OTC). Ap-proved for use in lactating dairy cattle. Milk withdrawal = 96 hours; Slaughte r withdrawal = 4 days. Cephapirin Benzathine Mastitis Tube; 300 mg cephapirin per 10 m L tube; T o MORROW® (Fort Dodge), Cefa-Dri® (Fort Dodge); (OTC). Approved for use in dry dairy cattle. Milk withdrawal = 72 hours after calving and must not be administered within 30 days of calving; Slaughter withdrawal = 42 days. HUMAN-LABELED PRODUCTS: None CETIRIZINE HCL (she-tih-ra-zeen) Zyrtec® 2nd GENERATION ANTIHISTAMINE Prescriber Highlights TT Oral, relatively non-sedating antihistamine TT Limited clinical experience in veterinary medicine; rec-ommended dosages for dogs & cats vary widely but the drug appears w ell tolerated TT Potentially may cause vomiting, hypersalivation, or som-nolence in small animals TT Expensive when compared to 1st generation antihista-mines; generic products becoming available Uses/Indications Cetirizine is a H 1 receptor blocking antihistamine agent that may be useful for the adjunctive treatment of histamine-mediated pru-ritic conditions in dogs or cats. Pharmacology/Actions Cetirizine, a human metabolite of hydroxyzine, is a piperazine-class non-sedating (when compared to first generation drugs) antihista-mine. It selectively inhibits peripheral H 1 rece ptors. Cetirizine does not possess significant anticholinergic or anti-serotonergic effects. T oleranc e to its antihistaminic effects is thought not to occur. Pharmacokinetics No specific information was located for the pharmacokinetics of cetirizine in dogs. In a study performed in cats (Papich, Schooley et al. 2006) after an oral dose of 5 mg, volume of distribution was 0. 26 L/kg and clearance about 0. 3 m L/L/minute. T erminal elimination half-life was approximately 11 hours. The mean plasma concentra-tions remained above 0. 85 mcg/m L (a concentration reported to be effec tive for humans) for 24 hours after dosing. After oral administration to humans, cetirizine peak concentra-tions occur in about one hour. Food can delay, but not affect the extent of, absorption. It is 93% bound to human plasma proteins and brain levels are approximately 10% of those found in plasma. Approximately 80% is excreted in the urine, primarily as unchanged drug. T erminal elimination half-life is around 8 hours; antihista-minic effect generally persists for 24 hours after a dose. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. In hu-mans, cetirizine is contraindicated in patients hypersensitive to it or hydro xyzine. Dosage adjustment is recommended in humans with severe renal or hepatic impairment, or older than 76 years of age. The combination product containing pseudoephedrine is not appro priate for use in dogs or cats. Adverse Effects Cetirizine appears well tolerated in dogs and cats. Vomiting or hypersalivation after dosing have been reported in some dogs. Drowsiness has been reported in small dogs at higher dosages. In humans, the primary adverse effects reported have been drowsiness (13%) and dry mouth (5%). Rarely, hypersensitivity re-actions or hepatitis have been reported. Reproductive/Nursing Safety In pregnant mice, rats, and rabbits, dosages of approximately 40X, 180X, and 220X respectively, of the human dose when compared on mg/m2 basis, caused no teratogenic effects. In humans, the FDA categorizes cetirizine 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 Beagles, approximately 3% of a dose was excreted into milk. Although p robably safe for use in nursing veterinary patients, the manufacturer does not recommend using cetirizine in nursing women. Overdosage/Acute Toxicity Limited information is available. Reported minimum lethal oral doses for mice and rats are 237 mg/kg (95X human adult dose on a mg/m2 basis) and 562 mg/kg (460X human adult dose on a mg/m2 basis), respectively. Unlike the earlier non-sedating antihistamines, terfenadine and astemizole (both no longer available in the USA), cetirizine does not appreciably prolong the QT interval on ECG at high serum levels. Overdoses of cetirizine products that also contain pseudoephed-rine (Zyrtec-D 12 Hour®) may be serious. It is advised to contact an animal poison c ontrol center in this event.

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Drug Interactions The following drug interactions have either been reported or are CHARCOAL, ACTIVATED theoretical in humans or animals receiving cetirizine and may be of (char-kole) Toxiban® significance in veterinary patients: ! !CNS DEPRESSANTS : Additive CNS depression if used with cetirizine ORAL ADSORBENT Laboratory Considerations Prescriber Highlights T ! None noted, however discontinue medication well in advance of any hypersensitivity skin testing TT Orally administered adsorbent for GI tract toxins/drug overdoses Doses TT Not effective for mineral acids/alkalis T ! DOGS: TT Too rapid administration may induce emesis/aspiration a) For atopic dermatitis: 1 mg/kg PO once daily with or without food. Satisfactory control of pruritus in 18% of dogs evalu-TT In small dogs & cats, monitor for hypernatremia ated in the study. (Cook, Scott et al. 2004) TT Handle with care as charcoal stains clothing very easily; b) For atopic dermatitis: 5-10 mg (total dose) PO once daily dry powder “floats” (Thomas 2005a) c) For allergic dermatitis: 1 mg/kg PO q12h (Hillier 2004) T ! CATS: Uses/Indications Activated charcoal is administered orally to adsorb certain drugs or a) For adjunctive treatment of non-responsive chronic rhi-toxins to prevent or reduce their systemic absorption. nosinusitis: 5 mg (total dose) PO q12h (Hawkins and Cohn 2006) Pharmacology/Actions b) For adjunctive treatment of eosinophilic dermatopathies: 5 Activated charcoal has a large surface area and adsorbs many chemi-mg (total dose) PO q12h (Hnilica 2003b) cals and drugs via ion-ion, hydrogen bonding, dipole and Van der c) For adjunctive treatment of pruritus: 2. 5-5 mg (total dose) Walle f orces in the upper GI tract thereby preventing or reducing PO once daily. (Mac Donald 2002a) their absor ption. Efficiency of adsorption increases with the mo-lecular size of the toxin and poorly water soluble organic substances Monitoring are better adsorbed than small, polar, water-soluble organic com-T ! Clinical efficacy pounds. T ! Adverse effects (vomiting, somnolence) While activated charcoal also adsorbs various nutrients and en-zymes from the gut, when used for acute poisonings, no clinical Client Information significance usually results. Activated charcoal reportedly is not ef-T ! Warn clients of the potential costs fective in adsorbing cyanide, but this has been disputed in a recent T ! Potential adverse effects include GI effects (vomiting, hypersaliva-study. It is not very effective in adsorbing alcohols, ferrous sulfate, tion) and somnolence lithium, caustic alkalies, nitrates, sodium chloride/chlorate, petro-T ! May be given without regard to feeding status leum distillates or mineral acids. Chemistry/Synonyms Pharmacokinetics Cetirizine HCl occurs as a white to almost white, crystalline powder Activated charcoal is not absorbed nor metabolized in the gut. that is free l y soluble in water. A 5% solution has a p H of 1. 2-1. 8. Cetirizine may also be known as: UCB-P071, P-071, cetirizina, Contraindications/Precautions/Warnings cetirizini, cetirizin, ceterizino, or Zyrtec®; many internationally reg-Charcoal should not be used for mineral acids or caustic alkalies as istered trade names are available. it is ineffective. Although not contraindicated for ethanol, metha-nol, or iron salts, activated charcoal is ineffective in adsorbing these Storage/Stability products and may obscure GI lesions during endoscopy. Tablets should be stored at 20-25°C; ex cur sions are permitted to 15-30°C. The oral syrup may be stored at room temperature or in Adverse Effects the refrigerator. Very rapid GI administration of charcoal can induce emesis. If aspi-ration occurs after activated charcoal is administered, pneumonitis/ Dosage Forms/Regulatory Status aspiration pneumonia may result. Charcoal can cause either con-VETERINARY-LABELED PRODUCTS: None stipation or diarrhea and feces will be black. Products containing The ARCI (Racing Commissioners International) has designated sorbitol may cause loose stools and vomiting. this drug as a class 4 substance. There have been reports of hypernatremia occurring in small dogs and cats after charcoal (with or without sorbitol) administration, HUMAN-LABELED PRODUCTS: presumably due an osmotic effect pulling water into the GI tract. Cetirizine HCl Tablets (film-coated): 5 mg & 10 mg; Zyrt ec® (Pfiz-Reduced sodium fluids (e. g., D5W, H nor mal saline/D2. 5W ) with er), generic; (Rx) warm water enemas can be administered to alleviate the condition. Cetir izine HCl Chewable Tablets (grape flavor): 5 mg & 10 mg; Charcoal powder is very staining and the dry powder tends to Zyrtec® (Pfizer), generic; (Rx) “float” covering wide areas. Cetirizine HCl Syrup: 1 mg/m L (banana-grape flavor) in 120 and Overdosage/Acute Toxicity 480 m L; Zyrtec® (Pfizer); (Rx) Potentially could cause electrolyte abnormalities; see Adverse Effects Cetir izine HCl 5 mg with Pseudoephedrine HCl 120 mg Extended-for more information. Release Tab lets; Zyrtec-D 12 Hour® (Pfizer); (Rx)

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TDrug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving charcoal and may be of significance in veterinary patients: !TOTHER ORALLY ADMINISTERED THERAPEUTIC AGENTS : Separate by at least 3 hours the administration of any other orally administered therapeutic agents from the charcoal dose !TDAIRY PRODUCTS : May reduce the adsorptive capacity of activated charcoal !TMINERAL OIL : May reduce the adsorptive capacity of activated charcoal !TPOLY ETHYLENE GLYCOL; ELECTROLY TE SOLUTIONS (e. g., Go-Lytely®): May reduce the adsorptive capacity of activated charcoal Doses !TDOGS & CATS: As a gastrointestinal absorbent: a) 10 m L of a 20% slurry (1 g of charcoal in 5 m L of water) per kg o f body weight by stomach tube (Carson and Osweiler 2003) For acute poisoning: a) After decontamination of the GI tract give activated charcoal at 1 -4 g/kg PO. Placement of a nasogastric tube can facili-tate administration and reduce the incidence of aspiration in the sedated/fractious animal particularly when repeated administration is desired; repeat every 4-6 hours for toxins that are recirculated through the intestinal capillary network. (Rudloff 2006b) b) 1-4 g/kg in 50-200 m L of water. Concurrent with or within 30 min utes of giving charcoal, give an osmotic cathartic. Re-peated doses of activated charcoal may also bind drugs that are e nterohepatically recycled. (Beasley and Dorman 1990) c) Administer in a bathtub or other easily cleanable area. Give ac tivated charcoal at 1-5 g/kg PO (via stomach tube using either a funnel or large syringe) diluted in water at a con-centration of 1 g charcoal/5-10 m L of water. Follow in 30 minutes with sodium sulfate oral cathartic. (Bailey 1989) !TRUMINANTS: a) 1-3 grams/kg PO (1 gram of charcoal in 3-5 m L of water) via stomach tube; give saline cathartic concurrently. May re-peat in 8-12 hours. (Bailey 1986b) !THORSES: a) Foals: 250 grams (minimum). Adult horses: up to 750 grams. Mak e a slurry by mixing with up to 4 L (depending on ani-mal's size) of warm water and administer via stomach tube. Lea ve in stomach for 20-30 minutes and then give a laxative to hasten removal of toxicants. (Oehme 1987b) Monitoring !TMonitoring for efficacy of charcoal is usually dependent upon the toxin/drug that it is being used for and could include the drug/ toxin's serum level, clinical signs, etc. !TSerum sodium, particularly if patient develops neurologic signs associated with hypernatremia (tremors, ataxia, seizures) Client Information !This agent should generally be used with professional supervi-sion; if used on an outpatient basis patients must be observed for at least 4 hours after administration for signs associated with too much sodium in the blood (weakness, unsteadiness, tremors, convulsions). Should these occur, patients must immediately be seen by a veterinarian. !TCharcoal can easily stain fabrics Chemistry/Synonyms Activated charcoal occurs as a fine, black, odorless, tasteless powder that is insoluble in water or alcohol. Commercially available acti-vated charcoal products may differ in their adsorptive properties, bu t one gram must adsorb 100 mg of strychnine sulfate in 50 m L of water to meet USP standards. Activated charcoal may also be known as: active carbon, acti-vated carbon, carbo activatus, adsorbent charcoal, decolorizing car-bon, or medicinal charcoal. There are many trade names available. Storage/Stability Store activated charcoal in well-closed glass or metal containers or in the manufacturer's supplied container. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Activated charcoal 47. 5%, Kaolin 10% granules (free flowing and wettable) in 1 lb bottles, and 5 kg pails: Toxiban® Granules (Vet-A-Mix); (OTC). Labeled for use in both large and small animals. Activated charcoal 10. 4%, Kaolin 6. 25% suspension in 240 m L bot-tles: Toxiban® S uspension (Vet-A-Mix); (OTC). Labeled for use in both large and small animals. Activated charcoal 10%, Kaolin 6. 25%, sorbitol 10% suspension in 240 m L bottles: Toxiban® Suspension with Sorbitol Vet-A-Mix); (OTC). Labeled for use in small animals. Activated Charcoal 10%, Attapulgite 20%, sodium chloride 35 mg/ m L, p otassium chloride 35 mg/m L Gel/Paste in 80 m L & 300 m L: D-Tox-Besc®(Agri Pharm); Activated Charcoal Gel with Electrolytes® & DVM Formula® (Bomac Plus Vet), Activated Charcoal Paste® (First Priority); (OTC). Labeled for use in small and large animals. Activated Hardwood Charcoal and thermally activated attapulgite cla y (concentrations not labeled) in an aqueous gel suspension in 8 fl oz bottle, 60 m L tube and 300 m L tube with easy dose syringe. UAA® (Universal Animal Antidote) Gel (Vedco); (OTC). Labeled for use in dogs, cats and grain overload in ruminants. HUMAN-LABELED PRODUCTS: Activated Charcoal Powder: 15 g, 30 g, 40 g, 120 g, 240 g and UD 30 g (Activated charcoal is also available in bulk powder form); ge-neric; (OTC) Activated Charcoal Liquid/Suspension with sorbitol: 15 g & 30 g in 150 m L & 50 g in 240 m L; Charco Aid®(Requa); 25 g in 120 m L & 50 g in 240 m L; Actidose® with Sorbitol (Paddock); (OTC) Activated Charcoal Liquid/Suspension without sorbitol: 15 g & 50 g in 120 m L & 240 m L; Charco Aid® 2000 (Requa); (OTC); 208 mg/ m L — 12. 5 g in 60 m L & 25 g in 120 m L; 12. 5 g in 60 m L, 15 g in 75 m L, 25 g in 120 m L, 30 g in 120 m L, 50 g in 240 m L; Actidose-Aqua® (Paddock); generic; (OTC) Activated Charcoal Granules: 15 g in 120 m L; Charco Aid® 2000 (Re qua); (OTC)

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CHLORAMBUCIL (klor-am-byoo-il) Leukeran® IMMUNOSUPPRESSANT/ANTINEOPLASTIC Prescriber Highlights TT Nitrogen mustard derivative immunosuppressant & antineoplastic TT Used for severe autoimmune diseases in cats (e. g., IBD, pemphigus, etc. ) as it is less toxic than cyclophosph-amide or azathioprine in cats TT Contraindications: Hypersensitivity to chlorambucil TT Caution: Preexisting bone marrow depression, infection TT Potential teratogen TT Adverse Effects primarily myelosuppression & GI toxicity Uses/Indications Chlorambucil may be useful in a variety of neoplastic diseases, in-cluding lymphocytic leukemia, multiple myeloma, polycythemia vera, macroglobulinemia, and ovarian adenocarcinoma. It may also be useful as adjunctive therapy for some immune-mediated condi-tions (e. g., glomerulonephritis, inflammatory bowel disease, non-erosiv e arthritis, or immune-mediated skin disease). It has found favor as a routine treatment for feline pemphigus foliaceous and severe feline eosinophilic granuloma complex due to the drug's rela-tive lack of toxicity in cats and efficacy. Pharmacology/Actions Chlorambucil is a cell-cycle nonspecific alkylating antineoplastic/ immunosuppressive agent. Its cytotoxic activity stems from cross-linking with cellular DNA. Pharmacokinetics Chlorambucil is rapidly and nearly completely absorbed after oral administration; peak levels occur in about one hour. It is highly bound to plasma proteins. While it is not known whether it crosses the blood-brain barrier, neurological side effects have been reported. Chlorambucil crosses the placenta, but it is not known whether it enters maternal milk. Chlorambucil is extensively metabolized in the liver, primarily to phenylacetic acid mustard, which is active. Phenylacetic acid mustard is further metabolized to other metabo-lites that are excreted in the urine. Contraindications/Precautions/Warnings Chlorambucil is contraindicated in patients who are hypersensi-tive to it or have demonstrated resistance to its effects. It should be used with caution in patients with preexisting bone marrow depres-sion or infection, or are susceptible to bone marrow depression or infect ion. Adverse Effects The most commonly associated major adverse effects seen with chlorambucil therapy is myelosuppression manifested by anemia, leukopenia, and thrombocytopenia and gastrointestinal toxicity. A greater likelihood of toxicity occurs with higher dosages. This may occur gradually with nadirs occurring usually within 7-14 days of the start of therapy. Recovery generally takes from 7-14 days. Severe bone marrow depression can result in pancytopenia that may take months to years for recovery. Alopecia and delayed regrowth of shaven fur have been reported in dogs; Poodles or Kerry blues are reportedly more likely to be affected than other breeds. In humans, bronchopulmonary dysplasia with pulmonary fi-brosis, and uric acid nephropathy have been reported. These effects are unco mmon and generally associated with chronic, higher dose therapy. Hepatotoxicity has been reported rarely in humans. Reproductive/Nursing Safety Chlorambucil's teratogenic potential remains poorly documented, but it may potentially cause a variety of fetal abnormalities. It is generally recommended to avoid the drug during pregnancy, but because of the seriousness of the diseases treated with chloram-bucil, the potential benefits to the mother must be considered. Chloramb ucil has been documented to cause irreversible infertility in male humans, particularly when given during pre-puberty and puberty. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the benefit of therapy clearly outweighs the risks. ) Overdosage/Acute Toxicity The oral LD 50 in mice is 123 mg/kg. There have been limited experi-ences with acute overdoses in humans. Doses of up to 5 mg/kg re-sulted in neurologic (seizures) toxicity and pancytopenia (nadirs at 1-6 weeks post ingestion). All patients recovered without long-term sequelae. Treatment should consist of gut emptying when appropri-ate (beware of rapidly changing neurologic status if inducing vom-iting). Monitoring of CBC's several times a week for several weeks should be p erformed after overdoses and blood component therapy may be necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorambucil and may be of significance in veterinary patients: T ! MYELOSUPPRESSIVE D RUGS (e. g., other antineoplastics, chlorampheni-col, flucytosine, amphotericin B, or colchicine ): Bone marrow depres-sion may be additive T ! IMMUNOSUPPRESSIVE D RUGS (e. g., azathioprine, cyclophosphamide, cyclosporine, corticosteroids ): Use with other immunosuppressant drugs may increase the risk of infection Laboratory Considerations T ! Chlorambucil may raise serum uric acid levels. Drugs such as allop-urinol may be required to control hyperuricemia in some patients. Doses For more information on using chlorambucil as part of chemo-therapy protocols, refer to the protocols found in the appendix or other dosag es/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withro w 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). T ! DOGS: For adjunctive therapy (as an immunosuppressant) in the treat-ment of glomerulonephritis: a) 0. 1-0. 2 mg/kg PO once daily or every other day (Vaden and Grauer 1992)

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For adjunctive therapy of lymphoreticular neoplasms, macro-globulinemia, and polycythemia vera: a) 2-6 mg/m2 PO once a day or every other day (Jacobs, Lums-den et al. 1992) b) For first level treatment of dogs of canine lymphoma where clie nts cannot afford, or will not accept combination chemo-therapy due to risks of toxicity: Prednisone alone (40 mg/m2 PO dail y for 7 days then every other day) or in combination with chlorambucil at 6-8 mg/m2 PO every other day. Per-form a CBC every 2-3 we eks. (Ogilvie 2006) c) For lymphoproliferative disease; macroglobulinemia: 2-4 mg/m2 PO q24-48h (Gilson and Page 1994) Fo r chronic lymphocytic leukemia: a) 20 mg/m2 PO every 1-2 w eeks or 6 mg/m2 PO daily (Vail and Ogilvie 1994) Fo r treatment of pemphigus complex: a) Prednisone 2-4 mg/kg PO divided q12h with chlorambucil 0. 2 mg/kg q24-48h (He lton-Rhodes 1994) b) Used in combination with corticosteroids. Chlorambucil 0. 1-0. 2 mg/kg once daily initially until marked improve-ment (or 75% improvement) of clinical signs (may require 4-8 w eeks). Then alternate day dosing is begun and main-tained for several weeks. If no exacerbation, alternately de-crease chlorambucil and corticosteroids until lowest possible dose is attaine d. (White 2000) For adjunctive treatment of inflammatory bowel disease: a) 1. 5 mg/m2 PO every other day (Marks 2007b) !TCATS: For adjunctive treatment of inflammatory bowel disease: a) As a second choice (corticosteroids first choice) or refractory or severe IBD: Cats greater than 4kg: 2 mg (total dose) PO q48 hours (every other day) for 2-4 weeks then tapered to the lowest effective dose (2 mg per cat q72-96 hours; every 3rd to 4th day). Cats less than 4 kg are started at 2 mg (total dose) q72 hours (every 3rd day). (Moore 2004) b) 15 mg/m2 PO once per day for 4 consecutive days, repeated ev ery 3 weeks (in combination with prednisolone) appears highly effective in managing cats with severe IBD or intesti-nal lymphoma. Alternatively, may dose at 2 mg (total dose) pe r cat every 4 days indefinitely. (Marks 2007b) c) For lymphocytic-plasmacytic enteritis (LPE): Chlorambucil is so metimes useful for cats that do not respond to diet, pred-nisolone and metronidazole; limited experience, but seems it should be administered with prednisolone. Two methods for dosing: 1) Initial dose is 2 mg/m2 PO for 4-7 days, then decreased to 1 mg/m2 for 7 days. If clinical signs are lessen-ing, continue daily dosing but only every other week; it is co mmon for patients to develop anemia. 2) Large cats (>7 lb. ) 2 mg PO twice weekly; smaller cats (<7 lb) 1 mg PO twice weekly. If a clinical response will occur, it should be seen in 4-6 weeks, after which the drug is slowly tapered to the low-est effective dose. Monitor CBC's anytime the cat seems to fe el bad. (Willard 2006a) For adjunctive treatment of pemphigus complex: a) Prednisolone 2-4 mg/kg PO divided q12h with chloram-bucil 0. 2 mg/kg q24-48h (He lton-Rhodes 1994) b) For generalized pemphigus foliaceous: If cats have a poor resp onse to prednisolone alone, may add chlorambucil at 0. 1-0. 2 mg/kg PO q24-48h; has slow onset of action and can cause bone marrow depression. (Hillier 2006f) For adjunctive treatment of FIP: a) Prednisolone 4 mg/kg PO once daily with chlorambucil 20 mg/m2 every 2-3 we eks (Weiss 1994) For chronic lymphocytic leukemia: a) Chlorambucil at 2 mg/m2 PO every other day or 20 mg/m2 ev ery other week; with or without prednisolone at 20 mg/m2 PO every other day. The authors state they have had more success with the high dose-every other week regimen. (Peter-son and Couto 1994) For lymphocytic leukemia: a) Chlorambucil 6 mg/m2 (2 mg/5. 3 kg cat) PO every other day and p rednisolone 5 mg/cat/day. Supplemental cobalamin (1 m L SC q2-3 weeks) and folate/B-complex vitamins should also be given. (Simpson 2003a) For feline pemphigus foliaceous or severe feline eosinophilic gr anuloma complex (in combination with corticosteroids): a) 0. 1-0. 2 mg/kg (usually H o f the 2 mg tablet or 1 mg) once daily initially until marked improvement (or 75% improve-ment) of clinical signs (may require 4-8 w eeks). Then alter-nate day dosing is begun and maintained for several weeks. If no exacerbation, alternately decrease chlorambucil and corticosteroids until lowest possible dose is attained. Most cats may ultimately be maintained on alternate day steroid therapy alone. (White 2000) For idiopathic pruritus when nothing else works: a) 0. 2 mg/kg PO q24-48h. C losely monitor during treatment. (Hnilica 2003c) !THORSES: For adjunctive therapy in treating lymphoma using the LAP protocol: a) Cytosine arabinoside 200-300 mg/m2 SC or IM once every 1-2 w eeks; Chlorambucil 20 mg/m2 PO every 2 weeks (al-ternating with cytosine arabinoside) and Prednisone 1. 1-2. 2 mg/kg PO every other day. If this protocol is not effective (no response seen in 2-4 weeks) add vincristine at 0. 5 mg/m2 IV once a week. Side effects are rare. (Couto 1994) Monitoring !TEfficacy !TCBC, Platelets once weekly (or once stable every other week) during therapy; once stable, dogs may require only monthly monitoring. If neutrophils are <3,000/micro L hold drug until re-covered and reduce dose by 25% or increase dosing interval. !TUric acid, liver enzymes; if warranted Client Information !TClients must understand the importance of both administering chlorambucil as directed and immediately reporting any signs associated with toxicity (e. g., abnormal bleeding, bruising, urina-tion, depression, infection, shortness of breath, etc. ) Chemistry/Synonyms A nitrogen mustard derivative antineoplastic agent, chlorambucil occurs as an off-white, slightly granular powder. It is very slightly soluble in water. Chlorambucil may also be known as: CB-1348, NSC-3088, WR-139013, chlorambucilum, chloraminophene, chlorbutinum, Chloraminophene®, Leukeran®, or Linfolysin®.

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Storage/Stability Chlorambucil tablets should be stored in light-resistant, well-closed containers under refrigeration (2-8˚C; 36-46˚F). Tablets can be stored at a maximum of 30°C (86°F) up to one week. An expiration date of one year after manufacture is assigned to the commercially available tablets. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Chlorambucil Tablets: 2 mg; Leukeran® (Glaxo Smith Kline); (Rx) CHLORAMPHENICOL CHLORAMPHENICOL SODIUM SUCCINATE (klor-am-fen-i-kole) Chloromycetin®, Duricol®, Viceton® BROAD-SPECTRUM ANTIBACTERIAL Prescriber Highlights TT Broad spectrum antibiotic TT Contraindications: Food animals (banned) TT Extreme caution/avoid use: Preexisting hematologic dis-orders, pregnancy, neonates, hepatic failure, renal failure (cats); IV use in patients with cardiac failure; use long-term (>14 days) in cats with caution TT May need to reduce dose in patients with hepatic or renal insufficiency TT Adverse Effects: GI; potentially myelosuppressive, especially with high dose, long-term treatment TT Potentially toxic to humans; have dosage-giver avoid direct contact with medication Uses/Indications Chloramphenicol is used for a variety of infections in small animals and horses, particularly those caused by anaerobic bacteria. The FDA has prohibited the use of chloramphenicol in animals used for food production because of the human public health implications. Pharmacology/Actions Chloramphenicol usually acts as a bacteriostatic antibiotic, but at higher concentrations or against some very susceptible organisms it can be bactericidal. Chloramphenicol acts by binding to the 50S ri-bosomal subunit of susceptible bacteria, thereby preventing bacterial prote in synthesis. Erythromycin, clindamycin, lincomycin, tylosin, etc., also bind to the same site, but unlike these drugs, chloramphen-icol appears to also have an affinity for mitochondrial ribosomes of rapidly proliferating mammalian cells (e. g., bone marrow) that may result in reversible bone marrow suppression. Chloramphenicol has a wide spectrum of activity against many gram-positive and gram-negative organ isms. Gram-positive aero-bic organisms that are generally susceptible to chlorampheni-col include many streptococci and staphylococci. It is also effec-tive against some gram-negative aerobes includ ing Neissie ra, Brucella, Salmonella, Shigella, and Haemophilus. Many anaerobic bacteria are sensi tive to chloramphenicol including Clostridium, Bacteroides (including B. fragilis), Fusobacterium, and Veillonella. Chloramphenicol also has activity against Nocardia, Chlamydia, Mycop lasma, and Rickettsia. Pharmacokinetics Chloramphenicol is rapidly absorbed after oral administration with peak serum levels occurring approximately 30 minutes after dosing. The palmitate oral suspension produces significantly lower peak se-rum levels when administered to fasted cats. The sodium succinate salt is rapid ly and well absorbed after IM or SC administration in animals and, contrary to some recommendations, need not be ad-ministered only intravenously. The palmitate and sodium succinate is hydrol yzed in the GI tract and liver to the base. Chloramphenicol is widely distributed throughout the body. Highest le vels are found in the liver and kidney, but the drug attains therapeutic levels in most tissues and fluids, including the aqueous and vitreous humor, and synovial fluid. CSF concentrations may be up to 50% of those in the serum when meninges are uninflamed and higher when meninges are inflamed. A 4-6 hour lag time before CSF peak levels occur may be seen. Chloramphenicol concentra-tions in the prostate are approximately 50% of those in the serum. Because o nly a small amount of the drug is excreted unchanged into the urine in dogs, chloramphenicol may not be the best choice for lower urinary tract infections in that species. The volume of dis-tribution of chloramphenicol has been reported as 1. 8 L/kg in the dog, 2. 4 L/kg in the cat, and 1. 41 L/kg in horses. Chloramphenicol is about 30-60% bound to plasma proteins, enters milk and crosses the placenta. In most species, chloramphenicol is eliminated primarily by hepatic me tabolism via glucuronidative mechanisms. Only about 5-15% of the drug is excreted unchanged in the urine. The cat, hav-ing little ability to glucuronidate drugs, excretes 25% or more of a dose as unchange d drug in the urine. The elimination half-life has been reported as 1. 1-5 hours in d ogs, <1 hour in foals and ponies, and 4-8 hours in cats. The elimi-nation half-life of chloramphenicol in birds is highly species vari-able, ranging from 26 minutes in pigeons to nearly 5 hours in bald eagles and peafo wl. The usual serum therapeutic range for chloramphenicol is 5-15 microgr ams/m L. Contraindications/Precautions/Warnings Chloramphenicol is prohibited by the FDA for use in food animals. Chloramphenicol is contraindicated in patients hypersensi-tive to it. Because of the potential for hematopoietic toxicity, the drug should b e used with extreme caution, if at all, in patients with preex isting hematologic abnormalities, especially a preexisting non-regenerative anemia. The drug should only be used in patients in hepatic failure when no other effective antibiotics are available. Chloramphenicol should be used with caution in patients with im-paired hepatic or renal function as drug accumulation may occur. Those patie nts may need dosing adjustment, and monitoring of blood levels should be considered. Chloramphenicol should be used with caution in neonatal ani-mals, particularly in young kittens. In neonates (humans), circula-tory collapse (so-called “Gray-baby syndrome”) has occurred with chloramp henicol, probably due to toxic levels accumulating second-ary to an inability to conjugate the drug or excrete the conjugate effec tively.

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Adverse Effects While the toxicity of chloramphenicol in humans has been much discussed, the drug is considered by most to have a low order of toxicity in adult companion animals when appropriately dosed. The development of aplastic anemia reported in humans, does not ap pear to be a significant problem for veterinary patients; however, a dose-related bone marrow suppression (reversible) is seen in all species, primarily with long-term therapy. Early signs of bone marrow toxicity can include vacuolation of many of the early cells of the myeloid and erythroid series, lymphocytopenia, and neutropenia. Other effects that may be noted include anorexia, vomiting, di-arrhea, and depression. It has been said that cats tend to be more sensitive to developing ad verse reactions to chloramphenicol than dogs, but this is prob-ably more as a result of the drug's longer half-life in the cat. Cats dose d at 50 mg/kg q12h for 2-3 weeks do develop a high incidence of adverse effects and should be closely monitored when prolonged high-dose therapy is necessary. Reproductive/Nursing Safety Chloramphenicol has not been determined to be safe for use dur-ing pregnancy. The drug may decrease protein synthesis in the fe-tus, particularly in the bone marrow. It should only be used when the b enefits of therapy clearly outweigh the risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduc-tion studies and no adequate studies in humans. ) 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. ) Because chloramphenicol is found in milk in humans at 50% of serum levels, the drug should be given with caution to nursing bitches or queens, particularly within the first week after giving birth. Overdosage/Acute Toxicity Because of the potential for serious bone marrow toxicity, large overdoses of chloramphenicol should be handled by emptying the gut using standard protocols. For more information on the toxicity of chloramphenicol, refer to the Adverse Effects section above. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chloramphenicol and may be of significance in veterinary patients ( Note : cats may be particularly susceptible to chloramphenicol's effects on the hepatic metabolism of other drugs): !TANTI-ANEMIA D RUGS (Iron, Vitamin B12, folic acid ): Chlorampheni-col may delay hematopoietic response !TBETA-LACTAM ANTIBIOTICS (penicillins, cephalosporins, aminoglyco-sides ): Potential for antagonism !TLIDOCAINE : Chloramphenicol may delay hepatic metabolism !TMYELOSUPPRESSIVE D RUGS (e. g., cyclophosphamide ): Potential for additive bone marrow depression !TPENTOBARBITAL : Chloramphenicol has been demonstrated to pro-long the duration of pentobarbital anesthesia by 120% in dogs, and 260% in cats !TPHENOBARBITAL : Chloramphenicol may inhibit hepatic me-tabolism and phenobarbital may decrease chloramphenicol concentrations !!PRIMIDONE : Anorexia and CNS effects may occur in dogs !!PROPOFOL : Chloramphenicol may prolong anesthesia !!RIFAMPIN : May decrease serum chloramphenicol levels Laboratory Considerations !TFalse-positive glucosuria has been reported, but the incidence is unknown. Doses !TDOGS: For susceptible infections: a) 45-60 mg/kg PO q8h; 45-60 mg/kg IM, SC or IV q6-8h (USPC 1990) b) 40-50 mg/kg IV, IM, SC or PO q8h; avoid in young animals or in breeding or pregnant animals; avoid or reduce dosage in animals with severe liver failure. (Vaden and Papich 1995) c) For urinary, rickettsial, localized soft tissue infections: 25-50 mg/kg PO q8h for 7 days. Fo r systemic infections: 50 mg/kg PO, IV, IM, SC q6-8h for 3-5 days For severe bacteremia, sepsis: 50 mg/kg IV, IM or SC q4-6h fo r 3 days (Greene and Watson 1998) d) For Rocky Mountain Spotted Fever: 15-20 mg/kg q8h PO, IM or IV f or 14-21 days (Sellon and Breitschwerdt 1995) e) For susceptible infectious otitis: 50 mg/kg PO q8h (Rosenk-rantz 2006b) !TCATS: For susceptible infections: a) 25-50 mg/kg PO q12h; 12-30 mg/kg IM, SC or IV q12h (USPC 1990) b) 50 mg (total dose) IV, IM, SC or PO q8h; avoid in young animals o r in breeding or pregnant animals; avoid or reduce dosage in animals with severe liver failure (Vaden and Papich 1995) c) For urinary, localized soft tissue infections: 50 mg per cat (to-tal dose) PO q12h for 14 days. Fo r systemic infections: 25-50 mg/kg PO, IV, IM, SC q12h for 14 days or less For severe bacteremia, sepsis: 50 mg per cat (total dose) PO, IV, IM or SC q6-8h for 5 days or less. (Greene and Watson 1998) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 30-50 mg/kg PO, SC, IM, IV q8-24h (I vey and Morrisey 2000) b) Hedgehogs: 50 mg/kg PO q12h; 30-50 mg/kg SC, IM, IV or IO q12h (Smith 2000) c) C hinchillas: 30-50 mg/kg PO, SC, IM q12h (Hayes 2000) d) Gerbils, Guinea Pigs, Hamsters, Mice, Rats: 20-50 mg/kg (suc cinate salt) SC q6-12h (Adamcak and Otten 2000) e) Guinea pigs for pneumonia: 30-50 mg/kg PO q12h (John-son 2006d) !TFERRETS: For proliferative colitis: a) 10-40 mg/kg q8h PO for 2 weeks or 50 mg/kg PO q12h for 10 day s (Fox 1995) b) 50 mg/kg q12h PO for 14-21 day s (Johnson 2006c) For susceptible infections: a) 50 mg/kg PO twice daily (using palmitate salt—may be un-available) or 50 mg/kg SC or IM twice daily (succinate salt) (W illiams 2000)

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T!THORSES: For susceptible infections: a) 55 mg/kg PO q6h (Foreman 1999) b) Chloramphenicol sodium succinate: 25 mg/kg IM q8h (Bag-got and Prescott 1987) c) Foals: Chloramphenicol sodium succinate: 50 mg/kg IV q6-8h (use longer dosage interval in premature foals and those less than 2 days old) (Caprile and Short 1987) d) 45-60 mg/kg PO q8h; 45-60 mg/kg IM, SC or IV q6-8h (USPC 1990) e) Foals: 20 mg/kg PO or IV q4h (Furr 1999) f) Foals: Chloramphenicol sodium succinate: 25-50 mg/kg IV q4-8h; c hloramphenicol base or palmitate: 40-50 mg/kg PO q6-8h (Brumbaugh 1999) !TBIRDS: For susceptible infections: a) Chloramphenicol sodium succinate: 80 mg/kg IM two to three times daily, 50 mg/kg IV three to four times daily Chlo ramphenicol palmitate suspension (30 mg/m L): 0. 1 m L/30 grams of body weight three to four times daily. Do not use for initial therapy in life-threatening infections. Must use parenteral form if crop stasis occurs. (Clubb 1986) b) Chloramphenicol palmitate suspension (30 mg/m L): 75 mg/ kg thr ee times a day; absorption is erratic, but well-tolerated and efficacious in baby birds with enteric infections being hand fed. Will settle out if added to drinking water. (Mc Don-ald 1989) c) Succinate: 50 mg/kg IM or IV q8h; Palmitate: 75 mg/kg PO q8h (Ho effer 1995) d) Ratites (not to be used for food): 35-50 mg/kg PO, IM, IV or SC 3 times dail y for 3 days (Jenson 1998) !TREPTILES: For susceptible infections: a) For most species using the sodium succinate salt: 20-50 mg/ kg IM or SC for up to 3 weeks. Chloramphenicol is often a good initial choice until sensitivity results are available. (Gau-vin 1993) b) 30-50 mg/kg/day IV, or IM for 7-14 day s (Lewbart 2001) Monitoring !TClinical efficacy !TAdverse effects; chronic therapy should be associated with routine CBC monitoring Client Information !TMUST NOT be used in any animal to be used for food production !There is evidence that humans exposed to chloramphenicol have an increased risk of developing fatal aplastic anemia. Products should be handled with care. Do not inhale powder and wash hands after handling tablets. !TCrushed tablets or capsule contents are very bitter tasting and ani-mals may not accept the drug if presented in this manner Chemistry/Synonyms Originally isolated from Streptomyces venezuelae, chloramphenicol is now produced synthetically. It occurs as fine, white to grayish, yel-low white, elongated plates or needle-like crystals with a p K a of 5. 5. It is freely soluble in alcohol and about 2. 5 mg are soluble in 1 m L of water at 25°C. Chloramphenicol sodium succinate occurs as a white to light ye llow powder. It is freely soluble in both water and alcohol. Commercially available chloramphenicol sodium succinate for in-jection contains 2. 3 m Eq of sodium per gram of chloramphenicol. Chlo ramphenicol may also be known as: chloramphenicolum, chlo-ranfenicol, cloranfenicol, kloramfenikol, or laevomycetinum; many tr ade names are available. Storage/Stability/Compatibility Chloramphenicol capsules and tablets should be stored in tight con-tainers at room temperature (15-30°C). T he palmitate oral suspen-sion should be stored in tight containers at room temperature and pr otected from light or freezing. The sodium succinate powder for injection should be stored at te mperatures less than 40°, preferably between 15-30°C. After re-constituting the sodium succinate injection with sterile water, the solu tion is stable for 30 days at room temperature and 6 months if frozen. The solution should be discarded if it becomes cloudy. The following drugs and solutions are reportedly compatible with chloramphenicol sodium succinate injection: all commonly used intravenous fluids, amikacin sulfate, aminophylline, ampicillin so-dium (in syringe for 1 hr. ) ascorbic acid, calcium chloride/glucon-ate, cephalothin sodium, cephapirin sodium, colistimethate sodium, co rticotropin, cyanocobalamin, dimenhydrinate, dopamine HCl, ephedrine sulfate, heparin sodium, hydrocortisone sodium succi-nate, hydroxyzine HCl, kanamycin sulfate, lidocaine HCl, magne-sium sulfate, metaraminol bitartrate, methicillin sodium, methyl-dopate HCl, methylprednisolone sodium succinate, metronidazole with or without sodium bicarbonate, nafcillin sodium, oxacillin so-dium, oxytocin, penicillin G potassium/sodium, pentobarbital sodi-um, phenylephrine HCl with or without sodium bicarbonate, phy-tonadione, plasma protein fraction, potassium chloride, promazine HCl, r anitidine HCl, sodium bicarbonate, thiopental sodium, vera-pamil HCl, and vitamin B-complex with C. The following drugs and solutions are reportedly incompatible (or compatibility data conflicts) with chloramphenicol sodium succinate injection: chlorpromazine HCl, glycopyrrolate, metoclo-pramide HCl, oxytetracycline HCl, polymyxin B sulfate, prochlo-rperazine edislyate/mesylate, promethazine HCl, tetracycline HCl, and vanc omycin HCl. Compatibility is dependent upon factors such as p H, concentra-tion, temperature and diluent used; consult specialized references or a hospital phar macist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Chloramphenicol Oral Tablets and Capsules: 50 mg (Duricol® only), 100 mg (Duricol® only), 250 mg, 500 mg, & 1 gram (Viceton® only); Approved for use in dogs only. Duricol® Chloramphenicol Capsules USP (VPC), Viceton® (Bimeda); (Rx) An ophthalmic 1% ointment (Vetrachloracin®—Pharmaderm) is also av ailable. HUMAN-LABELED PRODUCTS: Chloramphenicol Powder for Injection: 1 gram (100 mg/m L as so-dium succinate when reconstituted); Chlorom ycetin® Sodium Suc-cinate (Parke-Davis); generic; (Rx) Ophthalmic preparations are also available.

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CHLORDIAZEPOXIDE ± CLIDINIUM BR (klor-dye-az-e-pox-ide) ± (kli-din-ee-um) Librium®, Librax® BENZODIAZEPINE ± ANTIMUSCARINIC Prescriber Highlights TT Benzodiazepine for behavior problems (phobias, etc. ) & with an antimuscarinic (clidinium) for irritable bowel syndrome in dogs TT Not commonly used, so little has been published on ad-verse effects (similar to diazepam +/-atropine) TT Potentially teratogenic Uses/Indications Chlordiazepoxide alone may be a useful adjunct to treating certain behaviors where benzodiazepines may be useful including noise phobias in dogs; inter-cat aggression and urine spraying in cats. When combined with clidinium, it may be useful symptomatic therapy for dogs with irritable bowel syndrome. Pharmacology/Actions The subcortical levels (primarily limbic, thalamic, and hypotha-lamic) of the CNS are depressed by chlordiazepoxide and other benzo diazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant and anticonvulsant effects seen. The exact mech-anism of action is unknown but postulated mechanisms include: antagonism o f serotonin, increased release of and/or facilitation of gamma-aminobutyric acid (GABA) activity, and diminished re-lease or turnover of acetylcholine in the CNS. Benzodiazepine spe-cific receptors have been located in the mammalian brain, kidney, liver, lung, and heart. In all species studied, receptors are lacking in the white matter. Clidinium bromide is an antimuscarinic with its main action to reduc e GI motility and secretion similarly to atropine. Clidinium is a quaternary ammonium compound and, unlike atropine, does not cross appreciably into the CNS or the eye and should not exhibit the same extent of CNS or ocular adverse effects that atropine pos-sesses. For further information, refer to the atropine monograph. Pharmacokinetics Chlordiazepoxide is rapidly absorbed following oral administration. It is highly lipid soluble and is widely distributed throughout the body. It readily crosses the blood-brain barrier and is fairly highly bound to plasma proteins. Chlordiazepoxide is metabolized in the liver to several metabolites, including: desmethyldiazepam (nordi-azepam), desmethylchlordiazepoxide and oxazepam, all of which are phar macologically active and can have considerable half lives. These are eventually conjugated with glucuronide and eliminated primarily in the urine. Because of the active metabolites, serum val-ues of chlordiazepoxide are not useful in predicting efficacy. Little pharmacokinetic data for clidinium is available. The drug is incomple tely absorbed from the gut (small intestine). Effects in humans are seen in about an hour; duration of effect is about 3 hours. As the compound is completely ionized in vivo, it does not enter the CNS or the eye and therefore unlike atropine does not have effects on those systems. The drug is metabolized principally in the liver, but is also excreted unchanged in the urine. Contraindications/Precautions/Warnings Use benzodiazepines cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients. Chlordiazepoxide should only be administered very cautiously to patients in coma, shock or with significant respiratory depression. It is contrain-dicated in patients with known hypersensitivity to the drug. Chlordiaz epoxide should be used very cautiously, if at all, in ag-gressive patients as it may disinhibit the anxiety that may help pre-vent these animals from aggressive behavior. Benzodiazepines may impair the abilit ies of working animals. If administering the drug IV (rarely warranted), be prepared to administer cardiovascular or respiratory support. Give IV slowly. Clidinium, like other antimuscarinic agents should not be used in patients with tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ul-cerative colitis, obstructive uropathy, or myasthenia gravis. Antimuscarinic agents should be used with extreme caution in patients w ith known or suspected GI infections. Antimuscarinic agents can decrease GI motility and prolong retention of the caus-ative agent(s) or toxin(s) resulting in prolonged effects of the toxin. Antimuscar inic agents must also be used with extreme 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 can 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. Adverse Effects Chlordiazepoxide's adverse effects are similar to other benzodi-azepines, especially diazepam (they share several active metabo-lites). As there is much more information with respect to diazepam in dog s or cats than chlordiazepoxide, the following is extrapolated from diazepam information: Dogs could exhibit a contradictory response (CNS excitement) following administration of chlordi-azepoxide. The effects with regard to sedation and tranquilization are ext remely variable with each dog. Cats could exhibit changes in behavior (irritability, depression, aberrant demeanor) after receiv-ing chlordiazepoxide. There have been reports of cats developing hepatic fail ure after receiving oral diazepam for several days. It is unknown if chlordiazepoxide also shares this effect. Clinical signs have been reported to occur 5-11 days after beginning oral thera-py. Cats that receive diazepam should have baseline liver function tests. These should be repeated and the drug discontinued if emesis, lethargy, inappetence, or ataxia develops. Clidinium's adverse effects are basically extensions of the drug's pharmac ologic effects and are generally dose related. At usual doses effects tend to be mild in relatively healthy patients. More severe effects tend to occur with high or toxic doses. GI effects can in-clude dry mouth (xerostomia), dysphagia, constipation, vomiting, and thirst. GU effects may include urinary retention or hesitancy. Cardiovascular effects include sinus tachycardia (at higher doses), bradycardia (initially or at very low doses), hypertension, hypoten-sion, arrhythmias (ectopic complexes), and circulatory failure. Reproductive/Nursing Safety Benzodiazepines have been implicated in causing congenital ab-normalities in humans if administered during the first trimester of preg nancy. Infants born of mothers receiving large doses of benzo-diazepines shortly before delivery have been reported to suffer from apnea, impaire d metabolic response to cold stress, difficulty in feed-

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ing, hyperbilirubinemia, hypotonia, etc. Withdrawal symp toms have occurred in infants whose mothers chronically took benzodiazepines during pregnancy. The veterinary significance of these effects is un-clear, but the use of these agents during the first trimester of preg-nancy should only occur when the benefits clearly outweigh the risks associat ed with their use. In humans, the FDA categorizes chlordiaz-epoxide 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 acceptable despite its potential risks. ) Benzodiazepines and their metabolites are distributed into milk and may cause CNS e ffects in nursing neonates. Overdosage/Acute Toxicity When administered alone, chlordiazepoxide overdoses are generally limited to significant CNS depression (confusion, coma, decreased reflexes, etc. ). Hypotension, respiratory depression, and cardiac arrest have been reported in human patients but apparently are quite rare. 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. The use of analeptic agents (CNS stimu-lants such as caffeine) are generally not recommended. Flumazenil may be considered for adjunctive treatment of overdoses of benzo-diazepines. Drug Interactions The following drug interactions have either been reported or are the-oretical in humans or animals receiving chlordiazepoxide or other be nzodiazepines and may be of significance in veterinary patients: !TDIGOXIN : The pharmacologic effects of digoxin may be increased; monitor serum digoxin levels or signs of toxicity !TOTHER CNS DEPRESSANT D RUGS (e. g., barbiturates, opiates, anesthet-ics): Additive effects may occur !TPROBENECID : May interfere with benzodiazepine metabolism in the liver, causing increased or prolonged effects !TRIFAMPIN : May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines The following drugs may decrease the metabolism of chlordiazepox-ide and excessive sedation may occur: !!CIMETIDINE !!ERYTHROMYCIN ! !FLUOXETINE !!ISONIAZID !!KETO CONAZOLE !TMETOPROLOL !TPROPRANOLOL When using the product containing clidinium the following potential in-teractions noted with atropine may apply and the following drugs may e nhance the activity or toxicity of clidinium: !!AMANTADINE !!ANTICHOLINERGIC AGENTS (OTHER ) !!ANTICHOLINERGIC MUSCLE RELAXANTS !!ANTIHISTAMINES (e. g., diphenhydramine ) !!DISOPYRAMIDE !!MEPERIDINE !!PHENOTHIAZINES !!PROCAINAMIDE !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 atropine 2 hours after ketoconazole !TMETOCLOPRAMIDE : Atropine and its derivatives may antagonize the actions of metoclopramide Laboratory Considerations !TChlordiazepoxide can cause interference with the Zimmerman reaction for 17-ketosteroids, resulting in false results. !TIt can also cause a false-positive result in the Gravindex® pregnancy test. Doses !TDOGS: Chlordiazepoxide alone: For behavior indications (thunderstorm/noise phobias): a) 2. 2-6. 6 mg/kg PO as needed (start low) (Overall 2000) Chlordiazepoxide with clidinium: Fo r symptomatic treatment of irritable bowel syndrome: a) Using the combination product (e. g., Libr ax®), give 0. 1-0. 25 mg/kg of clidinium or 1-2 capsules PO two times to three times a day. Owner may give when abdominal pain or diar-rhea first noticed or if stressful conditions are encountered. Drug can us ually be discontinued in a few days. (Leib 2004a) b) Using the combination product (e. g., Libr ax®), give 0. 44-1. 1 mg/kg of clidinium PO two to three times a day. Use at first signs of cramping or abdominal pain. Most dogs only require for a day to 2 weeks. Some require long-term treatment at 1-2 doses per day. (Tams 2000) !TCATS: As an anxiolytic: a) Chlordiazepoxide: 0. 5-1 mg/kg PO q12-24h (V irga 2002) Monitoring !TClinical efficacy !TAdverse effects Client Information !TKeep out of reach of children and in tightly closed containers !TNotify veterinarian if animal's behavior worsens Chemistry/Synonyms A benzodiazepine, chlordiazepoxide HCl occurs as an odorless, white crystalline powder. It is soluble in water and alcohol, but is unstable in aqueous solutions. A synthetic quaternary antimuscarinic agent similar to glycopyr-rolate, clidinium bromide occurs as a white to nearly white, crystal-line powder. It is soluble in alcohol and water. Chlordiazepoxide HCl may also be known as: chlordiazep-oxidi hydrochloridum, methamino-diazepoxide hydrochloride, NSC-115748, o r Ro-5-0690; many trade names are available.

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Storage/Stability Chlordiazepoxide HCl capsules or tablets should be stored pro-tected from light. The chlordiazepoxide HCl injection should be prepar ed immediately prior to use and any unused portions dis-carded. The diluent should be stored in the refrigerator before use. Clidinium bromide and chlordiazepoxide capsules should be store d at room temperature in tight, light-resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more informa-tion. HUMAN-LABELED PRODUCTS: Chlordiazepoxide HCl Capsules: 5 mg, 10 mg & 25 mg; Librium® (ICN Pharmaceuticals); generic; (Rx, C-IV) Chlordiazepoxide HCl Powder for Injection: 100 mg in 5 m L amp with 2 m L amp of IM diluent;, Librium® (ICN Pharmaceuticals); (Rx, C-IV) Chlordiazepoxide HCl 5 mg and Clidinium Br 2. 5 mg Capsules; Librax® Caps ules (Valeant); generic; (Rx, C-IV) Also available in fixed dose combinations: tablets containing chlordiaz epoxide: 5 mg and 12. 5 mg amitriptyline or chlordiazep-oxide 10 mg and amitriptyline 25 mg; Limbitr ol® & Limbitrol DS® (Valeant); generic; (Rx, C-IV) CHLOROTHIAZIDE CHLOROTHIAZIDE SODIUM (klor-oh-thye-a-zide) Diuril® THIAZIDE DIURETIC Prescriber Highlights TT Thiazide diuretic used for nephrogenic diabetes insipidus & hypertension in dogs; udder edema in dairy cattle (cattle product now discontinued in USA) TT Contraindications: Hypersensitivity; pregnancy (relative contraindication) TT Extreme caution/avoid: Severe renal disease, preexisting electrolyte/water balance abnormalities, impaired he-patic function, hyperuricemia, SLE, diabetes mellitus TT Adverse Effects: Hypokalemia, hypochloremic alkalosis, other electrolyte imbalances, hyperuricemia, GI effects TT Many drug-drug & laboratory test interactions Uses/Indications In veterinary medicine, furosemide has largely supplanted the use of thiazides as a general diuretic (edema treatment). Thiazides are still used for the treatment of systemic hypertension, nephrogenic diabetes insipidus, and to help prevent the recurrence of calcium oxalate uroliths in dogs. Chlorothiazide is approved for use in dairy cattle for the treat-ment of post parturient udder edema, but the veterinary labeled prod uct has been discontinued in the USA. Pharmacology/Actions Thiazide diuretics act by interfering with the transport of sodi-um ions across renal tubular epithelium possibly by altering the metabolism o f tubular cells. The principle site of action is at the cortical diluting segment of the nephron; enhanced excretion of sodium, chloride, and water results. Thiazides also increase the ex-cretion of potassium, magnesium, phosphate, iodide, and bromide and decr ease the glomerular filtration rate (GFR). Plasma renin and resulting aldosterone levels are increased which contributes to the hypokalemic effects of the thiazides. Bicarbonate excretion is increased, but effects on urine p H are usually minimal. Thiazides initially have a hypercalciuric effect but with continued therapy, calcium excretion is significantly decreased. Uric acid excretion is also decreased by the thiazides. Thiazides can cause, or exacerbate, hyperglycemia in diabetic patients, or induce diabetes mellitus in prediabetic patients. The antihypertensive effects of thiazides are well known, and these agents are used extensively in human medicine for treating essential hypertension. The exact mechanism of this effect has not been established. Thiazides paradoxically reduce urine output in patients with diabetes insipidus (DI). They have been used as adjunctive therapy in patients with neurogenic DI and are the only drug therapy for nephrogenic DI. Pharmacokinetics The pharmacokinetics of the thiazides have apparently not been studied in domestic animals. In humans, chlorothiazide is only 10-21% absorbed after oral administration. The onset of diuretic activity occurs in 1-2 hours and peaks at about 4 hours. The serum half-life is approximately 1-2 hours and the duration of activity is from 6-12 hours. Like all thiazides, the antihypertensive effects of chlorothiazide can take several days to transpire. Thiazides are found in the milk of lactating humans. Because of the chance of idiosyncratic or hypersensitive reactions, it is recom-mended that these drugs not be used in lactating females or nursing mothers. Contraindications/Precautions/Warnings Thiazides are contraindicated in patients hypersensitive to any one of these agents or to sulfonamides, and those with anuria. They are also contraindicated in pregnant females who are otherwise healthy and have only mild edema; newborn human infants have developed thrombocytopenia when their mothers received thiazides. Thiazides should be used with extreme caution, if at all, in patients w ith severe renal disease or with preexisting electrolyte or water balance abnormalities, impaired hepatic function (may precipitate hepatic coma), hyperuricemia, lupus (SLE); or diabetes mellitus. Patients with conditions that may lead to electrolyte or water balance abnormalities (e. g., vomiting, diarrhea, etc. ) should be monitored carefully. Adverse Effects Hypokalemia is one of the most common adverse effects associ-ated with the thiazides but rarely causes clinical signs or progresses further; however, monitoring of potassium is recommended with chronic therapy. Hypochloremic alkalosis (with hypokalemia) may develop, es-pecially if there are other causes of potassium and chloride loss (e. g., v omiting, diarrhea, potassium-losing nephropathies, etc. ) or if the patient has cirrhotic liver disease. Dilutional hyponatremia and hypomagnesemia may also occur. Hyperparathyroid-like ef-fects of hypercalcemia and hypophosphatemia have been reported in humans, but have not led to effects such as nephrolithiasis, bone resorption, or peptic ulceration.

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Hyperuricemia can occur but is usually asymptomatic. Other possible adverse effects include GI reactions (vomiting, di-arrhea, etc. ), hypersensitivity/dermatologic reactions, GU reactions (pol yuria), hematologic toxicity, hyperglycemia, hyperlipidemias, and orthostatic hypotension. 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 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. ) Chlorothiazide enters maternal milk and can reduce milk vol-ume and suppress lactation. Generally, discontinuation of the drug or n ursing is recommended in humans. Overdosage Acute overdosage may cause electrolyte and water balance prob-lems, CNS effects (lethargy to coma and seizures), and GI effects (hy permotility, GI distress). Transient increases in BUN have also been reported. Treatment consists of emptying the gut after recent oral ingestion us ing standard protocols. Avoid giving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that may ensue. Monitor and treat electrolyte and water balance abnormalities sup-portively. Additionally, monitor respiratory, CNS and cardiovascular st atus; treat supportively and symptomatically, if re quired. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorothiazide and may be of significance in veterinary patients: !TAMPHO TERICIN B : Use with thiazides can lead to an increased risk for severe hypokalemia !TCORTICOSTEROIDS, CORTICOTROPIN : Use with thiazides can lead to an increased risk for severe hypokalemia !TDIAZOXIDE : Increased risk for hyperglycemia, hyperuricemia, and hypotension may occur !TDIGITALIS, DIGOXIN : Thiazide-induced hypokalemia, hypo-mag-nesemia, and/or hypercalcemia may increase the likelihood of digitalis t oxicity !TINSULIN : Thiazides may increase insulin requirements !TLITHIUM : Thiazides can increase serum lithium concentrations !TMETHENAMINE : Thiazides can alkalinize urine and reduce meth-enamine effectiveness !TNSAIDS : Thiazides may increase risk for renal toxicity and NSAIDs may reduce diuretic actions of thiazides !TNEUROMUSCULAR BLOCKING AGENTS : Tubocurarine or other nonde-polarizing neuromuscular blocking agents response or duration may b e increased in patients taking thiazide diuretics !TPROBENECID : Blocks thiazide-induced uric acid retention (used to therapeutic advantage) !TQUINIDINE : Half-life may be prolonged by thiazides (thiazides can alkalinize the urine) !TVITAMIN D or CALCIUM SALTS : Hypercalcemia may be exacerbated if thiazides are concurrently administered with Vitamin D or cal-cium salts Laboratory Considerations !TAMYLASE : Thiazides can increase serum amylase values in asymp-tomatic patients and those in the developmental stages of acute pancreat itis (humans) !TCORTISOL : Thiazides can decrease the renal excretion of cortisol !TESTROGEN, URINARY : Hydrochlorothiazide may falsely decrease to-tal urinary estrogen when using a spectrophotometric assay !THISTAMINE : Thiazides may cause false-negative results when testing for pheochromocytoma !TPARATHYROID-FUNCTION TESTS : Thiazides may elevate serum cal-cium; recommend discontinuing thiazides prior to testing !TPHENOLSULFONPHTHALEIN (PSP): Thiazides can compete for secre-tion at proximal renal tubules !TPHENTOLAMINE TEST : Thiazides may give false-negative results !TPROTEIN-BOUND IODINE : Thiazides may decrease values !TTRIIODOTHYRONINE RESIN UPTAKE TEST : Thiazides may slightly re-duce uptake !TTYRAMINE : Thaizides can cause false-negative results. Doses !TDOGS: For treatment of nephrogenic diabetes insipidus: a) 20-40 mg/kg PO q12h (Polzin and Osborne 1985), (Nichols 1989), (Behrend 2003b) Fo r treatment of systemic hypertension: a) 20-40 mg/kg PO q12-24h w ith dietary salt restriction (Cowgill and Kallet 1986) As a di uretic: a) 10-40 mg/kg PO twice daily (Morgan 1988) !TCATS: For treatment of diabetes insipidus: a) 20-40 mg/kg PO q12h may be tried (Behrend 2003b) !TCATTLE: a) 4-8 mg/kg once or twice daily PO for adult cattle (Howard 1986) b) 2 grams PO once to twice daily (Swinyard 1975) Monitoring !TSerum electrolytes, BUN, creatinine, glucose !THydration status !TBlood pressure, if indicated !THemograms, if indicated Client Information !TClients should contact veterinarian if signs of water or electrolyte imbalance occur (e. g., excessive thirst, lethargy, lassitude, restless-ness, reduced urination, GI distress, or rapid heart rate) Chemistry/Synonyms Chlorothiazide is a thiazide diuretic and occurs as a white to practi-cally white, odorless, crystalline powder having a slightly bitter taste. It is v ery slightly soluble in water and slightly soluble in alcohol. Chlorothiazide may also be known as: chlorothiazidum, cloroti-azida, Azide®, Chlorzide®, Chlotride®, Diachlor®, Diuril®, Diurigen®, Pahtlisan®, or Saluric®. Storage/Stability/Compatibility Tablets should be stored at room temperature. The oral suspension should be protected from freezing. The injectable preparation is stable for 24 hours after reconstitution. If the p H of the reconsti-tuted solution is less than 7. 4, precipitation will occur in less than 24 hours. C hlorothiazide sodium for injection is reportedly compatible with the following IV solutions: dextrose and/or saline products for IV infusion (with the exception of many Ionosol and Normosol prod-ucts), Ringer's injection and Lactated Ringer's, 1/6 M sodium lactate, De xtran 6% with dextrose or sodium chloride, and fructose 10%. It is

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also reportedly compatible with the following drugs: cime tidine HCl, lidocaine HCl, nafcillin sodium, and sodium bicarbonate. Chlorothiazide sodium is reportedly incompatible with the fol-lowing drugs: amikacin sulfate, chlorpromazine HCl, codeine phosphate, hydralazine HCl, insulin (regular), morphine sulfate, norepinephrine bitartrate, polymyxin B sulfate, procaine HCl, prochlorperazine edisylate and mesylate, promazine HCl, promet-hazine HCl, streptomycin sulfate, tetracycline HCl, trifluopromaz-ine HCl, and vancomycin HCl. 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: Chlorothiazide Tablets: 250 mg & 500 mg; Diuril® (Merck); Diuri-gen® (Goldline); generic; (Rx) Chlor othiazide Oral Suspension: 50 mg/m L in 237 m L; Diuril® (M erck); (Rx) Chlorothiazide Sodium Powder for Injection (lyophilized): 500 mg (0. 25 g mannitol) in 20 m L vials; Diuril® (Merck); (Rx) CHLORPHENIRAMINE MALEATE (klor-fen-ir-a-meen) Chlor-Trimetron® ANTIHISTAMINE Prescriber Highlights TT An alkylamine antihistamine used primarily for its anti-histamine/antipruritic effects; occasionally used for CNS depressant (sedative) effects TT Contraindications: Hypersensitivity. Caution: narrow angle glaucoma, hypertension, GI or urinary obstruction, hyper-tension, hyperthyroidism, cardiovascular disease TT Adverse Effects: Sedation, anticholinergic effects, GI effects Uses/Indications Antihistamines are used in veterinary medicine to reduce or help prevent histamine mediated adverse effects. Chlorpheniramine is one the more commonly used antihistamines in the cat for the treatment of pruritus. It may also be of benefit as a mild sedative in small animals due to its CNS depressant effects. Pharmacology/Actions Antihistamines (H 1-receptor antagonists) competitively inhibit histamine at H 1 receptor sites. They do not inactivate or prevent the release of histamine, but can prevent histamine's action on the cell. Besides their antihistaminic activity, these agents all have vary-ing degrees of anticholinergic and CNS activity (sedation). Some antihistamines hav e antiemetic activity (e. g., diphenhydramine) or antiserotonin activity (e. g., cyproheptadine, azatadine). Pharmacokinetics Chlorpheniramine pharmacokinetics have not been described in domestic species. In humans, the drug is well absorbed after oral administration, but because of a relatively high degree of metabo-lism in the GI mucosa and the liver, only about 25-60% of the drug is available to the systemic circulation. Chlorpheniramine is well distributed after IV injection; the highest distr ibution of the drug (in rabbits) occurs in the lungs, heart, kidneys, brain, small intestine, and spleen. In humans, the apparent steady-state volume of distribution is 2. 5-3. 2 L/kg and about 70% is bound to plasma proteins. It is unknown if chlorphe-niramine is excreted into the milk. Chlorpheniramine is metabolized in the liver and practically all the drug (as metabolites and unchanged drug) is excreted in the urine. In human patients with normal renal and hepatic function, the terminal serum half-life the drug ranges from 13. 2-43 hours. Contraindications/Precautions/Warnings Chlorpheniramine is contraindicated in patients who are hyper-sensitive to it or other antihistamines in its class. Because of their anticholinerg ic activity, antihistamines should be used with caution in patients with angle closure glaucoma, prostatic hypertrophy, py-loroduodenal or bladder neck obstruction, and COPD if mucosal secret ions are a problem. Additionally, they should be cautiously used in patients with hyperthyroidism, cardiovascular disease or hypertension. Adverse Effects Most commonly seen adverse effects are CNS depression (lethargy, somnolence) and GI effects (diarrhea, vomiting, anorexia). The seda-tive effects of antihistamines may diminish with time. Anticholinergic effec ts (dry mouth, urinary retention) are a possibility. The sedative effects of antihistamines may adversely affect the perf ormance of working dogs. Chlorpheniramine may cause paradoxical excitement in cats. Palatability is also an iss ue with this drug and felines. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is unknown if chlorpheniramine is excreted into milk; use with cautio n in dams nursing neonates. Overdosage/Acute Toxicity Overdosage may cause CNS stimulation (excitement to seizures) or depression (lethargy to coma), anticholinergic effects, respiratory depression, and death. Treatment consists of emptying the gut (if the ingestion was oral) using standard protocols. Induce emesis if the patient is alert and CNS status is stable. Administration of a saline cathartic and/ or activated charcoal may be given after emesis or gastric lavage. Treatment of other clinical signs should be performed using symp-tomatic and supportive therapies. Phenytoin (IV) is recommended in the tr eatment of seizures caused by antihistamine overdoses in humans; barbiturates and diazepam should be avoided. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorpheniramine and may be of significance in veterinary patients: T ! ANTICOAGULANTS (heparin, warfarin ): Antihistamines may partially counteract the anticoagulation effects of heparin or warfarin T ! MAO INHIBITORS (including amitraz, and possibly selegiline ): May prolong and exacerbate anticholinergic effects T ! OTHER CNS DEPRESSANT DRUGS : Increased sedation can occur

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Laboratory Considerations T ! Antihistamines can decrease the wheal and flare response to anti-gen skin testing. In humans, it is suggested that antihistamines be discontinued at least 4 days before testing. Doses Note : Contents of sustained-release capsules may be placed on food, but should not be allowed to dissolve before ingestion. T ! DOGS: a) 4-8 mg (maximum of 0. 5 mg/kg) PO q8-12h PO; many cli-nicians use as adjunctive treatment of chemotherapy of mast cell t umors (Papich 2000) b) 4-12 mg (total dose) two to three times daily (Mac Donald 2002a) c) 2-8 mg (total dose) per dog PO every 12 hours, not to exceed 0. 5 mg/kg every 12 hours (Cote 2005) As a trial f or pruritus in atopic dogs: a) 0. 4-0. 8 mg/kg two to three times daily (Rosychuk 2002) As a mild sedati ve: a) 0. 22 mg/kg PO q8h; 4-20 mg (total dose per day) divided q8-12h (Over all 2000) T ! CATS: a) 2 mg (total dose) per cat PO every 12 hours (Cote 2005) b) 2-4 mg per cat q12-24h PO (Hnilica 2003c), (Rosychuk 2002) c) Most common dosage in cats is: 2 mg per cat two to three times daily (Mac Donald 2002a) For pr uritus: a) 2-4 mg/cat twice daily; rarely may be maintained on once daily dosing. Palatability may be enhanced by dipping the split tablet into tuna fish “juice”, butter or petrolatum; placing split tablets into empty gelatin capsules or sprinkling or mix-ing timed release beads (partial contents of an 8 mg capsule) with foo d. (Messinger 2000) As a mild sedative: a) 1-2 mg per cat q12-24h (low d ose), 2-4 mg/cat PO q12-24h (high dose) (Overall 2000) T ! FERRETS: a) 1-2 mg/kg PO 2-3 times a day (W illiams 2000) Monitoring T ! Clinical efficacy T ! Adverse effects Client Information T ! Chlorpheniramine is approved for use in humans; the oral dosage forms are either prescription or non-prescription agents, depend-ing on the product's labeling T ! Most common adverse effects are drowsiness/sleepiness; cats may become excited T ! Do not crush or allow animal to chew sustained-release products Chemistry/Synonyms A propylamine (alkylamine) antihistaminic agent, chlorphenira-mine maleate occurs as an odorless, white, crystalline powder with a melting point between 130-135° C and a p K a of 9. 2. One gram is soluble in about 4 m L of water or 10 m L of alcohol. Chlorpheniramine maleate may also be known as chlorphe-namini maleas; many trade names are available. Storage/Stability Chlorpheniramine tablets and sustained-release tablets should be stored in tight containers. The sustained-release capsules should be stored in well-closed containers. The oral solution should be stored in light-resistant containers; avoid freezing. All chlorpheniramine products should be stored at room temperature (15-30°C). 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: Chlorpheniramine Maleate Tablets: 2 mg (chewable), Chlo-Amine® (Hollister-Stier); (OTC); 4 mg tablets, Aller-Chlor® (Rugby); Aller-Chlor® (Rugby); Allergy® (Major); Allergy Relief® (Zee Medical); ge-neric; (OTC); Chlorpheniramine Maleate Sustained-release Tablets & Capsules: 8 mg, 12 mg & 16 mg; Chlor-Trimeton® Allergy 8 or 12 Hour (Schering-Plough Healthcare); Efidac® 24 (Hogil); QDALL AR® (Atley); generic; (Rx & OTC) Chlorpheniramine Caplets: 8 mg (as tannate); ED-CHLOR-TAN ® (Edwards Pharmaceuticals); (Rx) Chlorpheniramine Maleate Syrup: 2 mg/5 m L in 118 m L; Aller -Chlor® (Rugby); (OTC); Oral Suspension: 8 mg (as tannate) in 473 m L; Pediatan® (Pro Ethic); (Rx) Many combination products are available that combine chlorphe-niramine with decongestants, analgesics, and/or antitussives. CHLORPROMAZINE HCL (klor-proe-ma-zeen) Thorazine® PHENOTHIAZINE SEDATIVE/ANTIEMETIC Prescriber Highlights TT Prototype phenothiazine used primarily as an antiemetic, occasionally as a pre-med sedative TT Generally contraindicated in horses TT Negligible analgesic effects TT Dosage may need to be reduced in debilitated/geriatric animals, those with hepatic or cardiac disease or when combined with other agents TT Use with caution in dehydrated patients because phe-nothiazines can cause vasodilation & reduce perfusion; rehydrate before use TT Inject diluted solution IV slowly; do not inject into arter-ies; do not inject IM in rabbits TT May cause significant hypotension, cardiac rate abnor-malities, hypo-or hyperthermia; may cause extrapyrami-dal effects at high doses in cats Uses/Indications The clinical use of chlorpromazine as a neuroleptic agent has di-minished, but the drug is still used for its antiemetic effects in small animals and oc casionally as a preoperative medication and tranquil-izer. As an antiemetic, chlorpromazine will inhibit apomorphine-induced emesis in the dog but not the cat. It will also inhibit the emetic effects of morphine in the dog. It does not inhibit emesis caused by copper sulfate, or digitalis glycosides.

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Once the principle phenothiazine used in veterinary medicine, chlorpromazine has been largely supplanted by acepromazine. It has similar pharmacologic activities as acepromazine, but is less po-tent and has a longer duration of action. For further information, re fer to the acepromazine monograph. Pharmacokinetics Chlorpromazine is absorbed rapidly after oral administration, but undergoes extensive first pass metabolism in the liver. The drug is also well absorbed after IM injection, but onsets of action are slow-er than after IV administration. Chlorpromazine is distributed throughout the body and brain co ncentrations are higher than those in plasma. Approximately 95% of chlorpromazine in plasma is bound to plasma proteins (primarily albumin). The drug is extensively metabolized principally in the liver and kidney s, but little specific information is available regarding its ex-cretion in dogs and cats. Contraindications/Precautions/Warnings Chlorpromazine causes severe muscle discomfort and swelling when injected IM into rabbits; use IV only in this species. Animals may require lower dosages of general anesthetics fol lowing phenothiazines. Use cautiously and in smaller doses in animals with hepatic dysfunction, cardiac disease, or general debili-tation. Because of its hypotensive effects, phenothiazines are rela-tively contraindicated in patients with hypovolemia or shock, and in pat ients with tetanus or strychnine intoxication due to effects on the extrapyramidal system. Intravenous injections must be diluted with saline to con-centrations of no more than 1 mg/m L and administered slowly. Chlo rpromazine has no analgesic effects; treat animals with appro-priate analgesics to control pain. Dogs with MDR1 mutations (many Collies, Australian shep-herds, etc. ) may develop a more pronounced sedation that persists long er than normal with this agent. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identi-fied or suspect of having this mutation. Phenothiazines should be used very cautiously as restraining age nts in aggressive dogs: it may make the animal more prone to startle and react to noises or other sensory inputs. Adverse Effects In addition to the possible effects listed in the acepromazine mono-graph (e. g., hypotension, contradictory effects such as CNS stimula-tion, bradycardia), chlorpromazine may cause extrapyramidal signs in the cat when used at high dosages. These can include tremors, shivering, rigidity and loss of the righting reflexes. Lethargy, diar-rhea, and loss of anal sphincter tone may also be seen. Horses may develop an ataxic reaction with resultant excitation and v iolent consequences. These ataxic periods may cycle with pe-riods of sedation. Because of this effect, chlorpromazine is rarely used in e quine medicine today. 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. ) Chlorpromazine is thought to be excreted into maternal milk and safe ty to nursing offspring cannot be assured. Overdosage/Acute Toxicity Most small overdoses cause only somnolence; larger overdoses can cause serious effects including coma, agitation/seizures, ECG changes/arrhythmias, hypotension and extrapyramidal effects. Contact an animal poison control center in the event of a suspected large o verdose or if multiple drugs are involved. Most overdoses can be handled by monitoring the patient and tr eating signs as they occur; massive oral overdoses should definite-ly be treated by emptying the gut if possible. Hypotension should not b e treated with epinephrine; use either phenylephrine or nor-epinephrine (levarterenol). Seizures may be controlled with barbi-turates or diazepam. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorpromazine or other phenothiazines and may be of significance in veterinary patients: !TACETAMINOPHEN : Possible increased risk for hypothermia !TANTACIDS : May cause reduced GI absorption of oral phenothiazines !TANTIDIARRHEAL MIX TURES (e. g., kaolin/pectin, bismuth subsali-cylate mixtures ): May cause reduced GI absorption of oral phenothiazines !TCNS DEPRESSANT AGENTS (barbiturates, narcotics, anesthetics, etc. ): May cause additive CNS depression if used with phenothiazines !TDIPYRONE : May cause serious hypothermia !TEPINEPHRINE : Phenothiazines block alpha-adrenergic receptors and concomitant epinephrine can lead to unopposed beta-activ-ity causing vasodilation and increased cardiac rate !TOPIATES : May enhance the hypotensive effects of the phenothiaz-ines; dosages of chlorpromazine may need to be reduced when used w ith an opiate !TORGANOPHOSPHATE AGENTS : Phenothiazines should not be given within one month of worming with these agents as their effects may be potentiated !TPARAQUAT : T oxicity may be increased by chlorpromazine !TPHENYTOIN : Metabolism may be decreased if given concurrently with phenothiazines !TPHYSOSTIGMINE : T oxicity may be enhanced by chlorpromazine !TPROCAINE : Activity may be enhanced by phenothiazines !TPROPRANOLOL : Increased blood levels of both drugs may result if administered with phenothiazines !TQUINIDINE : With phenothiazines may cause additive cardiac depression Doses !TDOGS: As an antiemetic: a) 0. 5 mg/kg IV, IM or SC three to four times daily (Dowling 2003a) b) 0. 5 mg/kg q6-8h IM or SC (P apich 2000) c) 0. 2-0. 4 mg/kg SC, IM q8h (Washabau 2006a) d) 0. 11-0. 44 mg/kg IM 3-4 times a da y (Hall 2000) As a sedative/restraining agent: a) 3 mg/kg PO q12h; 0. 5 mg/kg IM or IV q12h (Davis 1985b) As a p reanesthetic: a) up to 1. 1 mg/kg IM 1-1. 5 hour s prior to surgery (Booth 1988a) As a m uscle relaxant during tetanus: a) 2 mg/kg IM twice daily (Morgan 1988) As an a djunctive treatment for amphetamine toxicosis: a) 10-18 mg/kg IV (Dumonceaux 1995)

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T ! CATS: As an antiemetic: a) 0. 5 mg/kg IV, IM or SC three to four times daily (Dowling 2003a) b) 0. 5 mg/kg q6-8h IM or SC (Papich 2000) c) 0. 22 -0. 44 mg/kg IM 3-4 times a day (Hal l 2000) As a sedative/restraining agent: a) 3 mg/kg PO once daily; 0. 5 mg/kg IM or IV once daily (Davis 1985b) As a preanesthe tic: a) up to 1. 1 mg/kg IM 1-1. 5 hours p rior to surgery (Booth 1988a) T ! CATTLE: a) Premedication for cattle undergoing standing procedures: Up to 1 mg/kg IM (may cause regurgitation if animal undergoes general anesthesia) (Hall and Clarke 1983) b) 0. 22-1 mg/kg IV; 1-4. 4 mg/kg IM (Howard 1986) T ! HORSES: (Note : ARCI UCGFS Class 2 Drug) Note : Because of side effects (ataxia, panic reaction) this drug is not recommended for use in horses; use acepromazine or promazine if phenothiazine therapy is desired. T ! SWINE: a) Premedication: 1 mg/kg IM (Hall and Clarke 1983) b) 0. 55-3. 3 mg/kg IV; 2-4 mg/kg IM (Howard 1986) c) Restraint: 1. 1 mg/kg IM (effects are at peak in 45-60 min-ut es); Prior to barbiturate anesthesia: 2-4 mg/kg IM (Booth 1988a) T ! SHEEP & GOATS: a) 0. 55-4. 4 mg/kg IV, 2. 2-6. 6 mg/kg IM (Lumb and Jones 1984) b) Goats: 2-3. 5 mg/kg IV q5-6h (Booth 1988a) Monitoring T ! Cardiac rate/rhythm/blood pressure if indicated and possible to measure T ! Degree of tranquilization/anti-emetic activity if indicated T ! Body temperature (especially if ambient temperature is very hot or cold) Client Information T ! Avoid getting solutions on hands or clothing; contact dermatitis may develop. T ! May discolor the urine to a pink or red-brown color; this is not abnormal. Chemistry/Synonyms A propylamino-phenothiazine derivative, chlorpromazine is the prototypic phenothiazine agent. It occurs as a white to slightly creamy white, odorless, bitter tasting, crystalline powder. One gram is soluble in 1 m L of water and 1. 5 m L of alcohol. The commercially available injection is a solution of chlorpromazine HCl in sterile wa-ter at a p H of 3-5. Chlorpromazine HCl may also be known as aminazine, or chlo-rpromazini hydrochloridum; many trade names are available. Storage/Stability/Compatibility Protect from light and store at room temperature; avoid freezing the oral solution and injection. Dispense oral solution in amber bottles. Store oral tablets in tight containers. Do not store in plastic syringes or IV bags for prolonged periods as the drug may adsorb to plastic. Chlorpromazine will darken upon prolonged exposure to light; do not use solutions that are darkly colored or if precipitates have formed. A slight yellowish color will not affect potency or efficacy. Alkaline solutions will cause the drug to oxidize. The following products have been reported to be compatible when mixed with chlorpromazine HCl injection: all usual intravenous fluids, ascorbic acid, atropine sulfate, butorphanol tartrate, diphen-hydramine, droperidol, fentanyl citrate, glycopyrrolate, heparin so-dium, hydromorphone HCl, hydroxyzine HCl, lidocaine HCl, mep-eridine, metoclopramide, metaraminol bitartrate, morphine sulfate, pentazo cine lactate, promazine HCl, promethazine, scopolamine HBr, and tetracycline HCl. The following products have been reported as being incompatible when mixed with chlorpromazine: aminophylline, amphotericin B, chloramphenicol sodium succinate, chlorothiazide sodium, dimen-hydrinate, methicillin sodium, methohexital sodium, nafcillin so-dium, penicillin g potassium, pentobarbital sodium, phenobarbital sodium, and thiopental sodium. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references or a hospital pharmacist for more spe-cific information. 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: Chlorpromazine Tablets: 10 mg, 25 mg, 50 mg, 100 mg & 200 mg; Thorazine® (Glaxo Smith Kline); generic; (Rx) Rectal suppositories: 100 mg (as base); Thorazine® (Glax o Smith-Kline); (Rx) Injection: 25 mg/m L in 1 m L and 2 m L amps; Thorazine® (Glax o S-mith Kline); generic; (Rx) CHLORPROPAMIDE (klor-proe-pa-mide) Diabenese® SULFONYLUREA ANTIDIABETIC Prescriber Highlights TT Oral sulfonylurea antidiabetic agent sometimes used in dogs or cats for diabetes insipidus; potentially for diabe-tes mellitus TT Many contraindications/cautions TT Most likely adverse effects are hypoglycemia or GI distress Uses/Indications While chlorpropamide could potentially be of benefit in the adjunc-tive treatment of diabetes mellitus in small animals, its use has been primaril y for adjunctive therapy in diabetes insipidus in dogs and cats. Pharmacology/Actions Sulfonylureas lower blood glucose concentrations in both diabetic and non-diabetic patients. The exact mechanism of action is not known, but these agents are thought to exert the effect primarily by stimulating the beta cells in the pancreas to secrete additional endogenous insulin. Ongoing use of the sulfonylureas appears to en-

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hance peripheral sensitivity to insulin and reduce the production of hepatic basal glucose. The mechanisms causing these effects are yet to be fully explained. Chlorpropamide has antidiuretic activity, pre-sumably by potentiating vasopressin's effects on the renal tubules. It may also st imulate secretion of vasopressin. Pharmacokinetics Chlorpropamide is absorbed well from the GI tract. Its distribution characteristics have not been well described, but it is highly bound to plasma proteins and is excreted into milk. Elimination half-lives have not been described in domestic animals, but in humans the elimination half-life is about 36 hours. The drug is both metabo-lized in the liver and excreted unchanged. Elimination of chlorpro-pamide is enhanced in alkaline urine; decreased in acidic urine. Contraindications/Precautions/Warnings Oral antidiabetic agents are considered contraindicated with the following conditions: severe burns, severe trauma, severe infec-tion, diabetic coma or other hypoglycemic conditions, major sur-gery, ketosis, ketoacidosis, or other significant acidotic conditions. Chlo rpropamide should only be used when its potential benefits outweigh its risks during untreated adrenal or pituitary insuffi-ciency, thyroid, cardiac, renal or hepatic function impairment, pro-longed vomiting, high fever, malnourishment or debilitated condi-tion, or when fluid retention is present. Adverse Effects Hypoglycemia and GI disturbances are the most common adverse effects noted with this agent. Syndrome of inappropriate antidi-uretic hormone (SIADH), anorexia, diarrhea, hepatotoxicity, skin er uptions, lassitude or other CNS effects, and hematologic toxicity are all potentially possible. Reproductive/Nursing Safety Safe use during pregnancy has not been 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 reproduc-tion studies and no adequate studies in humans. ) Chlorpropamide enters maternal milk; in humans it is not rec-ommended for use during nursing. Overdosage/Acute Toxicity Profound hypoglycemia is the greatest concern after an overdose. Gut emptying protocols should be employed when warranted. Because of its long half-life, blood glucose monitoring and treat-ment with parenteral glucose may be required for several days. Ov erdoses may require additional monitoring (blood gases, serum electrolytes) and supportive therapy. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorpropamide and may be of significance in veterinary patients: !TALCOHOL : A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who have ingested alcohol within 48-72 hours of receiving chlorpropamide !!BARBITURATES : Barbiturate duration of action may be prolonged The following drugs may potentiate hypoglycemia if administered with chlorpropamide, or be displaced by chlorpropamide from plasma proteins thereby causing enhanced pharmacologic effects of the two drugs involved: !!CHLORAMPHENICOL !!BETA-BLOCKERS ! !MAOI'S (including amitraz and possibly, selegiline) !!NSAIDS !!PROBENECID !!SALICYLATES ! !SULFONAMIDES !TWAR FARIN The following drugs may potentiate hyperglycemia if administered with chlorpropamide: !!CALCIUM CHANNEL BLOCKERS (e. g., diltiazem, amlodipine ) !!CORTICOSTEROIDS !!ESTROGENS !!ISONIAZID !!PHENOTHIAZINES !!PHENYTOIN !!THIAZIDES !TTHYROID MEDICATIONS Laboratory Considerations !TChlorpropamide may mildly increase values of liver enzymes, BUN, or serum creatinine. Doses For adjunctive therapy in diabetes insipidus in dogs and cats. Beneficial effects may be seen in less than 50% of animals treated. A trial period of at least one week of therapy should be given before assessing effect. !TDOGS & CATS: For adjunctive treatment of diabetes insipidus in animals with partial ADH deficiency: a) 10-40 mg/kg PO daily (Randolph and Peterson 1994), (Beh-rend 2003b) b) Dogs: 50-250 mg (total dose) PO daily; Cats: 50 mg (total dose) PO dail y (Hoskins 2005b) Monitoring !TSerum electrolytes, plasma and urine osmolarity, urine output; if used for DI !TBlood Glucose Chemistry/Synonyms An oral sulfonylurea antidiabetic agent, chlorpropamide occurs as a white, crystalline powder having a slight odor. It is practically in-soluble in water. Chlorpropamide may also be known as: chlorpropamidum, Ant i-D®, Chlomide®, Clordiabet®, Copamide®, Deavynfar®, Diabecontrol®, Diabeedol®, Diabemide®, Diabenese®, Diabet®, Diabexan®, Diabiclor®, Diabines®, Diabitex®, Dibecon®, Glicoben ®, Gliconorm®, Glicorp®, Glycemin®, Glymese®, Hypomide®, Idle®, Insogen®, Normoglic®, Novo-Propamide®, Propamide®, or Trane®. Storage/Stability Chlorpropamide tablets should be stored in well-closed containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Chlorpropamide Tablets: 100 mg & 250 mg; Diabenese® (Pfizer); generic; (Rx)

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CHLORTETRACYCLINE (klor-te-tra-sye-kleen) Aureomycin®, Pennchlor® TETRACYCLINE ANTIBIOTIC Prescriber Highlights TT Tetracycline antibiotic used primarily in water or feed treatments or topically for ophthalmic use TT Many bacteria are now resistant; may still be very useful to treat mycoplasma, rickettsia, spirochetes, & Chlamydia TT Contraindications: Hypersensitivity. Extreme caution: Pregnancy. Caution: liver, renal insufficiency TT Adverse Effects: GI distress, staining of developing teeth & bones, superinfections, photosensitivity TT Drug-drug; drug-lab interactions Uses/Indications There are a variety of approved chlortetracycline products for use in food animals. It may also be useful in treating susceptible infections in dogs, cats, birds and small mammals (not Guinea pigs). For more information, refer to the Doses section below. Pharmacology/Actions Te t r a c ycl i n e s g e n e r a l l y a c t a s b a c te r i o s t a t i c a n t i b i o t i c s i n h i b i t i n g p ro-tein synthesis by reversibly binding to 30S ribosomal subunits of sus-ceptible organisms thereby preventing bind ing to those ribosomes of aminoacyl transfer-RNA. T etracyclines are believed to reversibly bind to 50S ribosomes and additionally alter cytoplasmic membrane per-meability in susceptible organisms. In high concentrations, tetracy-clines can inhibit protein synthesis by mammalian cells. As a class, the tetracyclines have activity against most mycoplas-ma, spirochetes (including the Lyme disease organism), Chlamydia, and Rick ettsia. Against gram-positive bacteria, the tetracyclines have activity against some strains of staphylococcus and streptococci, but resistance of these organisms is increasing. Gram-positive bac-teria that are usually covered by tetracyclines include: Actinom yces spp., Bacillus anthracis, Clostridium perfringens and tetani, Listeria monocytogenes, and Nocardia. Among gram-negative bacteria that tetracyclines usually have in vitro and in vivo ac tivity include Bordetella spp., Brucella, Bartonella, Haemophilus spp., Pasturella multocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides, Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines. While most strains of Pseu domonas aeruginosa show in vitro resistance to tetracyclines, those compounds attaining high urine levels (e. g., tetracycline, oxytetracycline) have been associated with clinical cures in dogs with UTI secondary to this organism. Oxytetracycline, chlortetracycline, and tetracycline share nearly identical spectrums of activity and patterns of cross-resistance and a tetracycline susceptibility disk is usually used for in vitro testing for chlortetracycline susceptibility. Pharmacokinetics Refer to the oxytetracycline monograph for general information on the pharmacokinetics of tetracyclines. Contraindications/Precautions/Warnings Chlortetracycline is contraindicated in patients hypersensitive to it or other tetracyclines. Because tetracyclines can retard fetal skeletal devel opment and discolor deciduous teeth, they should only be used in the last half of pregnancy when the benefits outweigh the fetal risks. Oxytetracycline, chlortetracycline and tetracycline are consid-ered more likely to cause these abnormalities than either doxycy-cline or minocycline. In patients with renal insufficiency or hepatic impairment, chlo-rtetracycline must be used cautiously. Lower than normal dosages are re commended with enhanced monitoring of renal and hepatic function. Avoid concurrent administration of other nephrotoxic or hepatotoxic drugs. Because it may cause clostridial enterotoxemia in guinea pigs, chlort etracycline should not be used this species. Adverse Effects Chlortetracycline given to young animals can cause discoloration of bones and teeth to a yellow, brown, or gray color. High dosages or chronic administration may delay bone growth and healing. T etracyclines in high levels can exert an antianabolic effect that can cause an incr ease in BUN and/or hepatotoxicity, particularly in patients with preexisting renal dysfunction. As renal function dete-riorates secondary to drug accumulation, this effect may be exacer-bated. In ruminants, high oral doses can cause ruminal microflora de-pression and ruminoreticular stasis. Rapid intravenous injection of undilute d propylene glycol-based products can cause intravascular hemolysis with resultant hemoglobinuria. Propylene glycol based products have also caused cardiodepressant effects when adminis-tered to calves. In small animals, tetracyclines can cause nausea, vomiting, an-orexia, and diarrhea. Cats do not tolerate oral tetracycline or oxytet-racycline very well; signs of colic, fever, hair loss, and depression may be see n. There are reports that long-term tetracycline use may cause urolith formation in dogs. Horses that are stressed by surgery, anesthesia, trauma, etc., may break w ith severe diarrheas after receiving tetracyclines (especially with oral administration). T etracycline therapy (especially long-term) may result in over-growth (superinfections) of non-susceptible bacteria or fungi. T etracyclines have been associated with photosensitivity reac-tions and, rarely, hepatotoxicity or blood dyscrasias. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category D (tetracy-clines-general) 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. ) T etracyclines are excreted in milk, but because much of the drug will b e bound to calcium in milk, it is unlikely to be of significant risk to nursing animals. Overdosage/Acute Toxicity T etracyclines are generally well tolerated after acute overdoses. Dogs given more than 400 mg/kg/day orally or 100 mg/kg/day IM of oxytetracycline did not demonstrate any toxicity. Oral overdoses would most likely be associated with GI disturbances (vomiting, an-orexia, and/or diarrhea). Should the patient develop severe emesis or diarrhea, fluids and electrolytes should be monitored and replaced if necessary. Chronic overdoses may lead to drug accumulation and nephrotoxicity. High oral doses given to ruminants, can cause ruminal microflora depr ession and ruminoreticular stasis. Rapid intravenous injection of undiluted propylene glycol-based products can cause intravas-cular hemolysis with resultant hemoglobinuria. Rapid intravenous injection of tetracyclines has induced tran-sient collapse and cardiac arrhythmias in several species, presum-ably due to chelation with intravascular calcium ions. Overdose quantities of drug could exacerbate this effect if given too rapidly

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T TIV. If the drug must be given rapidly IV (less than 5 minutes), some clinicians re commend pre-treating the animal with intravenous calcium gluconate. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlortetracycline and may be of significance in veterinary patients: T ! BETA-LACTAM OR AMINOGLYCOSIDE ANTIBIOTICS : Bacteriostatic drugs, like the tetracyclines, may interfere with bactericidal activ-ity of the penicillins, cephalosporins, and aminoglycosides; there is some c ontroversy regarding the actual clinical significance of this interaction, however T ! DIGOXIN : T etracyclines may increase the bioavailability of digoxin in a small percentage of patients (human) and lead to digoxin toxicity. These effects may persist for months after discontinua-tion of the tetracycline. T ! DIVALENT OR TRIVALENT CATIONS (oral antacids, saline cathartics or other GI products containing aluminum, calcium, iron, magnesium, zinc, or bismuth cations ): When orally administered, tetracyclines can chelate divalent or trivalent cations that can decrease the ab-sorption of the tetracycline or the other drug if it contains these cations; it is recommended that all oral tetracyclines be given at least 1-2 hours before or after the cation-containing products T ! WARFARIN : T etracyclines may depress plasma prothrombin activ-ity and patients on anticoagulant (e. g., warfarin) therapy may need dosage adjustment. Laboratory Considerations T ! etracyclines (not minocycline) may cause falsely elevated values of urine catecholamines when using fluorometric methods of de-termination. T ! etracyclines reportedly can cause false-positive urine glucose re-sults if using the cupric sulfate method of determination (Bene-dict's reagent, Clinitest®), but this may be the result of ascorbic acid that is found in some parenteral formulations of tetracy-clines. T etracyclines have also reportedly caused false-negative results in determining urine glucose when using the glucose oxi-dase method (Clinistix®, Tes-T ape®). Doses T ! DOGS/CATS: For susceptible infections: a) 25 mg/kg PO q6-8h (Papich 1992) b) T o prevent recurrence of mycoplasma or chlamydial con-junctivitis in large catteries where topical therapy is imprac-tical: soluble chlortetracycline powder in food at a dose of 50 mg per day p er cat for 1 month (Carro 1994) T ! RABBITS/RODENTS/SMALL MAMMALS: Note : Not recommended for use in guinea pigs a) Rabbits: 50 mg/kg PO q12-24h (Ivey and M orrisey 2000) b) Chinchillas: 50 mg/kg PO q12h (Hayes 2000) c) Hamsters: 20 mg/kg IM or SC q12h; Mice: 25 mg/kg SC or IM q12h; Rats: 6-10 mg/kg SC or IM q12h (Adamcak and Otten 2000) T ! BIRDS: a) For the treatment of chlamydiosis: In small birds add chlo-rtetracycline to food in a concentration of 0. 05%; larger psit-tacines require 1% CTC. (Flammer 1992) b) Ratites: 15-20 mg/kg PO three times daily (Jenson 1998) c) Pigeons: 50 mg/kg PO q6-8h; or 1000 -1500 mg/gallon drinking water; in warm weather mix fresh every 12 hours. Best used in combination with tylosin for ornithosis com-plex; calcium inhibits absorption therefore grit and layer pel-lets should be withheld during treatment. (Harlin 2006) T ! CATTLE AND SWINE: For susceptible infections: a) 6-10 mg/kg IV or IM; 10-20 mg/kg PO ( Note : Although not specified in this reference, chlortetracycline is generally ad-ministered once daily. ) (Howard 1993) Chemistry/Synonyms A tetracycline antibiotic, chlortetracycline occurs as yellow, odor-less crystals. It is slightly soluble in water. Chlortetracycline may also be known as clortetraciclina, A-377, NRRL-2209, SF-66, A ureomycin or CLTC® 100 MR. Storage/Stability Chlortetracycline should be stored in tight containers and pro-tected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: There are several feed additive/water mix preparations available containing chlortetracycline. Trade names include Aureomycin®; (Fort Dodge), CTC® (Agri Labs) CLTC® 100 MR (Philbro); (AL Labs); CLTC® 100 MR (Pennfield/Durvet). There are also combi-nation products containing chlortetracycline and sulfamethazine (Aureom ycin Sulmet®, Aureo S 700®), chlortetracycline, sulfamet-hazine and penicillin (Aureomix 500®, Pennclor SP 250 & 500®), chlort etracycline, sulfathiazole, and penicillin (Aureozol 500®) See individual labels for more information. HUMAN-LABELED PRODUCTS: None Chondroitin Sulfate — See Glucosamine/Chondroitin CHORIONIC GONADOTROPIN (HCG) (kor-ee-on-ic goe-nad-oh-troe-pin) Chorulon® REPRODUCTIVE HORMONE Prescriber Highlights TT Human hormone that mimics luteinizing hormone & some FSH activity; used for a variety of theriogenology conditions in many species TT Only administered parenterally TT Contraindications: Androgen responsive neoplasias, hypersensitivity TT Adverse Effects: Antibodies/hypersensitivity, pain on injection Uses/Indications The veterinary product's labeled indication is for “parenteral use in cows for the treatment of nymphomania (frequent or constant heat) due to cystic ovaries. ” It has been used for other purposes in several species; refer to the Dosage section for more information. Pharmacology/Actions HCG mimics quite closely the effects of luteinizing hormone (LH) but also has some FSH-like activity. In males, HCG can stimulate the differentiation of, and androgen production by, testicular inter-

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stitial (Leydig) cells. It may also stimulate testicular descent when no anatomical abnormality is present. In females, HCG will stimulate the corpus luteum to produce pro-gesterone and can induce ovulation (possibly also in patients with cyst ic ovaries). In the bitch HCG will induce estrogen secretion. Pharmacokinetics HCG is destroyed in the GI tract after oral administration, so it must be given parenterally. After IM injection, peak plasma levels occur in about 6 hours. HCG is distributed primarily to the ovaries in females and to the test es in males, but some may also be distributed to the proximal tubules in the renal cortex. HCG is eliminated from the blood in biphasic manner. The ini-tial elimination half-life is about 11 hours and the terminal half-life is app roximately 23 hours. Contraindications/Precautions/Warnings In humans, HCG is contraindicated in patients with prostatic car-cinoma or other androgen-dependent neoplasias, precocious puber-ty or having a previous hypersensitivity reaction to HCG. No labeled co ntraindications for veterinary patients were noted, but the above human contraindications should be used as guidelines. Antibody production to this hormone has been reported after re petitive use, resulting in diminished effect. Adverse Effects Potentially, hypersensitivity reactions are possible with this agent. HCG may cause abortion in mares prior to the 35th day of preg-nancy, perhaps due to increased estrogen levels. No other reported ad verse reactions were noted for veterinary patients. In humans, HCG has caused pain at the injection site, gyneco-mastia, headache, depression, irritability, and edema. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category X for use dur-ing pregnancy (Studies in animals or humans demonstrate fetal ab-normalities or adverse reaction; reports indicate evidence of fetal risk. The r isk of use in pregnant women clearly outweighs any possible ben-efit. ) It is unknown if HCG enters maternal milk. Overdosage/Acute Toxicity No overdosage cases have been reported with HCG. Drug/Lab Interactions No interactions have apparently been reported with HCG. Doses !TDOGS: For cryptorchidism: a) 500 Units injected twice weekly for 4-6 w eeks (Mc Donald 1988) Fo r HCG Challenge test (to determine if testicular tissue remains in castrated male dogs; in females to diagnose sexual differentia-tion disorders or if functional ovarian tissue remains after ovari-ohysterectomy): a) Male dogs or females with suspected sexual differentiation disor der: Take sample for resting testosterone level. Admin-ister 44 micrograms/kg HCG IM and take a 4 hour post sample. Female dogs: 100-1000 IU IM during apparent estrous epi-sode. Measure progesterone level in 5-7 da ys. If above 1 ng/ m L, this indicates functional ovarian tissue. (Shille and Olson 1989) T o produce luteinization of a persistent follicular cyst: a) 500 IU IM; repeat in 48 hours. If effective, will convert from pr oestrus to estrus in 1-2 days and sexual behavior should stop within 2 weeks. (Barton 1988) For infertile bitches cycling normally with low progesterone due to la ck of corpus luteum formation: a) Next cycle, give 500 IU HCG SC on days 10-11 o f heat cycle or when vaginal smear indicates breeding readiness. Breed 2 days after HCG administration. (Barton and Wolf 1988) For male infertility secondary to low testosterone, LH and FSH: a) HCG 500 IU SC twice weekly for 4 weeks. Add PMSG (Preg-nant Mare Serum Gonadotropin) 20 IU/kg SC 3 times weekly. If PMSG is unavailable, use FSH-P at same dose (1 mg FSH = ≈10-14 IU). Continue for 3 months. Once spermatogen-esis ensues, may continue with HCG only. (Barton and Wolf 1988) !TCATS: For HCG Challenge test (to determine if testicular tissue remains in castrated male cats; in females to diagnose sexual differentia-tion disorders or if functional ovarian tissue remains after ovari-ohysterectomy): a) Male cats or females with suspected sexual differentiation dis-order: Take sample for resting testosterone level. Administer 250 micro grams HCG IM and take a 4 hour post sample. Queens: 50-100 IU IM during apparent estrous episode. Meas ure progesterone level in 5-7 days. If above 1 ng/m L, this indicates functional ovarian tissue. (Shille and Olson 1989) For infertility, reduced libido, testis descent in male cats: a) 50-100 IU repeated if necessary (Verstegen 2000) Fo r infertility in queens due to confirmed ovulation failure: a) 100-500 IU IM (Barton and Wolf 1988) T o ind uce ovulation in anestrus queens: a) Give FSH-P 2 mg IM daily (for up to 5 days) until estrus is obse rved. Give 250 micrograms HCG on first and second day of estrus (Kraemer and Bowen 1986) After artificial insemination: a) 50-75 IU IM immediately after insemination; repeat insemi-nation and injection in 24 hours (Sojka 1986) !TFERRETS: a) 100 IU IM; repeat in 1 week as necessary. Most effective 14 day s after onset of estrus. (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Guinea pigs: For cystic ovaries: 1000 Units/animal IM, repeat in 7-10 day s (Adamcak and Otten 2000) !TBIRDS: T o reduce feather plucking (especially in female birds): a) Dosage is empirical; 500-1,000 units/kg IM. If no response in 3 da ys, repeat. If no response after second injection, unlikely to be of benefit at any dose. If reduces feather plucking, will need to repeat after 4-6 weeks. Major drawback is that with repeated usage, time between treatments is reduced. (Light-foot 2001) !TCATTLE: For treatment of ovarian cysts: a) 10,000 Units deep IM or 2500-5000 Units IV, may repeat in 14 da ys if animal's behavior or physical exam indicates a need for retreatment. Alternatively, 500-2500 Units injected di-rectly into the follicle. (Package Insert; Fo llutein®—Solvay)

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T ! HORSES: For cryptorchidism: a) Foals: 1000 Units injected twice weekly for 4-6 weeks (Mc-Donald 1988) ( Note : Many clinicians believe that medical treatment is unwarranted and that surgery should be per-formed. ) T o induce ovulation in early estrus when one, large, dominant follicle that is palpab le with a diameter >35 mm is present: a) HCG: 2000-3000 IU IV (preferable to treat mare 6 hours before mating) (Hopkins 1987) For t reatment of persistent follicles during the early transition period: a) 1000-5000 IU (results are variable) (Van Camp 1986) T o hasten ovulation and reduce variability of estrus after prostaglandin sync hronization: a) HCG: 1500-3300 IU 5-6 days after the second prostaglan-din treatment or on the first or second day of estrus (Bristol 1986) Chemistry/Synonyms A gonad-stimulating polypeptide secreted by the placenta, chori-onic gonadotropin is obtained from the urine of pregnant women. It oc curs as a white or practically white, amorphous, lyophilized powder. It is soluble in water and practically insoluble in alcohol. One International Unit of HCG is equal to one USP unit. There are at least 1500 USP Units per mg. Chorionic gonadotropin may also be known as: human chori-onic gonadotropin, HCG, h CG, LH 500, CG, chorionic gonadotro-phin, dynatropin, gonadotropine chorionique, gonadotrophinum chorio nicum, choriogonadotrophin, chorionogonadotropin, preg-nancy-urine hormone, or PU; there are many trade names inter-nationally. Storage/Stability Chorionic gonadotropin powder for injection should be stored at room temperature (15-30°C) and protected from light. After re-constitution, the resultant solution is stable for 30-90 days (de-pending on the product) when stored at 2-15°C. The lab els for the veterinary products, Chorulon® and P. G. 600® state to use the vial immediately after reconstituting with the supplied diluent. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Chorionic Gonadotropin (HCG) Injection: 10,000 Units per 10 m L double vial packs containing 10,000 USP units per vial with bacte-riostatic water for injection; single dose 10 m L vials of freeze-dried powd er and five 10 m L vials of sterile diluent; Chorulon ®(Intervet); (Rx). Approved for use in cows and finfish. No withdrawal time is required when used as labeled. Chorionic Gonadotropin freeze-dried powder: Single dose 5 m L vi-als when reconstituted contains pregnant mare serum gonadotro-pin (PMSG) 400 IU and human chorionic gonadotropin (h CG) 200 IU; five d ose 25 m L vials that when reconstituted contains pregnant mare serum gonadotropin (PMSG) 2,000 IU and human chorionic gonadotropin (h CG) 1,000 IU; P. G. 600 ® (Intervet); (OTC). Ap-proved for use in swine (prepuberal gilts and sows at weaning); no meat withdrawal t ime is required when used as labeled. HUMAN-LABELED PRODUCTS: Chorionic Gonadotropin Powder for Injection: 5,000 units/vial with 10 m L diluent (to make 500 units/m L; 10,000 units/vial with 10 m L diluent (to make 1,000 units/m L); 20,000 units/vial with 10 m L diluent (to make 2,000 units/m L) in 10 m L vials; Profasi® (Se-rono); Choron 10® (Forest); Gonic® (Hauck); Novarel® (Ferring); Pregnyl ® (Organon); generic; (Rx) CHROMIUM CHROMIUM PICOLINATE (kroe-mee-um pik-oh-lin-ate) TRANSITION TRACE METAL Prescriber Highlights TT Trace metal “nutraceutical” that may be useful as an ad-junctive treatment for diabetes mellitus & obesity in cats TT Efficacy in question, but probably safe Uses/Indications Chromium supplementation may be useful in the adjunctive treat-ment of diabetes mellitus or obesity, particularly in cats; there is contr oversy whether this treatment is beneficial. It does not appear to be useful in dogs with diabetes mellitus. Pharmacology/Actions Metallic chromium has no pharmacologic activity, but other va-lence states have activity. Chromium VI (hexavalent form) is used in the we lding and chemical industries and is considered a carcino-gen. Chromium III (trivalent) is the form used in supplements and found natur ally in foods. Chromium is thought to play a role in insulin function. It is an active component of so-called glucose tol-erance factor (GTF). GTF is a complex of molecules that includes glycine, glutamic acid, cystiene and nicotinic acid. Chromium's ex-act role in carbohydrate and nitrogen metabolism is not clear. It does not lower blood glucose levels in normal patients. In humans, chromium deficiency can cause impaired tolerance to glucose and insulin function, increased serum cholesterol and triglyceride lev-els, neuropathy, weight loss, impaired nitrogen metabolism, and decrease d respiratory function. Pharmacokinetics Chromium is not absorbed very well from the GI tract and most of a dose is excreted in the feces. When given as a salt (picolinate, chloride, nicotinate), lipophilicity and solubility are increased and absorption is enhanced. Absorbed chromium is eliminated via the kidneys. Contraindications/Precautions/Warnings Chromium supplements could, potentially, exacerbate renal insuf-ficiency; use with caution in these patients. Because the picolinate salt can pot entially alter behavior, consider using chromium chlo-ride, or chromium nicotinate in patients receiving SSRI's or other behav ioral therapies. Adverse Effects Chromium supplements (Cr III) at usual dosages appear to be well tolerated. Some human patients have complained of cognitive, per-ceptual, and motor dysfunction after receiving the picolinate salt. Reproductive/Nursing Safety In humans, chromium (up to 8 mcg/kg) is probably safe to use in pregnancy but information remains sketchy. Because cats may receive much higher dosages than the human dosages for treating diabetes, use cautiously in pregnant animals. Chromium supplements are likely to be safe to use in lactating animals.

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Overdosage/Acute Toxicity Little information on acute overdoses was located. There are at least two case reports of women developing renal failure after taking ex-cessive doses of chromium picolinate. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chromium and may be of significance in veterinary patients: T ! CORTICOSTEROIDS : May increase the urinary excretion of chromium T ! H2 BLOCKERS (cimetidine, ranitidine, famotidine, etc. ) or PROTON P UMP INHIBITORS (PPI's, omeprazole, etc. ): May decrease chromium levels by inhibiting their absorption; clinical significance is unclear T ! NSAIDs : May increase the absorption and retention of chromium; clinical significance is unlikely T ! ZINC : Theoretically, co-administration of zinc with chromium could decrease the oral absorption of both Laboratory Considerations No specific laboratory interactions or considerations noted Doses T ! CATS: For use as an oral hypoglycemic agent: a) Chromium picolinate 200 mcg PO once a day. (Dowling 2000); (Greco 2002b) For adj unctive treatment of feline obesity: a) Chromium picolinate 20 mcg/kg PO every other a day (Flores 2004) Monitoring T ! As there is no reliable way to measure chromium in the body, a clinical trial is the only way to determine whether chromium is effective in helping to control blood glucose. Standard methods of monitoring diabetes treatment efficacy should be followed (e. g., fasting blood glucose, appetite, attitude, body condition/weight, PU/PD resolution and, perhaps, serum fructosamine and/or gly-cosylated hemoglobin levels). Client Information T ! Clients should give the medication only as prescribed and not change brands without their veterinarian's approval. Chemistry/Synonyms A trace element (Cr; atomic number 24), oral chromium supple-ments are usually given as the picolinate salt (also known as chro-mium tripicolinate). Storage/Stability Chromium picolinate should be stored in tight containers. For stor-age recommendations, refer to the label for each product used. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: No oral products approved as pharmaceuticals. Injectable chromium: (as chromic chloride hexahydrate): 4 mcg/ m L (as 20. 5 mcg chromic chloride hexahydrate) and 20 mcg/m L (as 102. 5 mcg chromic chloride hexahydrate) in 5 m L (20 mcg/m L only), 10 m L & 30 m L; Chromic Chloride (various); Chroma-Pak® (Smith & Nephew Solo Pak); generic; (Rx) Oral chromium products are considered to be nutritional supplements by the FDA. No stan-dards have been accepted for potency, purity, safety or efficacy by regulato ry bodies. Supplements are available from a wide variety of sources. Most vet-erinary use in small animals is with chromium picolinate dosage forms. Common tablet sizes include 200 mcg, 400 mcg, 500 mcg and 800 mcg. Bioequivalence between products cannot be assumed. CIMETIDINE CIMETIDINE HCL (sye-met-i-deen) Tagamet® HISTAMINE 2 BLOCKER Prescriber Highlights TT Prototype histamine-2 blocker used to reduce GI acid production TT Newer H2 blockers (e. g., ranitidine, famotidine) & other agents (e. g., omeprazole) may be more effective, have longer duration of activity, & fewer drug interactions TT Contraindications: Hypersensitivity. Caution: Geriatric patients, hepatic or renal insufficiency TT Comparatively (with newer H2 blockers), many drug interactions Uses/Indications In veterinary medicine, cimetidine has been used for the treatment and/or prophylaxis of gastric, abomasal and duodenal ulcers, uremic gastritis, stress-related or drug-induced erosive gastritis, esophagi-tis, duodenal gastric reflux, and esophageal reflux. It has also been employed to treat hypersecretory conditions associated with gastri-nomas and systemic mastocytosis. Cimetidine has also been used investig ationally as a immunomodulating agent (see doses) in dogs. Cimetidine has been used for the treatment of melanomas in horses, but the drug's poor bioavailability and subsequent high doses (48 mg/kg/day) in adult horses makes it a very expensive, unproven treatment. Pharmacology/Actions At the H 2 receptors of the parietal cells, cimetidine competitively inhibits histamine thereby reducing gastric acid output both during basal conditions and when stimulated by food, pentagastrin, hista-mine, or insulin. Gastric emptying time, pancreatic or biliary secre-tion, and lower esophageal pressures are not altered by cimetidine. By de creasing the amount of gastric juice produced, cimetidine also decreases the amount of pepsin secreted. Cimetidine has an apparent immunomodulating effect as it has been demonstrated to reverse suppressor T-cell-mediated immune suppression. It also possesses weak anti-androgenic activity. Pharmacokinetics In dogs, the oral bioavailability is reported to be approximately 95%, serum half-life is 1. 3 hours and volume of distribution is 1. 2 L/kg. In horses, after intragastric administration oral bioavailability is only about 14%, steady-state volume of distribution 0. 77 L/kg, median plasma clearance 8. 2 m L/min/kg, and terminal elimination half-life is approximately 90 minutes. In humans, cimetidine is rapidly and well absorbed after oral administrat ion, but a small amount is metabolized in the liver be-

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fore entering the systemic circulation (first-pass effect). The oral bioavailability is 70-80%. Food may delay absorption and slightly decrease the amount absorbed, but when given with food, peak lev-els occur when the stomach is not protected by the buffering capa-bilities of the ingesta. Cimetidine is well distributed in body tissues and only 15-20% is b ound to plasma proteins. The drug enters milk and crosses the placenta. Cimetidine is both metabolized in the liver and excreted un-changed by the kidneys. More of the drug is excreted by the kid-neys when administered parenterally (75%) than when given orally (48%). T he average serum half-life is 2 hours in humans, but can be prolonged in elderly patients and those with renal or hepatic dis-ease. Peritoneal dialysis does not appreciably enhance the removal of cimetidine from the body. Contraindications/Precautions/Warnings Cimetidine is contraindicated in patients with known hypersensi-tivity to the drug. Cimetidine should be used cautiously in geriatric patients and in pat ients with significantly impaired hepatic or renal function. In humans meeting these criteria, increased risk of CNS effects (con-fusion) may occur; dosage reductions may be necessary. Adverse Effects Adverse effects appear to be very rare in animals at the dosages generally used. Potential adverse effects (documented in humans) that could be seen include mental confusion, headache (upon dis-continuation of the drug), gynecomastia, and decreased libido. Rar ely, agranulocytosis may develop and, if given rapidly IV, tran-sient cardiac arrhythmias may be seen. Pain at the injection site may oc cur after IM administration. Cimetidine does inhibit microsomal enzymes in the liver and may alter the metabolic rates of other drugs (see Drug Interactions below). 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 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 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 thes e drugs are safe if they are not administered when the animal is near term. ) Cimetidine is distributed into milk; while safety during nursing is not assured, it is usually considered compatible with nursing in humans. Overdosage/Acute Toxicity Clinical experience with cimetidine overdosage is limited. In labora-tory animals, very high dosages have been associated with tachycar-dia and respiratory failure; respiratory support and beta-adrenergic blo ckers have been suggested for use should these signs occur. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cimetidine and may be of significance in veterinary patients: Cimetidine may inhibit the hepatic microsomal enzyme system and thereby reduce the metabolism, prolong serum half-lives, and increase the serum levels of several drugs and/or reduce the hepatic blood flow and reduce the amount of hepatic extraction of drugs that have a high first-pass effect, including: !!BENZODIAZEPINES (e. g., diazepam ) !!BETA-BLOCKERS (e. g., propranolol ) !!CALCIUM CHANNEL BLOCKERS (e. g., verapamil ) !!CHLORAMPHENICOL !!LIDO CAINE ! !METRONIDAZOLE !!PHENYTOIN !!PROCAINAMIDE !!THEOPHYLLINE !!TRIAMTERENE !!TRICYCLIC ANTIDEPRESSANTS !TWARFARIN !TANTACIDS : May decrease the absorption of cimetidine; stagger doses (separate by 2 hours if possible) !TKETOCONAZOLE, ITRACONAZOLE, etc: Cimetidine may decrease the absorption of these drugs; give these medications at least two hours before cimetidine !TMYELOSUPPRESSIVE D RUGS : Cimetidine may exacerbate leukope-nias when used with myelosuppressive agents Laboratory Considerations !TCreatinine : Cimetidine may cause small increases in plasma crea-tinine concentrations early in therapy; these increases are gener-ally mild, non-progressive, and have disappeared when therapy is disco ntinued !TGastric Acid Secretion Tests : Histamine 2 blockers may antagonize the effects of histamine and pentagastrin in the evaluation of gas-tric acid secretion; it is recommended that histamine 2 blo ckers be discontinued at least 24 hours before performing this test !TAllergen Extract Skin Tests : Histamine 2 antagonists may inhibit histamine responses; it is recommended that histamine 2 blockers be discontinued at least 24 hours before performing this test Doses !TDOGS: For esophagitis: a) 5-10 mg/kg PO q6h (do not give with antacids) (Jones 1985) b) 4 mg/kg PO four times daily (Watrous 1988) Fo r prevention of drug-induced gastric erosion/ulceration: a) 5 mg/kg PO, SC, three times daily (Schunk 1988) Fo r chronic gastritis: a) 5-10 mg/kg PO, IM or IV three to four times daily (Hall and Twedt 1988) Fo r ulcer disease: a) 5-10 mg/kg PO, IM or IV three to four times daily (Hall and Tw edt 1988) b) 4-5 mg/kg PO, IV, or SC three to four times daily (Chiapella 1988) c) 5 mg/kg IV or PO four times daily (Moreland 1988) d) 5-10 mg/kg PO q6-8h o r 10 mg/kg q6h as a slow (over 30 minutes) IV infusion (De Novo 1986) e) 10 mg/kg PO, IM, IV q8h (Matz 1995) Fo r gastrinoma: a) 5-10 mg/kg PO, SC, IV q6-8h (Ze rbe and Washabau 2000)

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TT o prevent histamine-mediated gastric hyperacidity/ulceration sec ondary to mast cell tumors: a) 5 mg/kg q8h (Fox 1995) b) 5 mg/kg PO, IV, three to four times daily (Stann 1988) T o decrease gastric acid hypersecretion during the treatment of alkalosis: a) 5-10 mg/kg three to four times daily (Hardy and Robinson 1986) As an immunomodulating agent (reverses suppressor T-cell-me-diated immune suppression): a) 10-25 mg/kg PO twice daily (Desiderio and Rankin 1986) !TCATS: a) 5-10 mg/kg PO q6-8h o r 10 mg/kg q6h as a slow (over 30 minutes) IV infusion (De Novo 1986) !TFERRETS: For stress induced ulcers: a) 5-10 mg/kg PO, SC, IM or IV 3 times daily (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For GI ulcers: 5-10 mg/kg PO, SC, IM or IV q8-12h (Iv ey and Morrisey 2000) b) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 5-10 mg/kg PO, IM or SC q6-12h (Adamcak and Otten 2000) !THORSES: (Note : ARCI UCGFS Class 5 Drug) For foals: a) 1000 mg divided twice daily or three times daily PO, IV or IM (Ro binson 1987) b) 300-600 mg PO or IV 4 times a day (Clark and Becht 1987) Fo r adjunctive treatment of melanomas: a) 48 mg/kg/day (dosing interval not specified) PO for 2-3 w eeks following resolution of tumor growth; regression should be seen evident within 3 months of initiating treatment; if no improvement seen it will probably not be effective and should be discontinued. Some horses may require treatment their en-tire life. (Rashmir-Raven, Foy et al. 2006) !TSWINE: T o treat gastric ulcers: a) 300 mg per animal twice daily (Wass et al. 1986b) !TREPTILES: In most species: a) 4 mg/kg PO q8-12h (Gauv in 1993) Monitoring !TClinical efficacy (dependent on reason for use); monitored by decrease in symptomatology, endoscopic examination, blood in feces, etc. !TAdverse effects if noted Client Information !To maximize the benefit of this medication, it must be adminis-tered as prescribed by the veterinarian; signs may reoccur if dos-ages are missed. Chemistry/Synonyms An H 2-receptor antagonist, cimetidine occurs as a white to off-white, crystalline powder. It has what is described as an “unpleasant” odor and a p K a of 6. 8. Cimetidine is sparingly soluble in water and soluble in alcohol. Cimetidine HCl occurs as white, crystalline pow-der and is very soluble in water and soluble in alcohol. It has a p K a of 7. 11 and the commercial injection has a p H of 3. 8-6. Cimetidine may also be known as: cimetidinum, or SKF-92334; many t rade names are available. Storage/Stability/Compatibility Cimetidine products should be stored protected from light and kept at room temperature. Do not refrigerate the injectable product as precipitation may occur. Oral dosage forms should be stored in tight containers. The cimetidine injectable product is compatible with the com-monly used IV infusions solutions, including amino acid (TPN) so-lutions, but should be used within 48 hours of dilution. Cimetidine is also reported to be compatible with the following drugs: acetazol-amide sodium, amikacin sulfate, atropine sulfate, carbenicillin diso-dium, cefoxitin sodium, chlorothiazide sodium, clindamycin phos-phate, colistimethate sodium, dexamethasone sodium phosphate, digo xin, epinephrine, erythromycin lactobionate, furosemide, gen-tamicin sulfate, heparin sodium, insulin (regular), isoproterenol HCl, lidocaine HCl, lincomycin HCl, methylprednisolone sodium succinate, nafcillin sodium, norepinephrine bitartrate, penicillin G potassium/sodium, phytonadione, polymyxin B sulfate, potassium chloride, protamine sulfate, quinidine gluconate, sodium nitroprus-side, tetracycline HCl, vancomycin HCl, verapamil HCl, and vita-min B complex (with or without C). The following drugs are reported to be either incompatible with cimetidine or data conflicts: amphotericin B, ampicillin sodium, cefamandole naftate, cefazolin sodium, cephalothin sodium, and pentobarbital sodium. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 5 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Cimetidine Tablets: 200 mg, 300 mg, 400 mg, & 800 mg; Tagamet® &Tagamet® HB 200 (Glaxo Smith Kline & GSK Consumer); Acid Re-ducer 200® (Major); generic; (Rx, OTC) Cimetidine HCl Oral Solution: 300 mg (as HCl)/5 m L in 240 m L, 480 m L & UD 5 m L; g eneric; (Rx) Cimetidine HCl Injection: 150 mg/m L (as hydrochloride) in 2 m L vials and 8 m L multiple-dose vials; Cimetidine in 0. 9% Sodium Chloride: 6 mg (as hydrochloride)/m L in premixed 50 m L con-tainer; (Hospira); generic; (Rx)

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CIPROFLOXACIN (sip-roe-flox-a-sin) Cipro® FLU OROQUINOLONE ANTIBIOTIC Prescriber Highlights TT Human-label fluoroquinolone antibiotic TT In dogs, oral bioavailability lower than enrofloxacin TT Available as a true IV product TT Contraindications: Hypersensitivity. Relatively contra-indicated for young, growing animals due to cartilage abnormalities TT Caution: Hepatic or renal insufficiency, dehydration TT Adverse Effects: GI distress, CNS stimulation, crystalluria, & hypersensitivity TT Administer PO preferably on an empty stomach TT Drug interactions Uses/Indications Because of its similar spectrum of activity, ciprofloxacin could be used as an alternative to enrofloxacin when a larger oral dosage form or intravenous product is desired. But the two compounds cannot be considered equivalent because of pharmacokinetic dif-ferences (see below). Pharmacology/Actions Ciprofloxacin is a bactericidal and a concentration dependent agent, with susceptible bacteria cell death occurring within 20-30 minutes of exposure. Ciprofloxacin has demonstrated a significant post-antibiotic effect for both gram-negative and gram-positive bacteria and is active in both stationary and growth phases of bac-terial replication. Its mechanism of action is not thoroughly under-stood, but it is believed to act by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis. Both enrofloxacin and ciprofloxacin have similar spectrums of acti vity. These agents have good activity against many gram-negative bacilli and cocci, including most species and strains of Pseu domonas aeruginosa, Klebsiella spp., E. coli, Enterobacter, Campylobacter, Shigella, Salmonella, Aeromonas, Haemophilus, Proteus, Y ersinia, Serratia, and Vibrio species. Of the currently commercially available quinolones, ciprofloxacin and enrofloxacin have the lowest MIC values for the majority of these pathogens treated. Other organ-isms that are generally susceptible include Brucel la spp. Chlamydia trachomatis, Staphylococci (including penicillinase-producing and methicillin-resistant strains), Mycoplasma, and Mycobacterium spp. (not the etiologic agent for Johne's disease). The fluoroquinolones have variable activity against most Strep-tococci and are not usually recommended for use in treating these infect ions. These drugs have weak activity against most anaerobes and are ineffective in treating anaerobic infections. Resistance does occur by mutation,particularly with Pseudomonas ae ruginosa, Klebsiella pneumonia, Acinetobacter, and enterococci, but plasmid-mediated resistance does not seem to occur. Pharmacokinetics Both enrofloxacin and ciprofloxacin are well absorbed after oral ad-ministration in most species; in dogs however, enrofloxacin's bio-availabilit y is at least twice that of ciprofloxacin after oral dosing. In humans, the oral bioavailability of ciprofloxacin has been reported to be between 50-85%. Studies o f the oral bioavailability in ponies have shown that ciprofloxacin is poorly absorbed (2-12%) while enrofloxacin in foals apparently is well absorbed. In humans, the volume of distribution in adults for ciprofloxa-cin is about 2-3. 5 L/kg and it is approximately 20-40% bound to serum proteins. Ciprofloxacin is one of the metabolites of enrofloxacin. Appr oximately 15-50% of the drugs are eliminated unchanged into the urine by both tubular secretion and glomerular filtration. Enrofloxacin/ciprofloxacin are metabolized to various metabolites that are less active than the parent compounds. Approximately 10-40% of circulating enrofloxacin is metabolized to ciprofloxacin in most species. These metabolites are eliminated in both the urine and feces. Because of the dual (renal and hepatic) means of elimi-nation, patients with severely impaired renal function may have slightly p rolonged half-lives and higher serum levels but may not require dosage adjustment. The pharmacokinetics of ciprofloxacin has been studied in dogs, calv es, and pigs. Oral bioavailability is approximately 50% in calves and 40% (only one pig studied) in pigs and it has an elimina tion half-life of about 2. 5 hours in both species. Protein binding was sig-nificantly different for each species, with calves having about 70% of the drug b ound and pigs only about 23% bound to plasma proteins. Elimination half-life is reported to be about 2. 5 hours in dogs. Contraindications/Precautions/Warnings Ciprofloxacin, as is enrofloxacin, should be considered contraindi-cated in small and medium breed dogs from 2-8 months o f age. Bubble-like changes in articular cartilage have been noted when the drug was given at 2-5 times recommend doses for 30 days, although clinical signs have only been seen at the 5X dose. T o avoid cartilage damage, large and giant breed dogs may need to wait longer than the recommended 8 months since they may be in the rapid-growth phase past 8 months of age. Quinolones are also contraindicated in patients hypersensitive to them. Because ciprofloxacin has occasionally been reported to cause crystall uria, animals should not be allowed to become dehydrated during therapy with either ciprofloxacin or enrofloxacin. In hu-mans, ciprofloxacin has been associated with CNS stimulation and should be used with caution in patients with seizure disorders. Patients with severe renal or hepatic impairment may require dos-age adjustments to prevent drug accumulation. Use high dose ciprofloxacin in cats with caution. No reports of retinal toxicity (as can be seen with high dose enrofloxacin) second-ary to ciprofloxacin in cats were located and retinal toxicity appears to be less likely since it is less lipophilic than enrofloxacin; however caution is advised. Adverse Effects With the exception of potential cartilage abnormalities in young animals (see Contraindications above), the adverse effect profile of fluoroquinolones appears to be minimal. GI distress (vomiting, anorexia) is the most frequently, yet uncommon, reported adverse effect. Although not reported thus far in animals, hypersensitiv-ity reactions, crystalluria, and CNS effects (dizziness, stimulation) could pote ntially occur. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Ciprofloxacin is distributed into milk, but oral absorption should be ne gligible. No adverse effects have been reported in nurs-ing human infants of mothers receiving ciprofloxacin.

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Overdosage Little specific information is available. See the enrofloxacin mono-graph for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ciprofloxacin and may be of significance in veterinary patients: , Al +++!TANTACIDS/DAIRY PRODUCTS containing cations (Mg++, Ca++) may bind to ciprofloxacin and prevent its absorption; separate doses of these products by at least 2 hours from ciprofloxacin !TANTIBIOTICS, OTHER (aminoglycosides, 3rd-generation cephalosporins, penicillins—extended-spectrum : Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonas aeruginosa) with these compounds. Although enrofloxacin/cipro-floxacin has minimal activity against anaerobes, in v itro synergy has been reported when used with clindamycin against strains of Peptostreptococcus, Lactobacillus and Bacteroides fragilis. !TCYCL OSPORINE : Fluoroquinolones may exacerbate the nephrotoxic-ity, and reduce the metabolism of, cy clo sporine (used systemically) !TGLYBURIDE : Severe hypoglycemia possible !TIRON, ZINC (oral): Decreased ciprofloxacin absorption; separate doses by at least two hours !TMETHOTREXATE : Increased MTX levels possible with resultant toxicity !TNITROFURANTOIN : May antagonize the antimicrobial activity of the fluoroquinolones; concomitant use is not recommended !TPHENYTOIN : Ciprofloxacin may alter phenytoin levels !TPROBENECID : Blocks tubular secretion of ciprofloxacin and may increase its blood level and half-life !TSUCRALFATE : May inhibit absorption of ciprofloxacin; separate doses of these drugs by at least 2 hours !TTHEOPHYLLINE : Ciprofloxacin may increase theophylline blood lev-els !TWARFARIN : Potential for increased warfarin effects Laboratory Considerations !TIn some human patients, the fluoroquinolones have caused in-creases in liver enzymes, BUN, and creatinine and decreases in hema-tocrit. The clinical relevance of these mild changes is not known at this time. Doses !TDOGS: For susceptible infections: a) 5-15 mg/kg PO q12h; Avoid or reduce dosage of these drugs in animals with severe renal failure; avoid in young animals or in pregnant or breeding animals. (Vaden and Papich 1995) b) For UTI: 10 mg/kg PO once daily (q24h) for 7-14 day s For skin, soft tissue infections: 10-15 mg/kg PO once daily (q24h) fo r 7-14 days For bone systemic infections, bacteremia and more resistant pathogens (e. g., Enterobacter): 20 mg/kg PO once daily (q24h) fo r 7-14 days (Greene, Hartmannn et al. 2006) c) For pyoderma: 11 mg/kg PO q12h (Miller 2005b) !TCATS: For susceptible infections: a) Ciprofloxacin: 5-15 mg/kg PO q12h Av oid or reduce dosage of these drugs in animals with severe re-nal failure; avoid in young animals or in pregnant or breeding animals. ( Vaden and Papich 1995) !TFERRETS: For susceptible infections: a) 5-15 mg/kg PO twice daily (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 5-20 mg/kg PO q12h (Ivey and Morrisey 2000) b) Chinchillas, Gerbils, Guinea Pigs, Hamsters, Mice, Rats: 7-20 mg/kg PO q12h (Adamcak and O tten 2000) !TBIRDS: For susceptible gram-negative infections: a) Using ciprofloxacin 500 mg tablets: 20-40 mg/kg PO twice daily. Crushed tablet goes into suspension well, but must be shaken well before administering. (Mc Donald 1989) b) Ciprofloxacin (using crushed tablets): 20 mg/kg PO q12h (Bauc k and Hoefer 1993) c) Ciprofloxacin (using crushed tablets or suspend) 10-15 mg/ kg PO q12h (Ho effer 1995) d) Ratites: 3-6 mg/kg PO twice daily (Jenson 1998) Monitoring !TClinical efficacy !TAdverse effects Chemistry/Synonyms A fluoroquinolone antibiotic, ciprofloxacin HCl occurs as a faintly yellowish to yellow, crystalline powder. It is slightly soluble in water. Ciprofloxacin is related structurally to the veterinary-approved drug enrofloxacin (enrofloxacin has an additional ethyl group on the pip-erazinyl ring). Ciprofloxacin may also be known as ciprofloxacine, ciprofloxaci-num, ciprofloxacino, Bay-q-3939, or Cipro ®. Storage/Stability/Compatibility Unless otherwise directed by the manufacturer, ciprofloxacin tab-lets should be stored in tight containers at temperatures less than 30°C. P rotect from strong UV light. The injection should be stored at 5°-25°C and protected from light and freezing. Ciprofloxacin injection is reportedly compatible with the fol-lowing IV solutions and drugs: Dextrose 5%, D5 and G or H Na Cl, Ringer's, LRS, normal saline, amikacin sulfate, aztreonam, cimeti-dine, cyclosporine, dobutamine, dopamine, fluconazole, gentami-cin, lidocaine, midazolam, KCl, ranitidine, tobramycin, and vitamin B co mplex. Ciprofloxacin injection is reportedly incompatible with amino-phylline, amphotericin B, azithromycin, ceftazidime, cefuroxime, clindam ycin, heparin sodium, sodium bicarbonate, and ticarcillin. Compatibility is dependent upon factors such as p H, concentra-tion, temperature and diluent used; consult specialized references or a hospital phar macist for more specific information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ciprofloxacin Oral Tablets: 100 mg, 250 mg, 500 mg & 750 mg; Cip-ro® (Bayer); generic; (Rx) C iprofloxacin Extended-Release Tablets: 500 mg & 1000 mg; Cip ro XR® (Bayer); generic; (Rx) Ciprofloxacin Powder for Oral Suspension: 50 mg/m L (5%), 100 mg/m L (10%) whe n reconstituted; Cipro ®(Bayer); generic; (Rx) Ciprofloxacin Injection: 200 mg in 20 m L vials, 100 m L in 5% dex-trose flexible containers (0. 2%) and 120 m L bulk; 400 mg in 40 m L vials (1%), 200 m L in 5% dextrose flexible containers (0. 2%) and 120 m L bulk; Cipro® I. V. (Bayer); generic; (Rx)

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CISAPRIDE (sis-a-pride) PROMOTILITY AGENT Prescriber Highlights TT Oral GI prokinetic agent, used in several species for GI stasis, reflux esophagitis, & constipation/megacolon (cats) TT No longer commercially available, must be obtained from a compounding pharmacy TT Contraindications: Hypersensitivity, GI perforation or obstruction, hemorrhage TT Caution: Pregnancy TT Adverse effects appear to be minimal in veterinary patients TT Drug interactions Uses/Indications Proposed uses for cisapride in small animals includes esophageal reflux and treatment of primary gastric stasis disorders. Cisapride has been found to be useful in the treatment of constipation and megacolon in cats. Pharmacology/Actions Cisapride increases lower esophageal peristalsis and sphincter pres-sure and accelerates gastric emptying. The drug's proposed mecha-nism of action enhances the release of acetylcholine at the myen-teric plexus, but does not induce nicotinic or muscarinic receptor stimulatio n. Acetylcholinesterase activity is not inhibited. Cisapride blocks dopaminergic receptors to a lesser extent than does metoclo-pramide and does not increase gastric acid secretion. Pharmacokinetics Human data: After oral administration, cisapride is rapidly ab-sorbed with an absolute bioavailability of 35-40%. The dr ug is highly bound to plasma proteins and apparently extensively distrib-uted throughout the body. Cisapride is extensively metabolized and its elimination half-lif e is about 8-10 hours. Contraindications/Precautions/Warnings Cisapride is contraindicated in patients in whom increased gastro-intestinal motility could be harmful (e. g., perforation, obstruction, GI hemorr hage) or those who are hypersensitive to the drug. Adverse Effects Cisapride appears to be safe in cats at the dosages recommended. Occasionally vomiting, diarrhea, and abdominal discomfort may be noted. Although considered very rare in veterinary patients, pro-longed QT intervals or other cardiac arrhythmias are possibilities. In humans, the primary adverse effects are gastrointestinal re-lated with diarrhea and abdominal pain most commonly reported, but the drug was removed from the market due to concerns with QT-interval prolongation. Dosage may need to be decreased in patients with severe hepatic impairment. Reproductive/Nursing Safety Cisapride at high dosages (>40 mg/kg/day) caused fertility impair-ment in female rats. At doses 12 to 100 times the maximum recom-mended, cisapride caused embryotoxicity and fetotoxicity in rab-bits and rats. Its use during pregnancy should occur only when the benefits ou tweigh the risks. Cisapride is excreted in maternal milk in low levels; use with caution in nursing mothers. Overdosage/Acute Toxicity In one reported human overdose of 540 mg, the patient devel-oped GI distress and urinary frequency. LD 50 doses in v arious lab animals range from 160-4000 mg/kg. Adverse effects reported for overdoses in dogs include diarrhea, hypotonia, dyspnea, catalepsy, loss of righting reflex, tremors, or seizures. Significant overdoses should be handled using standard gut emptying protocols when appropriate; supportive therapy should be initiated when required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cisapride and may be of significance in veterinary patients: T ! ANTICHOLINERGIC AGENTS : Use of anticholinergic agents may di-minish the effects of cisapride T ! BENZODIAZEPINES : Cisapride may enhance the sedative effects of alcohol or benzodiazepines T ! WARFARIN : Cisapride may enhance anticoagulant effects; addi-tional monitoring and anticoagulant dosage adjustments may be requir ed T ! ORAL DRUGS WITH A NARROW THERAPEUTIC INDEX : May need serum levels monitored more closely when adding or discontinuing cisapride as cisapride can decrease GI transit times and poten-tially affect the absorption of other oral drugs As cisapride is metabolized via cytochrome P450 (3A4 in hu-mans), the following medications/foods that can inhibit this en-zyme may lead to increased cisapride levels with an increased risk for cisapr ide cardiotoxicity: ! !AMIODARONE ! !ANTIFUNGALS (ketoconazole, itraconazole, fluconazole ) ! !CHLORAMPHENICOL ! !CIMETIDINE ! !FLUVOXAMINE ! !GRAPEFRUIT JUICE/POWDER T ! MACROLIDE A NTIBIOTICS (except azithromycin ) Note: In one study in dogs erythromycin did not alter cisapride pharmacokinetics The following drugs may increase QT interval and use with cisap-ride may increase this risk: ! !AMIODARONE ! !CLARITHROMYCIN ! !MOXIFLOXACIN ! !PROCAINAMIDE ! !QUINIDINE T ! SOTALOL T ! TRICYCLIC ANTIDEPRESSANTS (amitriptyline, imipramine ) Doses T ! DOGS: As a promotility agent a) 0. 5 mg/kg three times daily; decrease dose if abnormal GI signs or abdo minal pain result (Hall 1994) b) T o reduce regurgitation associated with megaesophagus: 0. 55 mg/kg PO once to three times daily. Practically: 2. 5 mg per d ose for dogs weighing between 5-10 lbs. ; 5 mg per dose for dogs weighing between 11-40 lbs; and 10 mg per dose for dogs greater than 40 lbs. Administer no closer than 30 minutes before feeding. (Tams 1994)

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c) As an antiemetic: 0. 1-0. 5 mg/kg q8h PO (Washabau and Elie 1995) d) For esophagitis: 0. 25 mg/kg PO q8-12h. Part icularly effec-tive in preventing recurrence once esophagitis brought under contr ol. (Willard and Weyrauch 2000) e) For adjunctive treatment (with H-2 blockers or proton pump inhibitor s such as omeprazole—preferred) for esophageal re-flux: 0. 1-0. 5 mg/kg PO q8-24h (Willar d 2006c) T o stimulate detrusor contraction for micturition disorders: a) 0. 5 mg/kg PO q8h (Coat es 2004) T ! CATS: As a promotility agent: a) For chronic constipation (e. g., megacolon): In combination with a st ool softener (author recommends lactulose at a start-ing dose of 2-3 m L PO three times a day; then adjust as need-ed) and a bulk agent (e. g., psyllium or pumpkin pie filling) cisapride is given initially at 2. 5 mg (for cats up to 10 pounds) or 5 mg (for cats 11 pounds or heavier) three times daily, 30 minutes before food. Cats weighing greater than 16 pounds may require 7. 5 mg. (Tams 1994) b) For chronic constipation (e. g., megacolon): Used adjunctive-ly with conventional dietary therapeutics: 1. 25-2. 5 mg per cat two t o three times a day; cats with hepatic insufficiency should be treated with half the usual dose; probably most ef-fective when given 15 minutes before a meal. (Nixon 1994) c) For chronic constipation (e. g., megacolon): 0. 1-1 mg/kg q8-12h PO (Washabau and Holt 2000) d) F or chronic constipation (e. g., megacolon): 5 mg per cat (total dose) PO q8-12h (Scher k 2003b) e) For gastric stasis: 0. 1 mg/kg PO two to three times daily; cats tolerat e 2. 5 mg doses without problems (Twedt 2005b) T ! RABBITS/RODENTS/SMALL MAMMALS: a) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 0. 1-0. 5 mg/kg PO q12h (Adamcak and Otten 2000) b) Rabbits for GI stasis: 0. 5 mg/kg PO q6-12h. With IV or SC fluids depending on amount of dehydration, feeding a high fiber slurry and with or without metoclopramide (0. 2-1 mg/ kg PO, SC q6-8h). (Hess 2002b) c) For ileus if GI tract not obstructed in Guinea pigs, chinchillas: 0. 5 mg/kg q8-12h (Ro ute not specified; assume PO) (Orcutt 2005) T ! HORSES: As a promotility agent: a) Foals with periparturient asphyxia: 10 mg (total dose) PO q6-8h. Ade quate time for healing of damaged bowel before using prokinetic agents is essential. (Vaala 2003b) Monitoring T ! Efficacy T ! Adverse effects profile Client Information T ! Inform client to watch carefully and report any adverse effects noted. Chemistry/Synonyms An oral GI prokinetic agent, cisapride is a substituted piperidinyl benzamide and is structurally, but not pharmacologically, related to procainamide. It is available commercially as a monohydrate, but potency is expressed in terms of the anhydrate. Cisapride may also be known as: cisapridum, or R-51619; many trad e names are registered. Storage/Stability Unless otherwise instructed by the manufacturer, store cisapride tablets in tight, light-resistant containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: None Because of adverse effects in humans, cisapride has been removed from the US market. It may be available from compounding pharmacies. CISPLATIN (sis-pla-tin) Platinol-AQ® ANTINEOPLASTIC Prescriber Highlights TT Platinum antineoplastic agent used for a variety of carcinomas & sarcomas; palliative control of neoplastic pulmonary effusions with intracavitary administration; intralesional injection for skin tumors in horses TT Contraindications: Cats; history of hypersensitiv-ity; preexisting significant renal impairment or myelosuppression TT Primary adverse effects: Vomiting (pretreat with antie-metic); nephrotoxicity (use forced saline diuresis); myelo-suppression; many other adverse effects possible TT Drug related deaths possible TT Teratogenic, fetotoxic; may cause azoospermia TT Must be handled with care by dosage preparer/ administerer TT Must be given as slow IV infusion; fast administration (<5 minutes) may increase toxicity Uses/Indications In veterinary medicine, the systemic use of cisplatin is presently limited to use in dogs. The drug has been, or may be, useful in a variety of neoplastic diseases including squamous cell carcinomas, transitional cell carcinomas, ovarian carcinomas, mediastinal carci-nomas, osteosarcomas, pleural adenocarcinomas, nasal carcinomas, and thyro id adenocarcinomas. Cisplatin may be useful for the palliative control of neoplastic pulmonary effusio ns after intracavitary administration. In horses, cisplatin has been used for intralesional injection for skin tumors. Pharmacology/Actions While the exact mechanism of action of cisplatin has not been de-termined, its properties are analogous to those of bifunctional alky-lating agents producing inter-and intrastrand crosslinks in DNA. Cisplatin is ce ll cycle nonspecific. Pharmacokinetics After administration, the drug concentrates in the liver, intestines and kidneys. Platinum will accumulate in the body and may be detected 6 months after a course of therapy has been completed. Cisplatin is highly bound (90%) to serum proteins. In dogs, cisplatin exhibits a biphasic elimination profile. The ini-tial plasma half-life is short (approximately 20-50 minut es), but the

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